Program Schedule

Cancer Biology

Session Introduction

Constantinos Avgoustou
Second Surgical Department, Greece
Title: Unexpected gastrointestinal malignancy in emergent surgery for other prominent complicated pathology

Biography: I specialize in General Surgery, working in the Greek National Health System since 1988. My main areas of interest are colonic, pelvic, hepatobiliary, gastric and thyroid surgery. I have been Director of Surgery in Surgical Department of General Hospital ''Constantopoulion - Aghia Olga'' (Athens) since 2008. I am member of numerous Medical Societies. I have participated in hundreds of Congresses, and presented my work in 160, international in their majority. I have 112 publications, 42 of them in international medical Journals. I have been trained in specific surgical topics, such as laparoscopic, thoracic and pelvic surgery (Rome, Mestre, Zurich, Berlin).

Abstract: Although acute gastrointestinal conditions are severe, processed data about rational diagnostics and therapy have not yet been sufficient, neither have relative recommendations. Polymorbidity is frequent among these patients, which along with delayed presentation and lack of available time, may often limit the possibility of using optimal therapies. Endoscopy may not result in diagnosis or may be limited by the serious general condition of patient. We discuss surgical strategies in such difficult cases. An 88-year old man with severe comorbidities and paraesophageal hernia, hospitalized in Pathological Dept. for anaemia and dyspnea, was diagnosed with "intrathoracic stomach with pyloric stenosis" (computed tomography, gastroscopy without biopsies). He was transferred to Surgical Dept. after an acute episode of cardiorespiratory distress and chest pain. On emergent laparotomy, the entire stomach, along with omentum and spleen, were found migrated in the mediastinum. Reduction of hernia contents revealed antral ischaemia and obstructive prepyloric lesion. We performed distal gastrectomy, gastrojejunostomy, cruroraphy and fundopexy. Histology revealed a pT2 prepyloric adenocarcinoma. Postoperatively, he required support for pulmonary insufficiency and was discharged on day 28. His course is uneventful during a 19-month follow-up. A 70-year old man with severe comorbidities and chronic constipation was admitted with complete bowel obstruction. Computed tomography indicated obstructive rectosigmoid tumour and huge dolichocolon. On emergent laparotomy, we additionally found aplastic duodenum and a palpable mass in left colonic flexure. We performed subtotal colectomy, ileostomy, mobilization of two existed duodenal portions and adhesiolysis at mesenteries. The patient was discharged on day 7. Histology revealed pT3N1b rectosigmoid adenocarcinoma and a 2 cm in diameter c-kit+ stromal tumour in the colonic flexure. He received chemotherapy and Imatinib. Bowel continuity has been restored (ileorectal anastomosis). During 13-month follow-up, no recurrence has occurred. Gastrointestinal malignancies may incidentally be recognized during emergent surgery for other prominent acute pathology and need further treatment


Tapan K. Bera
National Cancer Institute, Bethesda,USA
Title: Recombinant immunotoxins targeting B cell maturation antigen are cytotoxic to myeloma cell lines and myeloma cells from patients.

Biography: Dr Bera received his M.S. and Ph.D. in Biochemistry from the Calcutta University, India and completed his postdoctoral research training at the Cancer Research Laboratory, UC Berkeley and at the Laboratory of Molecular Biology, National Cancer Institute. Dr Bera currently held the position of Senior Associate Scientist in the Molecular Biology section of the Laboratory of Molecular Biology, NCI, focusing on the development protein toxin targeting hematologic malignancies as well as discovery of new therapeutic target for prostate and breast cancer immunotherapy. Dr Bera have discovered several new and important genes whose expression is restricted to normal prostate and prostate cancer and are now being developed as therapeutic targets for the treatment of prostate cancer. He is using antibody engineering to develop a new therapy for cancer by making fusion proteins composed of the Fv portion of antibodies directed at receptor proteins on cancer cells fused to a genetically modified form of a powerful bacterial toxin, Pseudomonas exotoxin A. Dr Bera also identified a primate-specific gene family POTE that has restricted expression in normal prostate, prostate cancer and ES cells. To gain some insight on the biological function of POTE gene family, he has identified the POTE ancestor gene ANKRD26, and its mouse orthologue. To assess the function of Ankrd26, he generated a mutant mouse with partial inactivation of the Ankrd26 gene and shown that the homozygous mutant mice develop extreme obesity, insulin resistance and an increase in body size.

Abstract: Targeted therapy of cancer is getting more traction over the traditional chemotherapy to overcome the unavoidable side effects from the chemotherapeutic drugs. As scientists began to understand more about the molecular mechanism that distinguishes the cancer cells from its normal counterpart, they started to design novel approaches to attack the cancer cells more precisely. One of such successful approach is the development of monoclonal antibody against a cancer specific surface antigen that can be used as a delivery vehicle of toxic material selectively to the cancer cells. B cell maturation antigen (BCMA) is exclusively and highly expressed on normal and malignant plasma cells. Therefore, BCMA is a promising antigen for targeted therapy to treat multiple myeloma. Recombinant immunotoxins are chimeric proteins in which an Fv or Fab is fused with Pseudomonas exotoxin A (PE). We have generated a panel of monoclonal antibodies against BCMA. Two of them, BM24 and BM306, were used to make recombinant immunotoxins targeting BCMA, by genetically attaching their Fabs to a 24 kDa form of PE. The Fab immunotoxins specifically killed BCMA expressing cell lines and malignant plasma cells isolated from multiple myeloma patients. The immunotoxins are very potent and act rapidly, a 10-minute treatment of H929 cells was sufficient to kill almost all cells. Immunotoxin alone produced partial regressions of H929 tumors in mice and when combined with Abraxane produced complete and prolonged regressions.


Hamdi Cherif Mokhtar
Ferhat Abbas University of Setif,Algeria
Title: Algerian Network Cancer Registries : Incidence cancer data , 2014

Biography: Head of Epidemiology and Preventive Medecine Department . University Hospital of Setif , Algeria since 1984. Director of Cancer Registry of Setif in collaboration with the International Agency for Research on Cancer (WHO), Lyon, France since 1988. National Coordinator of Cancer Registries in Algeria Director of Laboratory of Environment and Health in Medicine Faculty, University of Setif President of Observatory of Tobacco Control in Francophone Africa (OTAF) President of Ennour Association

Abstract: The National Registry Network (RNRC) was created in 2014 as part of the 2015-2019 Cancer Plan and the institutionalization of cancer registries. The objective is to provide, for the first time, cancer incidence data for Algeria based on data from a network covering 52% of the population. Material and method These are the new cases recorded from 18 registers covering a population of 20 224 844, from a general population of 38 700 000 inhabitants for the year 2014. The data are entered and analyzed by the Canreg software 5, provided by IARC Results The coverage of national registration rate is 82% with a 52% coverage rate of 52% at 31/12/2014. The number of new cases during the year 2014 is 41,870 cases (16,748 men and 25,122 women). The overall crude rate is 106 / 100,000 (h), the standardized rate is 114.5 / 100,000. Crude and standardized rates in men are respectively 100.2 and 109.2 / 100,000. In women are respectively 111.8 and 119.8 / 100,000. In men, frequent cancers are lung, colon-rectum, bladder, prostate, stomach, pharynx naso, NHL, larynx and leukemia cancers. In women, breast cancers followed by colorectal, cervical, thyroid, NHL, stomach, biliary and leukemia cancers. The RNRC covers half of the Algerian population with the common incidence data for research and cancer control.


Djeumi Thomas Willy
University of Yaoundé, Cameroon
Title: OPERATIONS FOR UROLOGIC MALIGNANT TUMORS OR SUSPECTED NEOPLASMS IN CENTRAL HOSPITAL OF YAOUNDE(CAMEROON): TEN YEARS OF EXPERIENCE.

Biography:

Abstract: Cancer is a major health burden among non-communicable diseases and surgery in its management is essential. The incidence of urological cancers is steadily increasing in the world and will become an even more serious problem in the future. From 2000 to 2010, we proposed to study the epidemiological aspects of urological cancers operated at Yaounde Central Hospital. We conducted a descriptive and retrospective study of the last decade in the urology department of Yaounde Central Hospital. We included patients operated for malignancies or strongly suspected of malignancy. Ninety hundred and forty three patients were operated on for urological pathology. 223 patients (23.64%) had a malignancy or suspected malignancy. The average age in both sexes was 64.77 years. In women, it was 47.54 years old and in men 64.52 years old. The sex ratio was 5.96. In women, the most common urological malignancy was kidney tumor (38%); While in men prostate cancer dominated all other locations of tumors (86%). Surgical castration was performed in most patients with prostate cancer (95.81%). It is necessary to set up an effective cancer registry for better patient care and anticipation of needs.


HSIAO-SHENG LIU
National Cheng Kung University ,Taiwan
Title: Autophagy regulates two oncogenic factors to prevent hepatocellular carcinoma development

Biography: Hsiao-Sheng Liu has completed his PhD from Texas Tech University and postdoctoral studies from University of Cincinnati University School of Medicine. He was the chair of the Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan from 2003 to 2006 and now he is the distinguished professor of National Cheng Kung University. He now focuses on Ras-induced autophagy and the role of autophagy in regulation of the oncogenic factors including microRNAs in HCC development. He is also interested in viral induced autophagy and their relationship with viral replication and viral related pathogenesis.

Abstract: Autophagy, microRNA (miRNA) and cell cycle regulator cyclin D1 are important regulators during cancer cell tumorigenesis. Low autophagic activity as well as high levels of miR-224 and cyclin D1 are prevalent in hepatocellular carcinoma (HCC) patients in Taiwan. We reveal that in hepatitis B virus (HBV)-related HCC, dysfunction of autophagy leads to accumulation of miR-224 and cyclin D1. MiR-224 decreases the expression of its target gene Smad4, which is a suppressor of cancer cell migration and tumor formation. Cyclin D1 is responsible for cell cycle pregression and cell proliferation. We disclosed that autophagosome selectively recruits both miR-224 and ubiqutinated-cyclin D1 followed by lysosome fusion and degradation using different mechanisms. Importantly, we identified an off-label use drug “amiodarone” (an antiarrhythmic agent), which effectively suppressed HCC tumorigenesis through autophagy-mediated selective degradation of miR-224 and cyclin D1 both in vitro and in vivo. In summary, for the first time amiodarone was used as an autophagy inducer to regulates two oncogenic factors of HCC simultaneously through induction of autophagic activity. Our compelling findings imply that amiodarone as a repurposing drug is a novel autophagy inducer with the potential for suppression of tumor development in HCC therapy.


Dr HUAN YAN
The Third Affiliated Hospital of Zhengzhou University, Zhengzhou,China
Title: Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis

Biography:

Abstract: Long noncoding RNAs (LncRNAs) have been reported to be abnormally expressed in human ovarian cancer and associated with the proliferation and metastasis of cancer cells. The objective of this study was to investigate the role and the underlying mechanisms of LncRNA MAP3K20 antisense RNA 1 (MLK7-AS1) in ovarian cancer. Methods: The expression level of MLK7-AS1 was investigated in human ovarian cancer tissues and cell lines. The effects of MLK7-AS1 knockdown on ovarian cancer cell proliferation, migration, invasion and apoptosis were evaluated in vitro using MTT, colony formation assays, wound healing assays, transwell assays and flow cytometry. Furthermore, the in vivo effects were determined using the immunocompromised NSG female mice. Luciferase reporter assays were employed to identify interactions among MLK7-AS1 and its target genes. Results: In the current study, MLK7-AS1 was specifically upregulated in ovarian cancer tissues and cell lines. Knockdown of MLK7-AS1 inhibited the ability of cell migration, invasion, proliferation, colony formation and wound healing, whereas promoted cell apoptosis in vitro. By using online tools and mechanistic analysis, we demonstrated that MLK7-AS1 could directly bind to miR-375 and downregulate its expression. Besides, MLK7-AS1 reversed the inhibitory effect of miR-375 on the growth of ovarian cancer cells, which might be involved in the upregulation of Yes-associated protein 1 (YAP1) expression. Moreover, knockdown MLK7-AS1 expression inhibited primary tumor growth in ovaries and metastatic tumors in multiple peritoneal organs including liver and spleen in vivo, which were partly abolished by miR-375 inhibition. Mechanically, we found that MLK7-AS1 regulated the epithelial-mesenchymal transition (EMT) process by interacting with miR-375/YAP1 both in vivo and vitro, which promoted the expression of Slug. Conclusions: Taken together, our study showed for the first time that MLK7-AS1 interacted with miR-375 to promote proliferation, metastasis, and EMT process in ovarian cancer cells through upregulating YAP1.


Dr Mustapha Haddouche
University of Tlemcen,Algeria.
Title: Th1/Th2 ratio, nitric oxide (NO) and immunoglobulin in patients with newly diagnosed B-cell nonhodgkin’s lymphoma

Biography:

Abstract: To highlight the clinical association of baseline levels of conjugated dienes in low-density lipoprotein (LDL-BCD) and nitric oxide (NO) with immunoglobulins and Th1/Th2 ratio in patients with newly diagnosed B-cell non-Hodgkin’s lymphoma. Thirty two (32) newly diagnosed patients with aggressive B-cell NHL and 25 age-, sex and body mass index (BMI)-matched healthy controls were randomly selected for a cross-sectional case-control study conducted at the Hematology Department of Tlemcen University Medical Centre (Northwest of Algeria). Circulating levels of LDL-BCD and NO and those of IgA and IgM were significantly higher in patients than in controls. The levels of Th1/Th2 ratio and plasma total antioxidant capacity (ORAC) were significantly lower in patients compared with controls; while malondialdehyde (MDA) and protein carbonyl (PC) levels were significantly higher in patients. B-cell NHL was significantly associated with high levels of LDL-BCD from 25th to 75th percentile [25th percentile; RR = 2.26, 95% CI 1.42-3.59, p = 0.014, 50th percentile; RR = 2.84, 95% CI 1.72-4.68, p < 0.001, 75th percentile; RR = 5.43, 95% CI 2.58-11.42, p < 0.001]). Similarly, the disease was significantly associated with high levels of NO production from 25th to 75th percentile [25th percentile; RR = 2.07, 95% CI 1.25-3.44, p = 0.024, 50th percentile; RR = 2.78, 95% CI 1.63-4.72, p < 0.001, 75th percentile; RR = 4.68, 95% CI 2.21-9.91, p < 0.001]). Moreover, LDL-BCD levels were positively and significantly correlated with IFN-γ; whereas, NO levels were inversely and significantly correlated with IFN-γ and Th1/Th2 ratio. LDL-BCD and NO production seem to be associated with aggressive B-cell NHL and alteration of Th1/Th2 ratio. Our results had to be examined using ex vivo mechanistic studies leading to further investigations among them; an interest in the link between Epstein-Barr virus infection and NO and immunoglobulins.


Dr Jehad Zweiri
University of Liverpool,UK
Title: The impact of -irradiation on the induction of bystander killing by genetically engineered ovarian tumor cells: implications for clinical use as Cancer Vaccines.

Biography: DR Jehad Zweiri, lecturer in Cancer studies at the University of Liverpool Medical School, born and grew up in Jordan and received his Bachelor’s degree from the University of Jordan in 1990. He obtained his master degree from London School of Hygiene and Tropical Medicine/University of London, and then obtained his PhD degree in 2000 from Kings College Medical School/University of London, in the field of Immune Gene Therapy of Cancer under the supervision of Professor Farzin Farzaneh. He then started his work as Postdoctoral Associate at the department of Immunology and Medicine at the University of Liverpool in 2002. In 2010 he was appointed as a lecturer in the University of Liverpool Medical School and he is currently fellow of the British Higher Education Academy since 2012.

Abstract: Cellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines. This study examines the effect of -irradiation on a range of tumor cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumor cell lines. Following co-culture of HSV-TK modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovarian tumor cells were sensitive to -irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after -irradiation. Characterisation of tumor cell death showed that PA-STK cells underwent pyknosis (necrosis) after -irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal -irradiation (100Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal -irradiation (100Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy. This study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of whole cell tumour vaccination.


JISU MO
Wonkwang University,South Korea
Title: Common and specific target genes for knockout of MIR 196A1, A2 and B in colon cancer cells

Biography: Ph.D. Wonkwang University medical school, Korea 2011.03-2015.08 M.S. Wonkwang University public health, Korea 2004.09-2007.02 B.S. Eulji University clinical pathology, Korea 2001.03-2004.2

Abstract: miRNAs are non-coding RNAs that play important roles in the pathogenesis of human diseases by regulating target gene expression in specific cells or tissues. MicroRNA (miRNA) family is a group of miRNAs that derive from the common ancestor. Normally, members from the same miRNA family have similar physiological functions. miRNA families are important because they suggest a common sequence or structure configuration in sets of genes that hint to a shared function. However, Investigation of characteristics of miRNA families and the functions of family-specific miRNA genes are lacking. Therefore, we investigate the target gene and its function for miRNA 196 family group of MIR196A1, A2 and B. MIR196 A1, A2 and B deleted in the colorectal cancer cell line SW48 using the recently developed CRISPR CAS9 technology. Knocked out (KO) 196A1, A2 and B SW48 cells and control SW48 cells were analyzed by RNA-seq. Based on this, we performed functional studies between target mRNAs of MIR196A1, A2, and B. We identified MIR196A1, A2 and B as a colorectal cancer associated microRNA and reported MIR196A1, A2 and B putative target genes. Using RNA-seq analysis, We identified 2063 putative MIR196A1, A2 and B target genes by comparing between the mRNAs knocked out in MIR196A1, A2 and B cells and the assumed MIR196 family target genes predicted by public bioinformatics tools. In this study, MIR196 A1, A2 and B deleted in the colorectal cancer cell line SW48 using the recently developed CRISPR CAS9 technology. KO196 family SW48 cells and control SW48 cells were analyzed by RNA-seq. Based on this, we performed functional studies between target mRNAs of MIR196A1, A2, and B. Our study provide basis for producing mice knocked out of each MIR196 using the CRISPR CAS9 system. Also, we want to provide early detection of colon cancer and information for prevention and treatment.


Dr.Miguel Angel Mendoza Catalán
Autonomous University of Guerrero,Mexico
Title: Ezrin and E-cadherin expression profile in cervical cytology: a prognostic marker for tumor progression in cervical cancer

Biography: Doctor in Biomedical Science, Researcher and professor at Facultad de Ciencias Químicas from Universidad Autónoma de Guerrero, Mexico since 2013. The Dr. Mendoza develops research about the mechanisms of migration and invasion of cervical cancer cells and on search for phytopharmaceuticals against cancer. He has 5 international scientific publications, 18 undergraduate and 5 masters students.

Abstract: Cervical cancer (CC) is the fourth cause of mortality by neoplasia in women worldwide. The use of immunomarkers is an alternative tool to complement currently used algorithms for detection of cancer, and to improve selection of therapeutic schemes. Aberrant expression of Ezrin and E-cadherin play an important role in tumor invasion. In this study we analyzed Ezrin and E-cadherin expression in liquid-based cervical cytology samples and evaluated their potential use as prognostic immunomarkers. Immunocytochemical staining of Ezrin and E-cadherin was performed in cervical samples of 125 patients. The cytological or histological diagnostic was performed by Papanicolaou staining or H&E staining, respectively. HPV genotyping was determined using INNO-LIPA Genotyping Extra kit and the HPV physical status by in situ hybridization. Ezrin expression in HaCaT, HeLa and SiHa cell lines was determined by immunocytochemistry, immunofluorescence and Western blot. High Ezrin expression was observed in cervical cancer samples (70%), samples with multiple infection by HRHPV (43%), and samples with integrated viral genome (47%). High Ezrin expression was associated with degree of SIL, viral genotype and physical status. In contrast, low E-cadherin expression was found in cervical cancer samples (95%), samples with multiple infection by HR-HPV/LR-HPV (87%) and integrated viral genome (72%). Low E-cadherin expression was associated with degree of SIL and viral genotype. Interestingly, Ezrin nuclear staining was associated with degree of SIL and viral genotype. High Ezrin expression, high percent of nuclear Ezrin and low E-cadherin expression behaved as risk factors for progression to HSIL and cervical cancer. In conclusion, Ezrin and E-cadherin expression profile in cervical cytology samples could be a potential prognostic marker, useful for identifying cervical lesions with a high-risk of progression to cervical cancer.


Ms Ana A Roman-Rosales
National Autonomous University of Mexico,Mexico
Title: Mutant p53R273C and p53R148Q gain of function induces HER2 over-expression.

Biography: Ana A Roman-Rosales is a PhD candidate at the National Autonomus University of Mexico. She developed her principal research at the Cinvestav. Ms. Roman-Rosales conducted her research on the response of HER2 receptor expression to the presence of p53 mutants in cancer (Román-Rosales et al. 2018). Part of these results got the acknowledged in the national meeting of researchers from the Ministry of Health of Mexico (2013) and presented as a poster in the 6th International Mutant p53 Workshop in Toronto, Canada (2013). In addition to the research of Mutant p53, Ms. Roman-Rosales has participated as a co-author in the research on the effect of the HPV E7 oncoprotein and hormones on cervical tumorigenesis (Gutiérrez et al. 2015); on the role of p53 as a modulator of OxPhos (Hernández-Reséndiz et al. 2015), and on evaluating the effects of coumarin compounds over cell proliferation in cancer, because of their estrogenic effects (Jiménez-Orozco et al. 2011).

Abstract: The TP53 gene is often mutated in cancer with a high proportion of missense mutations, leading to the production of an over-expressed protein that differs from wild-type p53 by just one amino acid residue. Most of these mutations are mapped into DNA-binding domain arising in six ‘hotspot’ (R175, G245, R248, R249, R273 and R282) and usually abrogating its sequence specific DNA‑binding activity. Some mutant p53 proteins acquire oncogenic functions that enable them to promote invasion, metastasis, proliferation and cell survival. On the other hand, the membrane receptor HER2 over-expression is related to invasive breast cancer tumors and poor prognosis in patients. Therefore, elucidating the mechanism leading to HER2 over-expression is an important step in understanding the pathogenesis of particular aggressive subset of cancer types where HER2 is involved. Interestingly, in a breast cancer cohort, TP53 mutation carriers are commonly HER2+ (63-83 %). In our work, we analyzed if there is a regulation of HER2 by p53 mutants. We utilized, the cervical cancer cell line C33A (expressing the p53 mutant protein R273C (p53R273C) and ovarian cancer cell line OVCAR-3 (expressing the p53 mutant protein R248Q (p53R248Q). When we knockdown the p53 mutant expression in both cancer cell lines, the result was the inhibition of HER2 mRNA, as well as, HER2 protein expression. We also evaluated ectopic expression of mutant p53R273C and p53R248Q in Saos-2 cell line (p53-null cell line), where we observed an increase of HER2 mRNA and protein. To evaluate the possible mechanism for these results, we performed a ChIP assay evaluating distal and proximal regions of HER2 promoter, using the p53 mutant ectopically expressing cells (Saos-2). Our results indicate that both mutants of p53 can bind to the HER2 promoter in different sites, favoring the acetylation of histones (H3 and H4) which could contribute to the activation of HER2 expression. These findings show for the first time that elevated expression of p53R273C and p53R248Q mutants may exert a gain-of-function activity inducing the HER2 expression and thus may contribute to the invasive, metastatic, and angiogenic phenotypes in HER2-over-expressing cancer.


Dr.Saint Just Petnga Ngassam
University of Yaoundé I,Cameroon
Title: Giant congenital melanocytic nevus in a Cameroonian child: a case report

Biography:

Abstract: Background: Giant congenital melanocytic nevus is a very rare condition characterized by a large skin lesion and an increased risk of complications like neurocutaneous melanosis and malignant transformation. Reports of giant congenital melanocytic nevus are scarce in the sub-Saharan African literature and here we present a case of this disease in a Cameroonian adolescent. Case presentation: A 12-year-old Cameroonian girl from the "Baka" ethnic group, with no relevant family and medical histories presented with a progressively extensive brownish-black nodular hypertrophic skin lesion of approximately 45 cm, which she had had since she was 2-days old. The lesion covered her entire back giving an appearance of “turtle child”, which was highly suggestive of a giant congenital melanocytic nevus. She was booked in for a surgical intervention organized by a health campaign within her community. Meanwhile she was provided with psychological support and her family was counseled on warning signs of complications which would warrant an urgent consultation. Conclusions: Here we presented a case of giant congenital melanocytic nevus, apparently the first in the Cameroonian literature. In view of the potential severe complications as well as psychological trauma of this pathology, we draw clinicians’ attention to this extremely rare but real pathology in our country, for a timely diagnosis and management.


Mrs IRINA MALINOVA
A. TSYB MEDICAL RADIOLOGICAL RESEARCH CENTER,Russia
Title: Vitrification as a way to preserve and restore fertility in cancer patients of reproductive age

Biography:

Abstract: The aim of the study is to preserve biological material before specific treatment and restore reproductive function in cancer patients after treatment. Materials and methods: Fertility programmes are being actively implemented in many clinics around the world, including A. Tsyb Medical Radiological Research Centre. Ovarian tissue is obtained by laparoscopy alone or simultaneously with surgical treatment for the underlying disease. All samples of ovarian tissue (cortical layer) are frozen by vitrification, which avoids two main damaging factors of freezing: the formation of intracellular ice and cell dehydration. Vitrification is carried out using cryoprotectors (DMSO, ethylene glycol, sucrose). Ovarian tissue is stored in the Cryobank of the center. To date, the Cryobank is the tissue of 297 cancer patients and sperm samples of 200 patients. The main nosological forms of malignant diseases about which cryopreservation is made: lymphogranulomatosis, breast cancer, cervical cancer, osteogenic sarcoma, uterine sarcoma, uterine body cancer, thyroid cancer. Results: At the end of specific treatment, all patients had depletion of ovarian reserve. This paper describes the results of orthotopic transplantation of vitrified ovarian tissue in patients with a history of cancer. The main methods of cryopreservation are: 1) cryopreservation of unfertilized and fertilized oocytes (embryos); 2) cryopreservation of ovarian tissue. In vitrification of oocytes (embryos), the technology does not differ from that in conventional IVF. Preservation by vitrification and autotransplantation of ovarian tissue is a new and promising technology of fertility preservation in cancer patients. After the conclusion of the oncologist, orthotopic autotransplantation of vitrified ovarian tissue was performed. Further held ultrasound to monitor the recovery of folliculogenesis, controlling the level of hormones in dynamics. In our studies, a group of patients underwent laparoscopic transplantation of ovarian tissue. In all patients after ovarian tissue transplantation, changes in hormonal status (FSH, AMH) were recorded only after 6-8 months. In 57% there was an increase in AMH to 1, 8 ± 0.25 ng/ml, a decrease in FSH to 5.77 ±0.70 IU/L, in 29% of patients there was a slight increase in AMH to 1.0 ± 0.44 ng/ml and a decrease in FSH to 12.2 ± 1.31 IU / L, in 14% there were no changes in hormonal status. Follicle puncture was performed in 43% of patients – Mature oocytes were obtained, which were cultivated to the blastocyst stage. The embryos were frozen. In one patient who had previously undergone radiotherapy (thyroid cancer) after autotransplantation of vitrified ovarian tissue during follicle puncture in the natural cycle and transfer of 2 embryos, a single pregnancy was obtained . On August 25, 2015, a healthy child (boy) was born. Conclusion: the method of vitrification of the cortical layer of ovarian tissue can be used to preserve the reproductive function of women who will receive chemotherapy and radiation therapy. This method is patented and can be used to preserve the reproductive function of women with a history of cancer. Maintaining fertility should be an integral part of improving the quality of life of cancer patients after specific treatment.


Anindita Chakraborty
UGC DAE CONSORTIUM FOR SCIENTIFIC RESEARCH,India
Title: Crosstalk between cytoskeletal dynamics and Rho signaling proteins: an early indicative biomarker of liver cancer

Biography: Dr Anindita Chakraborty, a Gold medallist of Calcutta University, completed her PhD from Jadavpur University in 1996 and joined as a scientist at UGC –DAE Consortium for Scientific Research, Kolkata Centre. She is currently the Section-in-Charge of the Stress Biology/Radiation Biology Division of the Institute Dr. Chakraborty has been working on cellular stress and molecular mechanisms of stress response. Stress signaling cascades are omnipresent, evolutionary conserved cellular strategies to recover homeostasis. Her research unravels the link between failure to maintain homeostasis, cellular aberration and organismal pathologies, through study of signal transduction, cell cycle regulation, apoptosis, mitochondrial and/or nuclear DNA damage and genomic instability. She is also working on non-target effects of ionizing radiation highlighting cell signalling molecules and pathways involved in radiation induced bystander effects, aiming towards selective sensitization of tumor cells. Her contribution in the field of Trace element Sciences through studying role of trace elements in metabolomics to probe into elemental homeostasis and interaction of macro/micro elements with biological functions also deserves mention. Dr Chakraborty is the User Co-ordinator of the Centre coordinating utilisation of the Dept. of Atomic Energy Facilities at Variable Energy Cyclotron Centre,Kolkata, and Institute of Physics, Bhubaneswar.

Abstract: Hepatocellular carcinoma (HCC) is one of the most deadly malignancies worldwide. Prognosis of HCC is poor due to lack of early diagnosis, recurrence after surgery and resistance to chemotherapy. As such, there is a need to make deeper understanding of the process of development of HCC, so as to elucidate biomarkers for its early detection. Besides viral infection and other risk factors, exposure to chemicals also causes HCC. 4-Dimethylaminoazobenzene (p-DAB) and Diethylnitrosamine (DENA) are two such chemicals considered to be human carcinogens as both initiate liver cancer in experimental animals. Cytoskeleton, ubiquitous in cells of all domains of life, is involved in important cellular processes including cell-division, cellular transport, signal transduction, etc. Alteration of cytoskeletal structures play a pivotal role in controlling cell behaviour and is a hall mark in metastatic cancers. However, little is known about cytoskeletal status in early phase of the neoplastic transformation of cells. The present study reflects gross structural irregularities of microfilaments and microtubules concomitant to down regulation of Rho-family of GTPases including RhoA, Rac1 and Cdc42 in Swiss albino mice within six weeks of exposure to p-DAB and DENA. Results show LIMK1 induced modulation of expression of matrix metalloproteinases via involvement of intracellular calcium dynamics and inflammatory cytokines, viz TNF-α, IL-6. The study highlights disruption the cytoskeletal integrity is established in very early stage of carcinogenic development through direct crosstalk between Rho-GTPase signal transduction pathways and cell-cycle regulatory proteins in a free radical mediated process.


Flavia Biamonte
University Magna Graecia of Catanzaro,Italy
Title: H-ferritin knock-down drives 3D spheroid formation of ovarian cancer

Biography: Flavia Biamonte, PhD is a 33-years old Research Fellow at “Magna Graecia” University of Catanzaro (Italy). In February 2013, she completed her 3-years PhD Program in Experimental and Clinical Oncology at the University of Florence. As Research Fellow at University of Catanzaro, she is now coordinating the Lab group and her research program is focusing on the role of H-ferritin in the regulation of several cancer hallmarks. Here, she is also owner of the integrated teaching of Biology for different degree courses and she is serving as reviewer for several international scientific journals. She is author (co-author) of 24 original research articles.

Abstract: Epithelial ovarian cancer (EOC) displays a highly metastatic and chemotherapy-resistant phenotype. The detailed mechanisms underlying ovarian cancer aggressiveness is still under investigation; however, a consistent propagation of tumor-initiating cells (TICs) or cancer stem cells (CSCs) are believed to be responsible for the development of both primary tumor and metastatic lesions [1,2]. CSCs can be propagated in vitro using defined conditions to form 3D tumor spheroids [3]. Here, we show that H-ferritin (FHC) knock-down induces spheroid formation in the established epithelial ovarian cancer cell line SKOV-3. Spheroids (1° and 2° generations) and monolayer cultures were studied through a multidisciplinary approach including gene expression analyses, flow cytometry assays and analysis of metabolic fluxes. Notably, we found that FHC silencing promotes many of the cellular properties that ensure the correct architecture of the 3D spheroids: low FHC levels drive a pronounced shift from the epithelial to the mesenchymal phenotype of SKOV-3 cells, and this shift was associated with their acquisition of stem-like traits, Warburg metabolism, increased resistance to anoikis and tumor-propagating potential. In addition, monolayer and spheroid cultures were tested for vimentin, CD133, CD44, Ki‐67, E- and N- cadherins and collagen IV by means of immunohistochemistry. We observed that, the FHC-silenced spheroid cell cultures mimic the architecture of the in vivo tumour, in particular cell–cell and cell–matrix interactions. Overall, in this work we describe a new approach to image and analyze the properties of ovarian CSCs within 3D tumor spheroids, which can serve as the basis for defining the gene and protein signatures of CSCs. Moreover, we uncover a new role of FHC as potential target for developing therapeutic strategies that will effectively affect this critically important population of cells responsible for ovarian cancer progression.


HAN Xianlin
Peking Union Medical College Hospital, China
Title: Induction of ELK1 promotes pancreatic cancer progression under p38-JAK-STAT3 signaling

Biography:

Abstract: ETS-domain containing protein (ELK1) is recognized as an oncogene in cancer including thyroid, ovarian, prostate and bladder. ELK1 has been revealed to involve in tumor cell proliferation, apoptosis and differentiation. However, the function of ELK1 is remained to be studied in pancreatic cancer which is an aggressive malignancy with typically poor prognosis and low survival rate. In the present study, the purpose was to investigate the role of ELK1 in pancreatic ductal adenocarcinoma (PDAC) and potential signaling cascades. The results showed PDAC tissues expressed ELK1 significantly higher than para-cancer tissues. Survival curve analysis of TCGA database and our clinical cases indicated that high level of ELK1 significantly decrease survival rate. The oncogene of ELK1 were examined in PANC-1 cell line in vitro. The cell viability of PANC-1 is regulated by mediating ELK1 expression. The knock-down of ELK1 induced apoptosis, while overexpression of ELK1 reduced. Cell migration and invasiveness assays revealed that expression level of ELK1 has a negative effect on PANC-1 cancer cell aggressiveness. To survey the underline mechanisms, interaction between ELK1 and p38 (MAPK1) predicted from Unified Human Interactome was approved by Co-IP assay in PANC-1 cancer cell. Phosphorylation of ELK1 is controlled by p38 to activate c-FOS and EGR-1 in PANC-1. These results suggest that p38 signaling cascades control ELK1, thereby promoting pancreatic cancer progression through reduction of cell apoptosis and induction of cell aggressiveness.


Hayane Akopyan
University of Rzeszów,Poland
Title: Cytotoxic activity of selected plant extracts on human lung cancer cell lines

Biography: The author graduated of Biotechnology with a specialization in molecular biotechnology in 2016. During her studies, she gained valuable experience mainly in molecular biology and in analyses of the influence of external factors on in vitro cancerous cultures. During this period, she actively participated in research at her home university. She has been an employed at the Faculty of Medicine of the University of Rzeszow for two years, where she participates in several research projects concerning the influence of selected compounds of plant origin on in vitro tumor cell cultures and genetic and biochemical risk factors for breast and ovarian cancer.

Abstract: Lung cancer is the most commonly occurring cancer in men and the third most commonly occurring cancer in women. Despite the research efforts to optimize new treatments, lung cancer remains the most prevalent cause of cancer-related death in the world. The purpose of present study is therefore to ascertain the cytotoxic activity of selected plant extracts on human lung cancer cell lines H1975 and H1703. We used extracts from Japanese knotweed (Fallopia japonica) roots and leaves, Persian walnut (Juglans regia) pollen and pomegranate (Punica granatum) peel in the range of 0,5 – 100 µg. Cytotoxicity was assessed using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) and sulphorhodamine B assays. The study revealed the inhibition of lung cancer cells proliferation by tested extracts. The highest decrease in cell viability was revealed in H1703 cell line with the Persian walnut pollen extract. The inhibitory effect on the cell proliferation of other extracts was also noticeable. Obtained results indicate the cytotoxic effect of analyzed extracts on H1975 and H1703 cell lines in vitro.


Cancer Genetics

Session Introduction

Antoni Hurtado
University of Oslo,Norway
Title: FOXA1 predicts good outcome in HER2+ endometrial cancer patients by inhibiting EGFR/HER2 signaling

Biography: My research activity has been centered on the study of nuclear receptors and transcription factors in hormone-dependent tumors. In my Master’s degree I studied the effects of dietary factors in breast cancer initiation and progression in animal models, activity that I complemented teaching to second year medical students at the Autonomous University of Barcelona. Later, during my PhD at the Vall-Hebron Research Institute of Barcelona, my work focused on understanding the non-genomic actions of Estrogen Receptor (ER) in Prostate cancer. The main interest during my post-doctoral research at Cambridge University (UK) was to understand the mechanisms of resistance for endocrine treatment in luminal breast tumors, which led to four significant publications (i.e. Nature, Nature Genetics). In late 2011 I became young group leader at University of Oslo. Over the past six years, I have built a team and I have developed a research programin functional genomics and proteomics of breast, colon and endometrial cancers. In summer of 2019 I will lead a cancer genomics group at the Department of Biomedical Sciencies (Faculty of Medicine; University of Barcelona). My past research group has: (1) a proven track record with a total of 21 papers, (2) successfully established national and international research collaborations and (3) attracted significant external funding from several sources (Norwegian and Spanish funding bodies). In addition, I have trained several PhD students and undergraduate students. The scientific and educational supervision was complemented with teaching at the University of Oslo.

Abstract: HER2 is overexpressed in a significant number of endometrial cancer (EC) tumors. Yet, the prognostic and therapeutic implications of HER2 expression have not been clearly elucidated. Here we identify that FOXA1 expression stratifies tumors with HER2-high expression into two subgroups that significantly and independently associates with prognosis. Our study suggests that HER2-high tumors with low levels of FOXA1 possess innate resistance against HER therapies. The comparison of genes differentially expressed between FOXA1-high vs. FOXA1-low within the HER2-high subgroup of EC patients revealed an enrichment of a gene signature that have been found to be associated with response to the anti-EGFR drug Gefitinib. In EC cells, FOXA1 binds towards a significant number of these genes associated with response, and the increased expression of FOXA1 attenuates the expression of these genes by recruiting polycomb-associated proteins to FOXA1 binding sites. Moreover, the ectopic expression of FOXA1 results in a full response to anti-EGFR/HER2 therapies. This result suggests that in HER2-high tumors, FOXA1 represses the expression of genes key for EGFR-HER2 signaling and might explain why women with high FOXA1 and HER2 overexpressing EC show improved outcome. Moreover, these results might explain why women with HER2-high EC in general respond poorly to current HER2-directed therapies.


Cristina-Crenguta Albu
Bucharest "Carol Davila" University of Medicine, ROMANIA
Title: The importance of genetics investigation in early diagnosis of retinoblastoma

Biography: Dr. Cristina-Crenguta Albu is an Associate Professor of Department of Medical Genetics at Bucharest, "Carol Davila" University of Medicine and Pharmacy, Romania and General Manager of Bucharest "Alco San" Medical Clinic, Romania. She received her M.D. degree in Medicine from Bucharest, "Carol Davila" University of Medicine and Pharmacy, Romania, in 1991 and her Ph.D. degree in Medicine (Ophthalmology) from Bucharest "Carol Davila" University of Medicine and Pharmacy, Romania in 2001. Dr. Cristina-Crenguta Albu is a member of several scientific societies including International Society for Genetic Eye Disease & Retinoblastoma, American Society of Human Genetics, European Society of Human Genetics, Pan-American Association of Ophthalmology, American Academy of Ophthalmology, European Society of Pediatric Ophthalmology. She serves on the editorial board of International Journal of Medical and Clinical Research, Journal of Genetics and Genomes, Genetics and Genetic Disorders, Journal of Chemical Biology & Pharmaceutical Chemistry, International Gazette Of Research and ePublishers. Dr. Cristina-Crenguta Albu is author and co-author over 200 publications (medical textbooks, articles and studies published in medical journals and conferences) in the fields of prenatal genetics diagnosis and ophthalmology. Her Research Interest is focused on medical genetics, prenatal diagnosis, ophthalmogenetics and oculo-orbitar ultrasound examination.

Abstract: Retinoblastoma is a malignant eye tumor of early childhood, typically before the age of 5. This form of eye cancer it develops rapidly from the immature cells of a retina. The incidence of retinoblastoma is one case of retinoblastoma per 18,000 - 30,000 live births worldwide, in developed nations. Retinoblastoma is the most common malignant cancer of the eye in children. Retinoblastoma occurs in heritable (25-30%) and nonheritable (70–75%) forms. In 25-30% of cases, the mutation of the RB1 gene have been inherited from an affected parent (heritable form of Retinoblastoma) and in 70–75% of cases the mutation of the RB1 gene occurred in utero during early embryogenesis or before conception (nonheritable form of Retinoblastoma). Material and Metods: I present a very special case of heritable form of retinoblastoma, in a family with a structural abnormality of a chromosome 13: 13q deletion syndrome (13q del). Results and conclusion: The presence of positive family history is suggestive for the heritable form of Retinoblastoma.


Keehwan Kwon
Hallym University,Korea
Title: Clinical significance of CUB and Sushi multiple domains 1 inactivation in head and neck squamous cell carcinoma

Biography:

Abstract: Althoughthe genetic alteration of CUB and Sushi multiple domains 1 (CSMD1) have been known to be associated with poor prognosis in several cancers, there is a lack of clinical relevance in head and neck cancer. The aim of this study was to offer the insight into clinical significance of CSMD1 utilizing a multimodal approach that leverages publicly available independent genome wide expression datasets.CSMD1-related genes were found and were analyzed to examine the clinical significance of CSMD1 inactivation in HNSCC cohort of publicly available database. We analyzed the frequency of somatic mutation, clinicopathologic characteristics, the association with immunotherapy-related gene signature and the pathway of gene signature.We found 363 CSMD1-related genes.The prognosis of the CSMD1-inactivatedsubgroup was poor. A FBXW7, HLA-A, MED1, NOTCH2, NOTCH3, and TP53had higher mutation rates in the CSMD1-inactivated subgroups. The Interferon-gamma score and immune signature score were elevated in CSMD1-inactivated subgroups. We identified CSMD1-related several pathways,such as phosphatidylinositol signaling system and inositol phosphate metabolism.Our study suggests that CSMD1-related gene signatures using three large and independent datasets are associated with the prognosis of HNSCC patients.


Ms Afsaneh Mojtabanezhad Shariatpanahi
Reza Radiotherapy and Oncology Center,Iran
Title: Straightforward laboratory techniques to evaluate circulating DNA isolation

Biography:

Abstract: Cell-free DNA extracted from plasma or other body fluids could potentially replace invasive biopsies. It could be used to assess tumor genetic and epigenetic characteristics and has significant potential role for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies. Despite the extensive clinical utility of cfDNA, there are some challenges, and difficulties in its extraction and subsequently, its usage. CfDNA is frequently found in plasma at very low concentration and exists in fragmented condition. In addition, circulating tumor DNA (ctDNA) with genetic and epigenetic alterations can be mixed by normal free DNA, released in the bloodstream (1.0% of total cfDNA). Besides, tumors, themselves are a mixture of different cancer cell clones (inter-tumoral heterogeneity) which could lead to more complexity. Thus, isolation, quantification and evaluation of cfDNA is not a straightforward task and it requires a sensitive and reliable validation workflow. In this study, we designed and performed several simple experiments to perform this task. Material and methods: The abilities of the common QIAamp DNA Blood Mini Kit method to extract cfDNA were assessed by several approaches including purification of endogenous cfDNA and exogenous spike-in control material to plasma prior to extraction followed by quantitative-PCR. Results: By using this kit, nearly 27% (DAZ, 380 bp) to 35% (DYS221, 173 bp) cfDNA was recovered and there was a higher recovery for smaller size cfDNA (DYS221, 173 bp) in compare to larger sizes (DAZ, 380 bp). Conclusion: The suggested simple laboratory methods could be used to assess the efficiency of any cfDNA isolation method.


Aleksander Myszka
University of Rzeszów,Poland
Title: BRCA1 and BRCA2 mutations in women with breast and/or ovarian cancer from Poland determined by targeted massively parallel sequencing

Biography: Author has extensive experience in molecular biology and laboratory medicine. His experience includes working as an academic and laboratory diagnostician. He worked at the Cytogenetic Laboratory in Poland for seven years. He was responsible for molecular diagnostics of the genetic syndromes. He has gained the research experience in Poland and Australia. He has worked at the University of Rzeszow as an academic for the past thirteen years. He has conducted research in the cancer genetics area. He has participated in several research projects the results were published in the scientific journals and presented on the international conferences.

Abstract: Introduction Germline mutations in BRCA1 and BRCA2 genes are associated with increased risk of breast and ovarian cancer. Up to the age of 70, the lifetime risk of breast cancer development in BRCA1 mutation carriers was estimated at 65% (95% CI: 44%-78%) and ovarian cancer at 39% (95% CI: 18%-54%). In turn, in BRCA2 mutation carriers are at a 45% (95% CI: 31%-56%) increased risk of breast cancer but only an 11% (95% CI: 2,4%-11%) increased risk of ovarian cancer. Identification of germline mutations in BRCA1 and BRCA2 have tremendous significance in clinical counseling and could also have therapeutic implications. The aim The main purpose of the study was the identification of pathogenic variants that are associated with a high risk of breast and/ or ovarian cancers in the Polish population. Methods The study group consisted of 337 women from Poland diagnosed with breast cancer (242) and ovarian cancer (95). DNA samples were isolated from peripheral blood lymphocytes. Molecular studies were performed using the traditional method based on PCR (the first round of the study) and Hi-Plex technology incorporating massively parallel sequencing (the second stage of the study). Results In the first stage of the study, 33 founder mutations in BRCA1 (in 9,8% cases) but none in BRCA2 were identified. Using next-generation sequencing, 6 novel pathogenic mutations in the BRCA1 gene and 8 pathogenic mutations in BRCA2 were identified. All BRCA1 pathogenic variants were identified in women with the hereditary syndrome. In total 47 deleterious mutations (in 13,9% of the women tested) and a large number of unclassified variants in BRCA1 and BRCA2 that have uncertain or conflicting significance to breast and ovarian cancer risk were identified. Conclusions The use of Hi-Plex technology increased the detection of pathogenic mutations by 60%. This research confirms the usefulness of clinical-pedigree criteria in selection of women for genetic testing. The results will contribute to improved genetic testing in the Polish population that currently relies on the testing of specific mutations in BRCA1 and BRCA2. Advanced genetic risk assessment could also lead to improved cancer prevention in the Polish population.


Clinical Trials In Oncology

Session Introduction

Dr Zeng Xi
Sichuan University,China
Title: Evaluation of PTEN expression and CD4+FOXP3+ T cell infiltration as diagnostic and predictive factors in endometrial cancer: a case control study

Biography:

Abstract: Aims. CD4+FOXP3+ T cells and Pten expression were previously implicated in the development of some cancers. We have now investigated the potential role of Pten and CD4+FOXP3+ T cells in prognosis from endometrial cancer. Methods. Tissue samples and clinical data were collected from 200 patients with endometrial cancer and 100 control patients with benign uterine diseases. The expressions of Pten and CD4+FOXP3+ T cells were quantified by immunohistochemistry and immunofluorescence. After surgery, all patients were followed up for an average of years. Surgical effects were evaluated based on the patients’ symptoms and signs. A two-sided P value < 0.05 was considered significant. Results. Pten diminished and CD4+FOXP3+ T cells significantly accumulated in the progression of endometial cancer, in comparison to control tissues. Moreover, Pten expression is negatively correlated with CD4+FOXP3+ T cells. Importantly, Pten and CD4+FOXP3+ T cells were correlated with clinical characteristics, including tumor stage, differentiation and associated with patients’ disease-free survival. Conclusions. There are limited researches between the expressions of Pten and CD4+FOXP3+ T cells in patients with endometrial cancer. This data suggested the expressions of Pten and CD4+FOXP3+ T cells may possibility biomarkers of diagnosis and predictive in endometrial cancer.


Usama M. Ammar
Korea Institute of Science and Technology,Seoul
Title: Anticancer activity of newly synthesized imidazo[2,1-b]oxazole derivatives as V600EBRAF inhibitors for treatment of melanoma

Biography: • 2017-Now: Studying PhD program in Medicinal Chemistry, Korea Institite of Science & Technology (KIST School)/ University of Science & Technology (UST), South Korea • 2016: Got the master degree in Medicinal Chemistry, Faculty of Pharmacy, Cairo University, Egypt • 2010: Graduated from Faculty of Pharmacy, Ahram Canadian University, Egypt • 2005: Graduated from Faculty of Science, Biochemistry Department, Zagazig University, Egypt

Abstract: The aim of current study is to synthesis a new series of imidazo[2,1-b]oxazole with different substitutions at position 5 and 6. The in vitro antiproliferative activity of the novel compounds were tested against human melanoma cell lines (A375 and Skmel28). Compounds KIST 211, 212, 215, 216, 226, 231, 235, 236 and 242 showed high activity against human melanoma cell line (A375). Compounds containing m-OH phenyl at position 6 and 2-substituted pyrimidine at position 5 with ethyl bridge between pyrimidine and sulfonamide moiety with terminal trifluoro methyl (-CF3) showed the highest activity.


Cancer Biomarkers

Session Introduction

Benkang Shi
Qilu Hospital of Shandong University,China
Title: Role of APLP2 in the prognosis and clinicopathology of renal cell carcinoma

Biography:

Abstract: Identifying diagnostic and prognostic biomarkers is crucial for improved guidance of the treatment of renal cell carcinoma (RCC). Amyloid β precursor like protein 2 (APLP2) has been determined to serve an important role in the progression of a number of cancer types. However, the expression and significance of APLP2 in RCC remains unknown. In the present study, it was determined that the expression of APLP2 protein (n=10) and mRNA (n=8) expression was significantly decreased in clear cell RCC (CCRCC) tissues compared with that in matched normal renal tissues. The expression level of APLP2 was significantly associated with high Fuhrman grade, high pT stage, and presence of distant metastasis and lymph node metastasis (P<0.05). Multivariate analysis demonstrated that the expression of APLP2 was a significant independent predictor of disease specific survival in renal cell carcinoma (P=0.026). Notably, APLP2 expression was significantly associated with disease specific survival (P<0.001). APLP2 may be used to potentially predict patient prognosis, and to guide clinical diagnosis and treatment in CCRCC.


Babak otoukesh
Iran University of Medical Science,Iran
Title: Novel molecular insights and new therapeutic strategies in osteosarcoma

Biography:

Abstract: Osteosarcoma (OS) is one of the most prevalent malignant cancers with lower survival and poor overall prognosis mainly in children and adolescents. Identifying the molecular mechanisms and OS stem cells (OSCs) as new concepts involved in disease pathogenesis and progression may potentially lead to new therapeutic targets. Therefore, therapeutic targeting of OSCs can be one of the most important and effective strategies for the treatment of OS. This review describes the new molecular targets of OS as well as novel therapeutic approaches in the design of future investigations and treatment.


Bahram Boddouhi
Iran University of Medical Science, Iran
Title: Down-regulation of microRNA-182 and microRNA-183 predicts progression of osteosarcoma

Biography:

Abstract: Introduction: The aim of this study was to investigate the expression levels of microRNA-182 and microRNA-183 and their association with clinicopathological features in patients with osteosarcoma. Material and methods: Total RNA was purified from samples and noncancerous bone tissues and then quantitative real-time polymerase chain reaction was applied to evaluate the expression levels of microRNAs, and their relationship with clinicopathological features and survival in osteosarcoma patients. Results: Our findings showed that expression of MiR-182 was clearly lower in osteosarcoma bone tissue (mean ± SD: 2.84 ±.07) compared with noncancerous bone tissues (6.23 ±1.72, p = 0.004). On the other hand, lower expression of MiR-183 was seen in osteosarcoma bone tissue (1.43 ±0.59) when compared with normal tissues (4.36 ±2.47, p = 0.036). Decreased expression of MiR-182 was clearly correlated with advanced clinical stage (p = 0.001), metastasis or recurrence (p = 0.024), and large tumor size (p = 0.032). Decreased expression of MiR-183 was associated with advanced TNM stage (p = 0.004), and metastasis or recurrence (p = 0.002). A multivariate Cox proportional hazards model revealed that low expression of MiR-182 and MiR-183 (p = 0.02; p = 0.016), TNM stage (p = 0.04), and metastasis or recurrence (p = 0.03) were significantly associated with poor survival as independent prognostic factors. Conclusions: These findings suggest that MiR-182 and MiR-183 may be associated with progression and metastasis of osteosarcoma.


Maria Alexandra Brito
Universidade de Lisboa,Portugal
Title: Targets and biomarkers of breast cancer brain metastasization

Biography: Maria Alexandra Brito is Associate Professor with Tenure at the Faculty of Pharmacy, University of Lisbon. She is the head of the Neurovascular Laboratory, within the Neuron Glia Biology in Health and Disease Group, of the Research Institute for Medicines (iMed.ULisboa), at the same Faculty. She has studied the neurovascular alterations in brain pathologies, including primary and metastatic brain tumours, dissecting the signalling pathways and identifying biomarkers and targets for modulation. Her work has been presented in reputed scientific meetings and published in high impact journals, and has been awarded several grants and prizes.

Abstract: Breast cancer (BC) is the most frequent type of cancer in women. With the enormous advances in BC treatment the major concern shifted to metastasis. BC brain metastases occur in 15-25% of BC patients and the 1-year survival is only 20%. To these numbers account the fact that malignant cells’ transposition of the blood-brain barrier endothelium towards the brain and the players involved in the target organ colonization are poorly understood, together with the fact that early biomarkers of brain metastasization remain to be established. Our current studies directed to the clarification of the brain metastatic process and to the identification of precocious biomarkers in peripheral circulation will be presented. Moreover, specific targets for modulation will be pinpointed and risk identification relying on liquid biopsies will be pointed out.


Dr.Ana Elvira Zacapala Gómez
Autonomous University of Guerrero,Mexico
Title: ITGβ1 and LAMC1 expression in cervical cancer : Biomarkers

Biography: Young researcher with the distinction of candidate to SNI, publication of two articles in journals indexed with impact factor greater than 3, recognized at the national and state level, assessor of 4 thesis works, invited by indexed journals as a reviewer of three manuscripts, evaluator of a project submitted for analysis for funding (CONACyT) and twelve thesis reviewers. Full-time professor of the Universidad Autonoma de Guerrero, professor of the degrees of Chemistry Biologist Parasitologist, Biotechnology and Biology, invited professor in postgraduate programs.

Abstract: Cervical cancer (CC) is associated with HPV infection, it is the fourth most common cancer in women worldwide [1]. The cervical cancer-screening has not funtioned in developing countries, therefore, several studies continue to analyzing alternatives for diagnosis and prognosis of this pathology [2-3], biomarkers can be useful for the identification of precancerous lesions and CC. The ITG1 and LAMC1 proteins participate in cell-extracellular matrix interaction, and their overexpression has been associated with progression in different types of cancer [4-5], however, in CC have been not studied. We evaluated the expression of ITGβ1 and LAMC1 proteins in cervical samples, and their association with the degree of Squamous Intraepithelial Lesion (SIL), HPV-AR genotype and physical status. Also, we analyzed the overall and disease free survival and their relationship with ITGβ1 and LAMC1 expression. Cytological diagnosis was performed by PAP smears, HPV genotyping was performed by INNO-LiPA® Genotyping Extra Kit, HPV physical status was evaluated by in situ hybridization, ITGβ1 and LAMC1 expression was determined by immunocytochemistry and survival was addressed by Kaplan-Meier method and Cox-hazard model analysis in CC samples from TCGA database. A total of 96 patients were included and classified according to cervical lesion and HR-HPV infection in: 1) Non SIL/HPV (-) control group (n=20), 2) Non SIL/HR-HPV (+) study group (n=19), 3) LSIL/HR-HPV (+) study group (n=20), 4) HSIL/HR-HPV (+) study group (n=20) and 5) CC/HR-HPV (+) study group (n=20). The results show that ITGβ1 and LAMC1 expression increase according degree SIL. ITGβ1 and LAMC1 expression was associated with cytological diagnosis (p=0.003 and p=0.002, respectively), viral genotype (p=0.020 and p=0.007) and physical status of HPV (p=0.193 and p=0.007). High expression of ITGβ1 and LAMC1 was correlated with overall survival (p=0.0071 and p=0.03) and disease free survival (p=0.027 and p=0.41). In conclusion, our results suggest that ITGβ1 and LAMC1 expression could be a prognostic biomarker in CC.


Cancer diagnosis and Treatment

Session Introduction

George G Chen
The Chinese University of Hong Kong, Hong Kong
Title: The values of 15-lipoxygenases in the early detection of non-small cell lung cancer

Biography:

Abstract: Although many diagnostic methods/criteria of non-small cell lung cancer (NSCLC) have been developed, early diagnosis of NSCLC is still challenging and far from satisfactory. Early detection of NSCLC is very critical because if it can be detected at the earlier stage, most of cases can be cured via surgical resection of the tumor. Among various metabolites in NSCLC, we have discovered the changes in 15-lipoxygenases (15-LOXs) and their metabolites in the very early stage of lung tumorigenesis. Among them, 15(S)-hydroxy-eicosatetraenoic acid (15S-HETE) appears to be most promising. The data from high-risk population suggests that 15S-HETE is valuable for screening smoking population for early detection of NSCLC. (This study was supported by a grant from the Research Grants Council of the Hong Kong SAR, No: CUHK462613, and the National Natural Science Foundation of China National, No: 81472742. Contributors: Ming-Yue Li, Yi Liu, Ho RL, Leung BC, Fanny WS Ko, Bin Wu, Xiang Long, Jing Du, Jun Wu, Calvin SH Ng, Innes YP Wan, Tony SK Mok, David SC Hui, Malcolm J Underwood).


Yasser Ragab
Cairo University, Egypt
Title: Role of Bi-parametric MRI in the assessment of transitional zone prostatic carcinoma using 3Tesla scanner. Do we still need dynamic contrast enhancement for Pi- RADS V2 system?

Biography: Professor of Radiology Faculty of Medicine Cairo University Cairo Egypt Consultant Radiologist Dr .Erfan and Bagedo General Hospital Member of the Europian Society of Radiology. Member of the Radiological Society of North America. Member of the Radiological Society of Saudi Arabia . Member of the Egyptian Society of Radiology.

Abstract: Purpose: To determine the accuracy of Bi-parametric 3 Tesla MRI versus the usual Multi-parametric technique in cases of transitional zone (TZ) prostate cancer, based on Prostate Imaging Reporting and Data System (PI-RADS) version 2 scores. Methods and Materials: A total of 23 men underwent Multi-parametric( mp)- 3Tesla MRI ,revealing suspicious lesions in the transitional zones. . Of the included patients, , 92 % had TRUS-biopsy . Two radiologists separately assessed the mp-MRI examination (T2-weighted [T2W] imaging, diffusion-weighted imaging [DWI], apparent diffusion coefficient map [ADC-map] and dynamic contrast-enhanced imaging [DCE]). , The Bi-parametric (bp)-MRI version (T2W imaging, DWI, and ADC-map) was evaluated.PI-RADS) version 2 scoring system was applied and results were correlated with the hist pathological results. Results: Suspicious TZ lesions were more observed in the mp-MRI group than in the b-MRI group, although this difference was not statistically significant (; p=0.122). The overall detection rates of clinically significant cancers were not statistically significantly different between the two groups. In the 23 patients who had suspicious TZ lesions on MRI, the overall prostate cancer detection rate was (64.5%) in the mp-MRI group and (62.3%) in the b-MRI group (p=0.94). We compared the diagnostic accuracy using the sensitivity and specificity between mp-MRI and b-MRI. There were no statistical differences between the two.p values for sensitivity , specificity, PPV and NPV of both groups were (0.88, 0.23, 0.829 and 0.838 ) respectivley. Conclusion: The comparable accuracy of b-MRI technique could encourage its application in cases of TZ cancer lesions prior to biopsy.


Hafsa Javed
University of leeds,England
Title: Validity and Operator’s Reliability of Three Shear Wave

Biography: I am a final year medical student at the School of Medicine at the University of Leeds. I also hold a MSc in Medical Imaging with Distinction from the University of Leeds which I undertook between my medical studies.

Abstract: Introduction: Ultrasonic elastography can be used to assess the mechanical properties of soft tissue such as elasticity and thus the presence of pathology. Shear wave elastography (SWE) is a quantitative type of this technology. This study aimed to investigate the validity and operator’s reliability of three SWE systems in a phantom study. Materials and Methods: Two observers undertook a total of 2080 measurements of a phantom across three SWE systems; the GE LOGIQ E9 (GE-L), SuperSonic Imagine Aixplorer (SSI) and Siemens Acuson S2000 (SA). Inter-observer variation was assessed using box-plots and coefficient of variation. Validity and accuracy were assessed by calculating mean difference. Agreement was assessed by plotting mean difference and limits of agreement (LOA). Intraclass correlation coefficients were used to evaluate intra- and inter-observer, as well as inter-system reliability. Results: Measured elasticity decreased in softer inclusions as diameter increased, but increased for harder inclusions. Great biases between measured and actual elasticities were observed across all systems; though validity and accuracy were higher for softer inclusions. A pooled CV of 0.011-0.216 m/s across systems indicated low variability and high reproducibility. The LOAs were wide compared to the mean differences: GE-L: 0.509 [95 LOA: -2.43, 3.45]; SSI: 0.842 [95%LOA: -2.20, 3.88]; SA: -0.136 [95%LOA: -3.54, 3.26]. Inter-observer reliability was ‘almost perfect’ for all systems; ICC: 0.975- 0.994; 95%CI [0.916- 0.998]. Intra-observer reliability was 'almost perfect' for all inclusions and systems, ICC= 0.861-0.999; 95%CI [0.598-0.999] bar one inclusion per observer for the SA; ICC= 0.476-0.528; 95%CI [0.157-0.979], which was 'moderate' reliability. Inter-system reliability was higher across all systems for the experienced observer but varied between systems from 'poor' to 'almost perfect'. Conclusion: The accuracy of SWE readings are influenced by ROI size, inclusion stiffness and the system employed; thus, standardization of methodology and technology is required. Operator experience may improve inter-system reliability but showed little influence on intra- and inter-observer reliability.


Jaap Dronkers
Gelderse Vallei Hospital, Ede, the Netherlands
Title: Muscles matter in oncology

Biography: Dr. Jaap Dronkers took Master’s degrees in Education and Health Sciences. When working in the Gelderse Vallei Hospital, he investigated the role of physical fitness in elderly patients scheduled for major abdominal surgery and completed his doctorate on this subject in 2013. As senior researcher in the research group Innovation of Human Movement Care at the University of Applied Sciences in Utrecht, he has extended his studies and expertise to include abdominal and thoracic oncological surgery and the physical fitness (or lack thereof) of patients during hospital admission. At the University of Applied Sciences, he coordinates the Master’s program Physiotherapy.

Abstract: Muscle function is an important determinant of physical fitness and is not only needed for movement and locomotion. Muscle function encompasses muscle mass, strength and use. Muscle mass has an important role as protein store. In the case of impaired food intake or undernutrition, the body uses muscle proteins to cope with disease and inflammatory processes and treatment, in particular surgery. This is why patients lose muscle mass during illness and treatment. Muscle strength is also lost during illness. Cancer and its treatment (surgery and chemotherapy) cause an acute and rapid decrease in both muscle mass and strength, and especially in older patients, who often fail to regain lost muscle mass and strength, leading to long-lasting and sometimes permanent loss of functional mobility. Muscle is also a secretory organ, and muscle use leads to the release of myokines, which have important metabolic and anti-inflammatory actions. Physical activity has beneficial effects on health, improving immune function and aiding recovery from medical treatment. Cancer patients need to be as physically fit as possible in order to cope with the challenge of having the disease and undergoing treatment. Patients should be encouraged to use the preoperative period to improve their physical condition before treatment starts: ‘Better in’ means ‘better out’. Being physically active and having muscle mass and strength reduces the risk of complications and death. And appropriate muscle use after cancer treatment may reduce the risk of cancer recurrence.


Pedram Keshavarz
Shiraz University of Medical Science, Iran
Title: Evaluation of non-mass breast lesions with shear-wave elastography; A comparison trial in palpable and non-palpable non-mass lesions

Biography:

Abstract: Purpose: We demonstrated parallel B-mode and SWE images of non-mass lesions (NML) to determine the role of SWE in assessment of NML detected in ultrasound. Methods and Materials: B-mode and shear-wave elastography images were correlated with pathological results. Quantitative elasticity values were measured by drawing a Q box over the stiffest portion and another Q box on adjacent normal breast tissue. Qualitative and quantitative tissue elasticity were displayed with color-coded map and color scale ranging from 0 kPa (dark blue; soft) to180 kPa (red; stiff). Pathologically the NML were categorized into4groups of low risk benign, high risk benign, DCIS and invasive carcinoma. The maximum stiffness color scale was measured Morphologically NML were categorized into four categories of NM ductal, NM non-ductal, tissue distortion and shadowing. Maximum and mean stiffness, were compared between the benign and malignant pathologies. Descriptive statistics were given for each category Results: Out of 567US guided CNB’s, 84 patients had NML including 58 non-high risk benign lesions, 7 high-risk benign lesions, 7 DCIS and 12 invasive carcinomas. There were 47 non-palpable lesions included 38benign lesions including 4 high risk and 34 non-high risk lesions, 5 DCIS and 4 invasive carcinomas. Palpable lesions included 27 benign lesions including 3 high risk and 24 non-high risk, 2DCIS and8invasive lesions. Within the non-palpable NML, there were24lesions with ductal pattern, 20with non-ductal pattern, 4 lesions with tissue distortion and 4 lesions only had shadowing. Among the palpable NML, there were 11 lesions with ductal pattern, 24 lesions with non-ductal pattern, and 3 with some calcification, 6 lesions with tissue distortion and 3 lesions with shadowing. The mean, max and ratio were different between the four groups in palpable as well as non-palpable NML. (P=0.002, 0.005and0.038) (P=0.008, 0.006and0.35). Conclusion: Shear-wave elastography might contribute to categorize lesions not only in benign or malignant but also, high versus low risk. The value is retained whether the NML is palpable or not.


Trends in Cancer Research and Therapies

Session Introduction

Celine Cano
Northern Institute for Cancer Research,UK
Title: Development of potent inhibitors of the DNA-dependent protein kinase (DNA-PK

Biography: Celine Cano is Assistant Professor (Reader) in Medicinal Chemistry at Newcastle University. She graduated from the University of Poitiers, receiving her Ph.D. in 2004 for her work on the synthesis of biomolecules by 1,3-dipolar cycloadditions with carbohydrates. In 2004, she carried out post-doctoral work in the group of Professor John A. Joule at the University of Manchester working on the synthesis of analogues of cofactors of oxomolybdoenzymes. In 2005 she joined the Northern Institute for Cancer Research at Newcastle University as a research fellow, working on the synthesis of inhibitors of the DNA-dependent protein kinase (DNA-PK). She was appointed to a lectureship in Medicinal Chemistry at Newcastle University in 2008 and has since played a key role in helping to establish Newcastle as an internationally recognised centre for anti-cancer drug discovery. Celine was awarded the Elsevier Reaxys 2016 Prize for Medicinal Chemistry in recognition of her research into anticancer drug discovery. She is the academic lead for the Medicinal Chemistry and Chemical Biology Group within the School of Natural and Environmental Sciences.

Abstract: The cellular response to DNA double-strand break (DSB) formation is an essential component of normal cell survival, following exposure to DNA-damaging chemicals (e.g. cisplatin and doxorubicin) and ionising radiation [1]. The serine/threonine kinase DNA-dependent protein kinase (DNA-PK) is a member of the phosphatidylinositol (PI) 3-kinase related kinase (PIKK) family of enzymes, and plays an important role in DNA DSB repair via the non-homologous end-joining (NHEJ) pathway [2]. DNA-PK inhibitors may, therefore, be useful as agents to improve the activity of radio- and chemo-therapy in the treatment of cancer [3]. Identification of the lead benzo[h]chromen-4-one DNA-PK inhibitor NU7026 (IC50 = 0.23 uM), guided the subsequent development of the potent and selective ATP-competitive chromenone NU7441 (DNA-PK IC50 = 30 nM) [4]. Although proof-of-principle studies with NU7441 confirmed promising activity in vitro as a chemo- and radio-potentiator in a range of human tumour cell lines [5], further biological studies with NU7441 were hampered by sub-optimal pharmaceutical properties.In collaboration with AstraZeneca Pharmaceuticals, structure-activity relationship studies for DNA-PK inhibition by chromenone-derivatives were conducted in conjunction with homology modelling. This approach predicted several positions on the pendant dibenzothiophen-4-yl substituent of NU7441 as tolerant to substitution, without detriment to DNA-PK inhibitory activity. We will describe the rational design and syntheses of analogues that optimised the physicochemical and pharmacokinetic properties of NU7441. These studies resulted in the identification of compounds that combined potent DNA-PK inhibition with excellent aqueous solubility (20-40 mg/mL as acid salts), without compromising cellular activity. Prominent amongst these derivatives is KU-0060648 (DNA-PK IC50 = 8.6 nM), which exhibits 20-1000 fold selectivity for DNA-PK over related PIKK enzymes and PI3K family members. The discovery and further development of KU-0060648 and analogues will be described, including in vivo efficacy and combination studies [6-8].


Kumari Anuja
KIIT University,India
Title: DNA damage response in colorectal cancer stem-like cells with Ionizing Radiation effect

Biography: Kumari Anuja has completed her M.Sc from KIIT University, School of Biotechnology, Bhubaneswar, India. She is currently working as Research scholar in KIIT University. Her research topic is role cancer stem cells in therapeutic radio-resistant. She has also published her previous research in reputed journals

Abstract: Radiotherapy is an integral part of current treatment modality which is confined to use of Ionizing Radiation (IR) for colorectal cancer. IR behaves as mutagen and induces double stand break which affects the genome integrity leading to cell apoptosis. Existence of cancer stem-like cells (CSCs) population showing resistance to IR may contribute to treatment failure and tumor relapse. Thus, characterization of effect of IR in colorectal cancer may serve to elucidate possible mechanisms associated with it. In this study, colorectal cancer cells (HCT116 and HCT-15) and derived clonospheres were irradiated with different doses and based on cell survival assay and cell cycle analysis dose was optimized. Presence of cancer stem- like cells population was characterized by CD44 expression. The extent of DNA damage response (DDR) and repair was elucidated by γH2AX foci formation with different time-points post-irradiation, and further confirmed by COMET assay. Expression level of DNA damage repair proteins ATM, ERCC1 was checked with western blotting and mRNA fold change post treatment. It was observed that percentage cell death was less in clonospheres post irradiation and clonospheres also exhibited less γH2AX foci, decreased olive tail moment and increased ERCC1 expression than its parental counterpart which corresponds to efficient DDR in clonospheres post irradiation. This study highlighted the presence of CSC phenotype in clonospheres having increased DNA repair capacity and enhanced expression of ERCC1 in clonospheres may contribute in radioresistance property of CSCs and therapeutic treatment failure and recurrence.


Jens Hahne
The Institute of Cancer Research,UK
Title: MicroRNA expression pattern in the context of translational research and as tool for cancer patient stratification

Biography:

Abstract: MicroRNAs are pivotal regulators for RNA silencing and post-transcriptional regulation of gene expression under physiological as well as pathological conditions. MicroRNAs can be detected in tissues and in most biologic fluids including serum, plasma and urines. Secreted microRNAs are either incorporated into micro-vesicles or circulate bound to proteins. In both cases microRNAs are protected from RNase degradation so that they may remain intact for long periods of time. Therefore they might represent potential new biomarkers. We analysed expression of 800 miRNA’s using nCounter Nanostring technology in cancer cell lines, formalin fixed paraffin embedded tissues and plasma from cancer patients. Potential clinical applications of microRNA detection for cancer patients’ management will be discussed.


Cheng-Wen Wu
Institute of BioMedical Sciences,Taiwan
Title: Novel Cancer Therapy Approach based on Auger Effect, Mediated by Monoenergetic X-ray and Heavy Atom

Biography:

Abstract: The Auger effect is a physical phenomenon in which the filling of an inner-shell vacancy of an atom is accompanied by the emission of an electron from the same atom. An Auger electron is estimated to have a travel distance around 2-100 μm, within which an energy up to 106 gray is released. Therefore, if Auger effect can be induced in cancer cell DNA, it could mediate immense damage concentrated in cancer genome, providing a potential approach for cancer therapy. Auger effect can be induced by radioactive isotope itself, like 125I, or monoenergetic X-Ray in combination with specific heavy atom. Conventionally, monoenergetic X-Ray can be produced only in a synchrotron radiation accelerator, which hinders its application in medical use. Here, our study showed that a novel design of X-Ray tube allowing electron beams to pass through the target metal can generate monoenergetic X-ray efficiently. This design substantially minimizes the size of X-Ray generator to be portable, and can generate 3-fold higher X-Ray production than traditional X-ray tube under the same voltage and current-exposure time. The monoenergetic X-Ray generated by the novel design (denominated as NanoRay hereafter) contains >20% of K-characteristic photon, up to 29-fold higher than traditional X-Ray in the same energy range. For anti-cancer analysis, 14 and 33 keV NanoRays were combined with Thymidine analogues BrdU and IdU, respectively, in cancer cell treatment. The results showed that while single treatments showed low cytotoxicity, the combination of Nanorays with BrdU or IdU induced significant cancer cell death synergistically in vitro. In contrast, combined treatments of conventional radiation with BrdU or IdU did not show any synergistic effect. In vivo tumor treatment combining 33 keV NanoRay and IdU showed a tumor reduction rate up to 80% as compared to Nanoray alone. Likewise, combination of conventional radiation with IdU showed no synergistic anti-tumor effect. DNA damage analysis found that NanoRay produced 2-fold more double-strand breaks (DSBs) in cancer cells incorporating BrdU or IdU than control cells, validating the Auger effect induced and applied in cancer genome damage. In summary, the current study presents that NanoRay, a new generation of medical X-Ray with highly specific monoenergetic spectrum, can be generated from a transmission tube within a portable apparatus. When NanoRay is applied to cancer DNA incorporating specific heavy atoms, such as BrdU or IdU, it induced significantly more pronounced DNA DSBs and cell death through Auger effect, thus lowering the dose necessary for corresponding anti-tumor effect induced by conventional radiation. NanoRay serves as a novel medical X-Ray source with low dose, low cost, and high efficiency, holding great promise in future cancer therapy.


Gwyn Bebb
Tom Baker Cancer Centre,Canada
Title: Implications of ATM loss in non-small cell lung cancer

Biography:

Abstract: Background: ATM is a critical first responder to DNA damage in the cell, but despite being one of the most mutated genes in lung cancer, the prognostic and therapeutic value of ATM loss has yet to be determined. Unlike the therapeutic biomarkers EGFR and ALK, there are no predictable mutation hot spots in the ATM gene that are actionable in a clinical setting. Systemic ATM loss results in ataxia telangiectasia, characterized by compromised immunity, susceptibility to radiation, and predisposition to cancer formation. Our work over the last several years has sought to determine the implications of cancer-specific ATM loss in NSCLC and we have shown that loss of ATM protein expression and phenotype, or “ATMicity”, regardless of mechanism, yields important consequences for cancer patients at the cellular level. Clinical Implications: We have used quantitative immunohistochemistry to accurately determine cancer-specific ATM protein levels in resected tissue from a cohort of 165 stage I and II NSCLC patients. ATM protein was quantified in tumour and stromal components of the resected tissue and the tumour levels were normalized to stromal levels to define an ATM expression index (ATM-EI). Approximately 22% of patients were found to have low ATM-EI and had both poorer 5-year progression free survival (PFS) and poorer overall survival (OS) than patients with high ATM-EI. Therapeutic Implications: In our cohort, a subset had received adjuvant chemotherapy following surgical resection, typically comprised of a platin/vinca alkaloid doublet. Patients with high ATM-EI saw no benefit from adjuvant treatment from a PFS or OS perspective, however those with low ATM-EI did see increased survival benefit. We investigated these findings in an in vitro setting and observed that NSCLC cells with endogenous ATM loss, or cells in which ATM had been knocked out by CRISPR had increased sensitivity to cisplatin treatment. These cells also have high sensitivity to PARP inhibition, and we have shown that a combination of cisplatin and low-dose PARP inhibitor is particularly lethal to ATMic cells. Determining ATMicity: We have shown that tumour ATM protein expression is predictive of survival, however we have been seeking to validate ATM loss by other means. While no clinically relevant hot spot mutations have been described for ATM, we have demonstrated in silico that ATM mutations correlate with an increased mutation burden in lung and other cancer cell lines. We have also performed RNA-seq and Oncofinder analysis on patient samples to determine the mRNA expression of ATM and ATM-related pathway activation. Conclusions: Our cumulative work suggests that ATM is an important predictor of survival for early-stage NSCLC and may be a potential indicator of therapeutic response to low-dose platins and PARP inhibitors. We are exploring methods to best determine ATMicity, by protein expression, mRNA expression and pathway activation, or by mutation and mutation burden. Although unlikely to displace EGFR or ALK as a dominant biomarker for targeted therapy in NSCLC, therapy based upon ATM status may provide benefit for those patients with no current actionable targets.


Che-Hung Shen
National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
Title: TRPM1 protein is critical for melanoma progression

Biography: Che-Hung Shen is now an assistant investigator of National Institute of Cancer Research, National Health Research Institutes, Taiwan. He has completed his Ph.D. degree from National Taiwan University in 2008 and postdoctoral studies from Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard University in 2016. His research interest is focused on the molecular mechanisms of drug-resistant development in melanomas and colorectal cancers, and preclinical studies of the potential therapeutic targets.

Abstract: TRPM1, a transient receptor potential cation channel subfamily M member 1, is an important diagnostic and prognostic marker for primary cutaneous melanoma. The TRPM1 transcripts were negatively correlated with melanoma progression and had been suggested as a predictor of the risk of metastatic progression in melanoma. However, the protein function of TRPM1 in melanoma progression and the drug resistant development remains large unknown. To study the function of TRPM1 in development of BRAFi resistant melanoma, we created dabrafenib resistant (DR) cell in two malignant BRAFV600E melanoma cell lines: A375 and Mel1617. We found the expression of TRPM1 was in a variety of melanoma cell lines and was up-regulated in the DR cells, compared to their drug sensitive counterpart. Next, we expressed TRPM1 shRNAs in DR cells and found that the knockdown of TRPM1 inhibited the cell growth of DR cells dramatically. Importantly, we found the expression of TRPM1 was downregulated in response to AUY922 (HSP90 inhibitor) treatment and TRPM1 physically associated with HSP90 complex. More, we found AUY922 triggered melanoma cell death. Finally, AUY922 inhibited the cell viability efficiently in both short-term and long-term treatment. All together, we found TRPM1 protein is expressed in malignant melanoma cells and is essential for DR melanoma cell growth. AUY922 suppresses melanoma cell growth through down-regulating TRPM1 protein and triggering cell death.


Saloua Sahbani
Université de Sherbrooke,, Canada
Title: Asteraceae plant extract enhance cancer cell death by gamma radiation

Biography:

Abstract: Skin cancer is a common and a locally destructive cancerous growth of the skin. There are three major types of skin cancer: (1) basal cell carcinoma, (2) squamous cell carcinoma and (3) melanoma, though more dangerous, than the first two varieties. Radiation therapy is very effective for treating skin cancer. The use of and search for drugs derived from plants have accelerated in recent years. Plants are rich in a wide variety of secondary metabolites, which have been found in vitro to have antimicrobial properties. The purpose of our study was to report the effectiveness of the combination of the Asteraceae plant extract and radiotherapy in the treatment of the skin cancer. The Asteraceae plant extract used in traditional medicine to treat skin burning in Tunisia. Here we investigate the radioprotector effect of the aqueous Asteraceae plant extract on a DNA plasmid (pGEM-3Zf-). Aqueous solutions of the samples were irradiated with 137Cs -rays at various doses in the presence or absence of Asteraceae plant extract. Gel electrophoresis analysis shows that the aqueous Asteraceae plant extract prevent radiation-induced DNA damage. Moreover, we found that the aqueous Asteraceae plant extract has antibacterial, antiviral and antifungal activity. These results encourage us to continue our study in vivo to show the effectiveness of the Asteraceae plant extract to enhance cancer cells death with γ-radiation and to selectively protect the normal tissues against the tumoricidal effects of radiation.


Amir Jafri
CEO/Founder, Immunicom, Inc., San Diego, CA, USA.
Title: Unleashing Endogenous TNF-alpha as a Cancer Therapeutic

Biography: Amir Jafri is the founder of Immunicom and has served as Immunicom’s President and Chief Executive Officer since the company’s inception in 2013. Amir has over 25 years of experience in healthcare technology and devices. As a senior executive in Fortune 50 companies and his own startups, he has managed multi-billion-dollar products on a global basis and is highly experienced with global regulatory environments. He was COO at West Health Institute; VP/CTO, VP R&D and VP Operations at Cardinal Health managing products with $1B in annual revenue (NYSE: CAH); VP/General Manager Healthcare Division at Manpower Group, responsible for the healthcare practice nationwide across 35 locations (NYSE: MAN). Prior to joining Manpower, Amir founded various healthcare startups that were subsequently acquired. He has successfully managed global businesses and has a track record of success in every business he has led. Amir serves on the Board of various healthcare technology startup companies and non-profit organizations. Amir received his Bachelors of Science Degree from Houston Baptist University with a double major in Chemistry and Biology and a minor in History. He attended medical school at the University of Texas but pursued an entrepreneurial and corporate path.

Abstract: Tumor necrosis factor alpha (TNF-alpha) is a major cytokine involved in inflammation caused by bacterial infections and endotoxin release. TNF-alpha is cytotoxic to cancer cells and stimulates anti-cancer immune responses. Natural attenuation of TNF-alpha is through soluble TNF-receptors sTNF-Rs, sTNF-R1 and sTNF-R2 to control deleterious inflammatory responses. However, tumors shed sTNF-Rs as a survival mechanism to downregulate TNF-alpha anti-cancer immune responses and cancer patients have elevated levels of these receptors. Immunicom has developed a novel ligand affinity device to capture and remove these immune inhibitors from patients plasma in conjunction with apheresis in order to promote TNF activity as a cancer treatment. A preclinical study has been completed for treatment of canine cancers using Immunicom’s LW-02 device together with the Terumo Optia apheresis system. This treatment approach was demonstrated to be safe and effective with a best overall response rate of approximately 60%. Advancement to human clinical studies will be discussed.


Rita Morigi
University of Bologna,Italy
Title: Targeting DNA G-quadruplex structures: an attractive strategy for anticancer drug discovery

Biography: Rita Morigi is Assistant Professor of Medicinal Chemistry at the Department of Pharmacy and Biotechnology, University of Bologna. In 1999 she obtained the Ph.D. in Pharmaceutical Sciences at the University of Bologna. During her PhD period, she joined the laboratory directed by Dr. Markus A. Christen at NOVARTIS Pharma Corporate Research (Basel, CH), and worked on a project focused on the synthesis of novel tyrosine kinases inhibitors as potential antitumor agents. Nowadays, her main research interest is the synthesis of new compounds endowed with antitumor activity. A research line recently developed concerns G-quadruplex-binding molecules, currently perceived as possible anticancer therapeutics.

Abstract: G-quadruplexes (G4s) are four-stranded DNA structures composed of stacked guanine tetrads which can form within G-rich tracts of genomic DNA. The interest in these non-canonical DNA secondary structures as targets for novel and selective anticancer drugs is exponentially growing, due to their involvement in a number of critical cancer-related genomic aberrations and pathways, and much effort is currently underway to discover effective and selective ligands [1]. The present talk will focus on hydrazone-based compounds, designed as analogues of a promising lead [2], which were synthesized and evaluated as G4 binders [3]. This study led to the identification of potent G4 stabilizers with high selectivity over duplex DNA and preference for one G4 topology over others. Selected derivatives have been shown to trap G4 structures in the nucleus of cancer cells and this behavior correlated with efficient cytotoxic activity in human osteosarcoma cells. Interestingly, the only mono-hydrazone of the series resulted the most selective, indeed it significantly stabilized only the c-myc G4. These promising results, provided the basis for the design of novel mono-hydrazone compounds characterized by a simplified core. In 2014, another approach led us to study bis-indolinone derivatives able to selectively stabilize G-quadruplex over duplex DNA [4]. These molecules were formed by an aromatic core linked with two indolinone moieties. Molecular docking calculations showed that only one indolinone moiety is involved in specific interactions with the target. These findings have inspired us the design of new G-quadruplex binders which can be viewed as “hybrid” molecules characterized by an aromatic core linked with only one indolinone nucleus, whereas the other indolinone was substituted by an iminoguanidine or a hydrazinylimidazoline, the nitrogenous chains of the lead compounds previously identified [2, 3]. The in vitro G4 binding properties of the new compounds have been evaluated by CD-melting experiments employing both human telomeric and oncogene promoter G4s with different folding topologies. On the basis of the results obtained, some derivatives have been selected to investigate their effects at cellular levels. Specifically, nuclear G4 structures in human U2OS cells have been visualized by immunofluorescence microscopy using the BG4 antibody, specific against G4s. Finally, the cytotoxic activity on U2OS and HeLa cells has also been determined.


Kalliopi Diamantopoulou
General Hospital of Athens, Greece
Title: Osteosarcoma of the cervical vertebra: a case report and review of new therapeutic strategies

Biography: She is a Pathologist with special interest to tumors of bone and soft tissue as well as CNS tumors. She is Head of Pathology Department of the General Hospital of Athens “KAT”, a 800-beds Hospital, where she has been working for 10 years now. KAT Hospital possesses about 10 Orthopaedic Depts, specializing in different issues and belongs to the National Health System(NHS) of Greece. She has also worked as a consultant for about 7 years in General Hospital of Voula “Asklepieio”, another NHS Hospital, which also specializes in Orthopaedics. She has written a chapter about the handling directions and microscopic reporting of pathological specimens, published by the Greek Society of Pathologists, as well as about 15 full text articles. She has attended many Greek, European and International conferences and congresses with participation with talks, lectures and oral and poster presentations.

Abstract: Background: Osteosarcoma(OS) is one of the most malignant cancers in bone, especially of the long bones, mainly seen in children and adolescents with a second incidence peak in the elderly. About 20% of patients with OS develop lung metastases with a 10-50% overall survival rate. Despite surgery and chemotherapy, 30-40% of patients with localized OS experience relapse. The survival rates for patients with metastatic and recurrent OS is less than 30%. Resistance to chemotherapy commonly happens and leads to a reccurent tumor. This is why understanding the biology of OS stem cells(OSCs) and Cancer Stem Cells(CSCs) might offer novel tools for molecular targeted therapies. Objective: To present a case of a relatively unusual location of OS (spinal vertebra) of an adult man and discuss possibly new therapeutic approaches through molecular targeting. Materials and Methods: A white man, aged 48, came with a cervical spinal mass due to a lytic lesion of the 6th cervical vertebra, measured 4.5cm in greatest diameter, expanding in surrounding soft tissue. After surgical excision of the whole lesion, which was practically very difficult because of the critical location of the tumor, paraffin-embedded tissue was stained with Haematoxylin-Eosin and Van Gieson. Results: Microscopically, a malignant osteoblastic neoplasm was revealed, consisting of spindle and/or large anaplastic pleomorphic cells with irregular large nuclei and eosinophilic cytoplasm, producing abundant osteoid. Osteoclast-like giant cells and areas of necrosis were also observed. Diagnosis: Osteosarcoma, conventional type. Discussion / Conclusion: Surgery and chemotherapy have been considered as primary therapeutic approaches for OS. OSCs have been linked to resistance, reccurence, and metastasis through self-renewal and differentiation. Furthermore, CSCs are thought to be more malignant as compared to differentiated cancer cells. The regulation of intracellular markers including IALDH, cell surface markers(CD133, CD117, CD44, CD271) and stemness genes(Nestin, Sox-2, OCT3/4, and Nanog) are proposed to be useful in isolating OSCs of tumors. Many therapeutic strategies are suggested to regulate the CSC-related pathways including Wnt, Hedgehog, Notch, PI3K/AKT and TGFβ. Based on clinical trials, new therapeutic approaches for OS, such as IGF-R inhibitors, mTOR and multitarget inhibitors, and WNT/β-catenin inhibitors, as well as as novel therapeutic agents targeting osteoclasts and immune system are used. All together radio- and chemotherapy, surgery, or immunotherapy with OSCs-targeting agents and/or targeting the tumor microenvironment of CSCs could possibly be an effective therapeutical approach for OS.