Madridge Journal of Cancer Study & Research

ISSN: 2640-5180

3rd International Cancer Study & Therapy Conference

May 2-4, 2018, Rome, Italy
Scientific Session Abstracts
DOI: 10.18689/2640-5180.a3.002

The Potential Role of miR-126 as a Prognostic Biomarker in Renal Cell Carcinoma

Jessica Carlsson1*, Jesper Christiansen2, Sabina Davidsson1, Francesca Giunchi3, Michelangelo Fiorentino3 and Pernilla Sundqvist1

1Department of Urology, Faculty of Medicine and Health, Örebro University, Sweden
2Faculty of Medicine and Health, Örebro University, Sweden
3Department of Pathology, F. Addari Institute of Oncology, S. Orsola Hospital, Italy

Renal cell carcinoma (RCC) is the most common renal tumor, consisting of ~3% of all malignancies worldwide. The prognosis of RCC can vary widely, and detecting patients at risk for recurrence at an early stage could improve the outcome for the patient. The factors used in the clinics today cannot reliably predict the natural history of the disease, thus there is a need for finding new biomarkers that can aid in predicting patient outcome. Several studies indicate that miRNAs are potential candidates as prognostic biomarkers for patients suffering from RCC. The aim of this study was to validate the potential of miR-126 to predict prognosis in a Swedish cohort of RCC patients.

Methods: The expression of miR-126 was measured using quantitative PCR (qPCR) in formalin-fixed paraffin-embedded (FFPE) tumor tissue from 116 patients diagnosed with RCC between 1987 and 2010.

Results: miR-126 was found to be differentially expressed between malignant and adjacent benign tissue. The expression of miR-126 was also differentially expressed between tumor grades, and stages of RCC. We could furthermore show that in a univariate model, a low expression of miR-126 was associated with shorter time to recurrence of the disease. Conclusion: Our results indicate that miR-126 expression has a potential to be used as a prognostic biomarker for patients suffering from RCC. However, further studies are needed in order to confirm these results.

Jessica Carlsson is a researcher working in the Department of Urology at Orebro University Hospital in Sweden. Jessica completed her Ph.D. in 2012, with the focus of microRNA expression in prostate cancer. Her primary area of expertise is molecular studies in urological cancers, and she currently focuses on the role of inflammation and immunity in cancer development and progression.

A Novel Cellular Crosstalk Promoting Tumor Progression and Metastasis

Andrei V. Bakin1*, Justin Zonneville1, Alfiya Safina2, Alexander M. Truskinovsky3, Carlos L. Arteaga4

1Department of Cancer Genetics, Roswell Park Cancer Institute, USA
2Department of Cell Stress Biology, Roswell Park Cancer Institute, USA
3Department of Pathology, Roswell Park Cancer Institute, USA
4Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, USA

Treatment of cancer patients with advanced or recurrent disease presents a considerable challenge. The reasons behind disease progression and spread are not fully understood. Our goals are to define what drives metastatic progression and to develop novel therapies that would eliminate the mortality associated with metastatic disease.

Emerging data support a key role of the tumor microenvironment (TME) in cancer progression, development of metastases, and response to therapy. Research indicates that tumor cells are involved in a complex and dynamic crosstalk with various cellular components of TME. Our team investigates the interaction of tumor cells with tumor-associated fibroblasts in breast carcinoma models. We have recently reported that the interaction of tumor cells with fibroblasts alters production and signaling by pro-inflammatory cytokines, e.g. TNF and IL1, and anti-inflammatory TGF-β cytokines. Our studies revealed that the cytokine crosstalk may exert synergistic and neutral (cytokine-specific) responses. The overall force of these complex interactions leads to promotion of tumor blood vessels through a process of angiogenesis, changes in fibrotic material, and alterations in immune cell populations within the TME. The lecture will present updates on the molecular details underlying these cellular and cytokine interactions. We will also discuss the translational implications of our research and potential new venues for therapeutic intervention into cancer progression.

Professor Andrei Bakin has received a doctoral degree from Moscow Lomonosov University. He was trained in cancer research with Professor Tom Curran at St. Jude Childrenʼs Research Hospital, and in breast cancer with Professor Carlos Arteaga at Vanderbilt University. He is currently a principal investigator at Roswell Park Cancer Institute. Dr. Bakin has done pioneering studies on EMT in cancer progression and metastasis. His group has identified novel therapeutic targets driving metastasis to the bone and lungs. He has mentored over ten graduate students. He is also a member of Editorial Board of several scientific journals and active member of AACR.

PD-L1 Expression is Associated with Poor Prognosis in Renal Cell Carcinoma

Sabina Davidsson1*, Pernilla Sundqvist1, Vezira Kosuta1, Anna Fält1,2, Francesca Giunchi3, Michelangelo Fiorentino3 and Jessica Carlsson1

1Department of Urology, Faculty of Medicine and Health, Örebro University, Sweden
2Clinical Epidemiology and Biostatistics, School of Medical Sciences; Örebro University, Sweden
3Molecular Pathology Laboratory, Addarii Institute of Oncology, Department of Hematology-Oncology, University of Bologna, Italy

Programmed death ligand 1 (PD-L1) is an immunosuppressive membrane protein which, when interacting with its receptor programmed death 1 (PD-1), acts as a negative regulator of the anti-tumor T cell-mediated immune response. Overexpression of PD-L1 in different malignancies such as melanoma and gastric cancer is associated with poor clinical outcomes. The prognostic value of PD-L1 expression in renal cell carcinoma (RCC) has been controversial to some extent. In this study, the prognostic value of PD-L1 expression in RCC was evaluated by analyzing PD-L1 immunoreactivity in tumor cells and tumor infiltrating immune cells (TIICs) in 358 RCC patients with long term follow-up. Since the discrepancy between previous studies may be due to the lack of standardized methodology for evaluating PD-L1 expression by immunohistochemistry, the agreement between two anti-PD-L1 antibody clones, 28.8 and SP142, was also compared.

PD-L1 positivity in tumor cells was associated with higher Fuhrman nuclear grade (p<0.001), recurrence (p=0.006), and death due to RCC (p=0.05). PD-L1 positivity in TIICs was associated with higher Fuhrman grade (p<0.001), higher AJCC-stage (p=0.019), and death due to RCC (p=0.001). A multivariate regression analysis revealed a significant positive association of time to cancer-specific death with both PD-L1 positive tumor cells and TIICs (p= 0.014 and p= 0.004, respectively). To conclude, RCC patients with PD-L1 positive tumor cells and TIICs are at significant risk for cancer progression, and the expression of PD-L1 on those cell types may be used as a complementary prognostic factor in the management of RCC patients.

Sabina Davidsson work as a researcher at the department of Urology at the University Hospital of Orebro, Sweden. She defended her thesis “Infection induced chronic inflammation and its association with prostate cancer” 2013. The current focus of her research concerns which role different immune/inflammatory cells plays in the development of a number of urological cancer types, including renal cancer, penile cancer, bladder cancer, and prostate cancer.

Anti-FIRs (PUF60) Auto-Antibodies were Detected in the Sera of Early-Stage Colon Cancer Patients. Identification of Specific and Common Diagnostic Antibody Markers for Gastrointestinal Cancers by SEREX Screening Using Testis cDNA Phage Library

Kazuyuki Matsushita and Sohei Kobayashi

Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics
Chiba University Hospital, Japan

Anti-PUF60, poly(U)-binding-splicing factor, autoantibodies are reported to be detected in the sera of dermatomyositis and Sjogrenʼs syndrome. PUF60 is identical with far-upstream element-binding protein-interacting repressor (FIR) that is a transcriptional repressor of c-myc gene. In colorectal cancers, a splicing variant of FIR that lacks exon2 (FIRΔexon2) is overexpressed as a dominant negative form of FIR. The autoantibodies for FIRs were examined in the sera of 87 colorectal cancer patients. Anti-FIRs antibodies were surely detected in the preoperative sera of 28 colorectal cancer patients (32.2% of positive rates), and the detection rate was significantly higher than that in healthy control sera by Alpha (amplified luminescent proximity homogeneous assay)-LISA assay. The level of anti-FIRs antibodies significantly decreased after the operation. Furthermore, the area under the curve of receiver operating characteristic for anti-FIRs antibodies was significantly larger (0.85) than that for anti-p53 antibodies or CA19-9. In conclusions, Anti-FIRs antibodies were detected in relatively early-stage colorectal cancers.

Further, we have screened auto-antibodies by phage expression cloning and identified novel fourteen antigens. As for autoantibodies against fourteen antigens, Alpha-LISA assay was performed in the sera of gastrointestinal cancers patients to confirm the results. Serum antibody levels against these fourteen recombinant proteins as antigens between healthy donors (HD) and esophageal squamous cell carcinoma (ESCC) patients, gastric cancer (GC), or colon cancer (CC) were compared. Receiver operating curve (ROC) revealed similar results except CCNL2 in CC. AUC values calculated by ROC were higher than 0.7 in TPI1, HOOK2, PUF60, PRDX4, HS3ST1, TUBA1B, TACSTD2, AKR1C3, BAMBI, DCAF15 versus ESCC, TPI1, HOOK2, PUF60, PRDX4, TACSTD2, AKR1C3, BAMBI, DCAF15 versus GC, and TPI1, HOOK2, PUF60 versus CC. AUC of the combination of HOOK2 and p53 antibodies versus ESCC was observed to be as high as 0.8228. Higher serum antibody levels against 10 antigens could be potential diagnostic tool for ESCC. Higher serum antibody levels against 8 antigens could be potential diagnostic tool for GC, and serum antibody levels against 3 antigens could be potential diagnostic tool for CC.

Keywords: auto-antibody, cancer biomarker candidate, colorectal cancer, far-upstream element-binding protein-interacting repressor (FIR); poly(U)-binding-splicing factor (PUF60).

Kazuyuki Matsushita in 1988 graduated from Chiba University and was awarded with MD. In 1995 maintained his PhD at the Graduate Scholl of Medicine, Chiba University in Japan. From 1997 through 2000 was a visiting fellow, of the NCI, NIH, USA. In 2015, he was listed as a Board of Laboratory Medicine, Japanese Society of Laboratory Medicine, Japanese Board of Medical Genetics, form the Japan Society of Human Genetics. In 2010, he got the Board of Specialty in Cancer Treatment from Society of Japanese Cancer Treatment Society. At present he is a Professor of Department of Laboratory medicine, Director of Laboratory Medicine, Division of Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, Japan. He has been studying c-myc transcriptional regulation, especially demonstrated on c-myc transcriptional repressor FIR (FBP interacting repressor) in carcinogensis. Proteomic and genomic analysis in cancinogenesis and DNA damage repair pathway for clinical validities such as cancer treatment and diagnosis. Establishment of biobanks network of human clinical samples in Japan for novel biomarkers research are studied in his group.

NGS Approach for New Ovarian Cancer Biomarker Discovery

Stefania Brandini1*, Arianna Consiglio1, Flavio Licciulli1, Sabino Liuni1, Anna Napoli2, Eugenio Maiorano2, Leonardo Resta2 and Elda Perlino1

1Institute of Biomedical Technologies - National Research Council (ITB-CNR), Italy
2Department of Emergency and Organ Transplantation, Operating Unit of Pathological Anatomy, ‘Aldo Moroʼ University, Italy

Ovarian cancer is the sixth most common cancer in women and is called ‘the silent killerʼ as most women are not diagnosed until the cancer has already spread, thus resulting in low chances of survival. Given the complex and heterogeneous nature of this neoplasm, it is crucial the identification of molecular biomarkers that might be used for focused and efficient diagnosis, prognosis and therapy.

In order to contribute to the identification of new biomarkers for ovarian cancer, we used the Next Generation Sequencing (NGS) technology allowing simultaneous testing of the coding and non-coding RNAs from 21 samples belonging to the most representative histological types of ovarian, serous and endometrioid carcinomas.

Among the molecular factors involved in the process of tumor transformation, many small noncoding miRNAs and their target genes have been found. Some of these genes have already been reported to be involved in cell proliferation and death pathways, and might be considered as possible targets for specific treatment purposes.

The differentially expression analysis revealed more than one thousand mismatches in the tumor expression profiles of both long and miRNAs in comparison to the control tissues. These data shed light on new possible molecular biomarkers for ovarian cancer.

Stefania Brandini is a biologist with a Ph.D. in ‘Genetics, Molecular and Cellular Biologyʼ obtained in January 2017 at the University of Pavia. Since 2010 she worked and collaborated with different research teams acting in various environments (i.e. University, hospital and CNR) and experienced the methods used in genetics and molecular biology. Recently, she focused on cancer epigenetics and in particular on the characterization of new biomarkers useful for the diagnosis/prognosis/therapy of proliferative diseases by NGS methods. She was co-author of 6 original articles, 2 of which selected for the covers of the journal Molecular Biology and Evolution.

Pancreatic Ductal Adenocarcinoma (PDAC): The Patient's Journey and Highest Unmet Need

Luboš Petruželka*, Michal Vočka and Jan Špaček

Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital in Prague, Czech Republic

PDAC outcomes are unyieldingly poor even despite improvement in the overall picture for many cancers. Stage for stage, PDAC is associated with the lowest survival rates of any major cancer type. There has been little progress in improving outcomes over the past years and remains one of the most deadly cancers. Reasons for this include the lack of early detection and effective treatments. PDAC is the only one of the top five cancer killers for which deaths are projected to increase. Such figures justify the positioning of PDAC as a cancer of significant unmet need.

The early detection: The best chance for curing the disease is early detection. PDAC is relatively uncommon, the average person has only a 1% chance developing PDAC over life time. General screening is not recommended and the future is in selective screening of people who are at high risk for malignant tumours to detect premalignant tumours or early stage potentially curable by surgery.

The total diagnostic interval is longer for PDAC than for other cancers. The diagnostic workup time to the start of treatment should be as short as possible, less than one month since the occurrence of the initial suspicious findings.

Biomarkers for early detection: There remains no clinically useful test today to detect early PDAC and/or high-grade PanINs.

Treatment: Parallel improvements in systemic and locoregional therapies and rapid implementation of novel therapeutics to clinical practice are needed. There is no effective targeted therapy available in the clinics and immunotherapy has so far disappointed.

Conclusion: PDAC remains a difficult, and growing, problem in oncology. We are now better understanding the biology, especially with respect to genomic (both somatic and germline) alterations as pathogenic, predictive, and prognostic factors. The ultimate goal of considerable improvement in clinical outcomes will require continued scientific and clinical investigations, multidisciplinary care of patients, and focus on collaborative research across various institutions.

Professor Petruzelka graduated as MD from First Medical Faculty of Charles University in 1976, achieving PhD at the same Institution in 1997. He is certified specialist in Radiotherapy and in Medical Oncology (including ESMO Certification in 1995). Since 2001 he works as head of Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital in Prague and also head of Institute for Radiation Oncology and Department of Oncology First Faculty of Medicine Military Hospital in Prague. Professor Petruzelka is actively involved in pre-gradual and post-gradual teaching and academic activities in clinical oncology and in 2008 was designated as Professor of Medicine and Oncology at Charles University in Prague. His major clinical and research interests include area of gastrointestinal and lung cancer, new drugs, targeted therapy, immunotherapy of solid tumours and predictive oncology. He is currently member of the board of Czech Society of Clinical Oncology and member of other international Societies (ASCO, EORTC, AACR, SITC). He was a national representative of the Czech Republic in ESMO. He is an active member PCE platform (pancreaticcancereurope). He is also active as member of CELC-Central European Lung Cancer board and as member of scientific and educational board of CECOG – Central European Cooperative Oncology Group. He is author of numerous scientific publications and chapters in medical books, chairman of international editorial board for Central European version of Lancet Oncology and member of editorial boards in Magazine of European Medical Oncology and local professional journals (Journal of Czech Physicians, Clinical Oncology, Oncology Care).

Evaluation of the Predictive and Prognostic Role of Bcl2 in Non-Metastatic Locally Advanced Triple-Negative Breast Cancer Patients: A Clinicopathologic and Immunohistochemical Study

Asmaa E1*, Hanan S1 and Dareen M2

1Department of Oncology, Tanta University, Egypt
2Department of Pathology, Tanta University, Egypt

Breast cancer is considered to be a common malignancy and the second most common leading cause of cancer death in females. So, continuous researches for new prognostic markers which will aid in therapy is mandatory. Bcl2 has been associated with estrogen receptor positivity and good prognosis in breast cancer. However contradictory data have been reported in several studies concerning the role and the prognostic impact of this marker in triple-negative breast cancers (TNBCs). The aim of this work is to study the expression of Bcl2 in locally advanced non-metastatic TNBCs and to correlate these data with clinicopathologic findings and patient disease free survival (DFS) to assess its prognostic significance. In addition to evaluate the role of Bcl2 as a surrogate predictive marker of response to neoadjuvant chemotherapy.

Patients & Methods: Paraffin blocks obtained from 61 female patients with non-metastatic locally advanced invasive TNBCs were analyzed for Bcl2 immunohistochemical expression. All patients treated by neoadjuvant chemotherapy (NAC), with a sequential regimen containing anthracycline and taxanes -based regimen at Clinical Oncology Department, Faculty of Medicine, Tanta University Hospital during the period between January 2009 and December 2014.

Results: The study included 61 female patients with non-metastatic locally advanced TNBCs. BCL2 showed positivity in 29 cases (47.54%). BCL2 was inversely correlated with response to neoadjuvant chemotherapy (P = 0.005). Tumor grade showing a border line significant correlation with it, with a higher frequency of grade III cancers being BCL2 negative (p= 0.0598). There was no statistical significance when looking at the correlation between BCL2 positivity and tumor size, (p= 0.807), nodal status (p= 0.948), age (p= 0.933), as well as lympho-vascular invasion (p= 0.705). The 1 year, 2 year, and 3 year DFS for patients whose tumors are positive for BCL2 without residual disease after neoadjuvant chemotherapy was 92 %, 81% and 70% compared to 91%, 80% and 65% for the women with BCL2 negative tumors, respectively. (P = 0.799). The 1 year, 2 year, and 3 year DFS for patients whose tumors are positive for BCL2 with residual disease after neoadjuvant chemotherapy was 95 %, 79% and 70% compared to 85%, 53% and 40% for the women with BCL2 negative tumors, respectively. (P = 012).

Conclusion: In TNBC patients, adding Bcl2 to the panel of markers used in current clinical practice could provide prognostic and predictive information. Bcl2 appears to be potentially useful marker of good prognosis in patients with non-metastatic locally advanced TNBCs who had residual disease, with a sequential regimen containing anthracycline and taxanes -based regimen and can be used to detect cases with aggressive biological behavior that can benefit from more aggressive therapy.

Keywords: Bcl2, Triple-negative breast cancer, Clinicopathologic Study, Immunohistochemical Study.

Asmaa Mohamed Elkady is MD of Clinical Oncology 2015 Lecturer of Clinical Oncology at Faculty of medicine, Tanta University, Egypt – Cairo.

Identification of a Native Novel Oncolytic Immunoglobulin on Colon Epithelial Cells: An IgA/IgG Bispecific Heterodimeric Chimera

Padmanabhan Nair

The Johns Hopkins University Bloomberg School of Public Health and NonInvasive Technologies LLC, USA

The colonic mucosa undergoes rapid renewal with a turnover rate of approximately five days. Conventional dogma has contended that these mucosal cells after exfoliation undergo apoptosis and are excreted in a necrotic state. In 1991 we provided evidence that showed that these cells in large measure transit the fecal stream intact and viable and can be isolated from stool samples for further investigation. We developed a robust technology to isolate millions of these cells from small aliquots (0.5 gm) of fresh stool samples and examine them for biomarkers and other characteristics. This technology, that we termed COPROCYTOBIOLOGY allowed us to assess the expression of a number of biomarkers among which we identified IgA and a subpopulation of cells that co-expressed both IgA and IgG. This heterodimer was then shown to mediate a broad spectrum cytotoxicity against human tumor cells. In tissue culture these cells continued to generate this chimeric antibody over several generations. When we screened a cohort of about 60 subjects we observed a total absence of this immunoglobulin in two individuals of African/American origin suggestive of a germline deletion in these subjects.

Padmanabhan Nair, Ph.D., FAAAS has done his B. Sc.(1946)University College, Travancore University, Trivandrum, Kerala, India; M.Sc, (1954) Ph.D. (1956) Royal Institute of Science, Bombay (Mumbai), India; Research Officer, (1958-1960) All-India Institute of Medical Sciences, New Delhi, India; Fulbright Scholar and McCollum-Pratt Fellow,(1960-19963) The Johns Hopkins University, Baltimore, Maryland; Head of Medical Research,(1963- 1983) Sinai Hospital of Baltimore, Inc; Research Scientist (1983-1998) Beltsville Human Nutrition Research Center, ARS, USDA, Beltsville, Maryland; Founding President and CEO, (2000) NonInvasive Technologies LLC, Elkridge, Maryland; Adjunct Professor of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.

Cancer Cell-derived IL-6 Promotes MDSC, TAM, PD-1 Expression in Peripheral Blood Mononuclear Cells

Ge Jin1*, Lechuang Chen1, Rui Chen2, Akina Tamaki3, Chad Zender3 and Thomas McIntyre2

1Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, USA
2Department of Cellular and Molecular Medicine, Cleveland Clinic Foundation, USA
3Ear, Nose, and Throat Institute, University Hospitals Cleveland Medical Center, USA

Monocytes, myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) have emerged as key immune modulators in various tumor models and human malignancies that suppress innate and adaptive immunity to support tumorigenesis. Programmed Cell Death Protein 1 (PD-1), which is up-regulated on T cells upon activation and remains high on exhausted T cells, also plays critical roles in immunosuppression. The increased presence of MDSCs, TAMs and PD-1 in the tumor is associated with progression of disease and poor prognosis in several cancer types. However, the mechanism remains unclear. We used conditioned media (CM) from head and neck cancer (HNC) and lung cancer cell lines to treat peripheral blood mononuclear cells (PBMCs) and found that the CM treatment increased the population of MDSCs (Lin-/CD11b+/CD33+/HLA-DR) and TAMs (CD11b+/CD68+/CD163+) in PBMCs. We assessed the expression of inflammatory cytokines in cancer cells associated with PBMC PD-1 and its ligands PD-L1 and PD-L2, Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), Lymphocyte-Activation Gene 3 (LAG-3), T-Cell Immunoglobulin and Mucin-Domain Containing-3 (TIM-3), and cytokines. We found that the CM from all cancer cell lines significantly stimulated expression of IL-1β, PD-1, and CTLA-4 in PBMCs. Most importantly, we discovered that IL-6, but not IL-4, was significantly elevated in cancer cell CMs and played a major role in promoting the immunosuppressive phenotype of PBMCs. In this study, we provide evidence that cancer cell-derived IL-6 increases the population of MDSCs, TAMs, PD-1- and PD-L1-expressing immune cells, thereby establishing an immunosuppressive tumor microenvironment for progression.

Supported by NIH R01DE025284 (GJ)

Ge Jin, Ph.D., is an Associate Professor in the Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, USA. Dr. Jinʼsresearch interest focuses on the mechanism underlying cancer cell-derived cytokines and/or metabolites and immune response and the role of HIVinfection in the development and progression of non-AIDS-defining cancers.

Synergistic Effects of Oncolytic Virotherapy in a Bortezomib Resistant Syngeneic Mouse Model of Multiple Myeloma is Mediated Via Immune Modulation

ChandiniThirukkumaran1*, Zhong-Qiao Shi1, Jerry Nuovo2, Joanne Luider3, Karen Kopciuk1, Marta Chesi4, Leif Bergsagel4, Yuan Dong1, Ahmed Mostafa1, Kathy Gratton1, Satbir Thakur1 and Don Morris1

1Tom Baker Cancer Centre, University of Calgary, Canada
2Calgary Laboratory Services, Canada
3Department of Pathology, Ohio State University, USA
4Mayo Clinic, USA

Introduction: Multiple myeloma (MM) is a plasma cell neoplasm that is considered incurable. Despite the advent of new agents the majority of MM patients relapse secondary to therapy resistance. The potential of reovirus (RV) as a novel therapeutic agent for MM under in vitro, in vivo and ex vivo conditions has been demonstrated by us and a phase I clinical trial of MM with RV therapy has shown indications of efficacy. Utilizing the syngeneic transplantable Vk*MYC bortezomib (BTZ) resistant MM mouse model, we demonstrate that mice harbouring BTZ insensitive MM tumors significantly respond to RV+BTZ combined treatment better than monotherapy. Our data indicate that this RV+BTZ synergy is manifested via, direct oncolysis in conjunction with enhanced immune activation.

Methods: C57BL/6 wt mice were divided into 2 groups and transplanted with Vk*MYC myeloma (Vk12598) and were treated as follows, (N=8): 1) vehicle control (VC), 2) live reovirus (LV), 3) dead reovirus (DV), 4) BTZ, 5) LV+BTZ, 6) DV+BTZ. Mice in group 1 were sacrificed after 4 days of treatment and their spleens and bone marrow (BM) were formalin fixed and paraffin embedded. These were assessed for CD138+ MM tumour as well as viral RNA and protein in the tumour microenvironment (TME) and a variety of immune correlates as well as apoptotic markers. Mice in group 2 were assessed for serum gamma globulins (M-spike) on a weekly basis and overall survival analysis was conducted.

Results: Mice treated with RV+BTZ demonstrated highly significant (P<0.001) reductions in their M-spikes at 3 and 4 weeks post treatment and superior overall survival (P<0.001). Analysis of tumour viral delivery/replication and immune activation in the TME as early as 4 days post treatment initiation indicated significant (P<0.01) viral replication, caspase 3 activity, CD3+ and NK cell accumulation in the RV+BTZ treatment.

Conclusions: Our data indicate that this RV+BTZ synergy is manifested by enhanced apoptosis, successful viral delivery via tumour associated endothelial and follicular dendritic cells and immune modulation. Since the progression of MM is associated with concomitant immune suppression and drug resistance, these results have significant implications for shaping future clinical trials.

Dr. Chandini Thirukkumaran is a Research Associate Professor at the Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta. She received her PhD in microbiology in 1994 from the University of Calgary. Following completion of a post- doctoral fellowship in signal transduction at the University of Calgary she joined the Translational Research Laboratories at the Tom Baker Cancer Centre, Calgary as a Research Assistant Professor in 1999. Since then her work has focused on oncolytic viruses as treatment modality for cancer. Presently she is conducting research on multiple myeloma and breast cancer and the effects of oncolytic viruses on immune modulation when given in conjunction with “standard of care therapies” for these malignancies

HER-2 B Cell Epitope Peptide-Based Cancer Vaccines and Combination Immunotherapies with EGFR, HER-3, IGF-1R, VEGF and a novel PD-1 Vaccine

Pravin T. P Kaumaya

Division of Vaccine Development/Peptide & Protein Engineering Laboratory, The Ohio State University Medical Center and the James Comprehensive Cancer Center, USA

We have created and established a portfolio of validated B-cell peptide epitopes against multiple receptor tyrosine kinases to expedite the development of new paradigm shifting cancer immunotherapies. We have identified the most biologically effective combinations of EGFR (HER-1), HER-2, HER-3, VEGF, IGF-1R and PD-1 peptide vaccines/mimics to selectively inhibit multiple receptors and signaling pathways. We have translated two HER-2 combination peptide vaccines to the clinic in a Phase 1/2b trial to safely deliver curative and transformative cancer immunotherapies to advanced cancer patients. The potential safety, efficacy, durability, usability and cost a B-cell peptide vaccine may/could benefit a variety of patients: Stimulates the immune system to produce natural Abs, potentially safer, Stimulates the immune system to produce natural Abs, potentially safer, Antibodies continuously produced a lasting immune response to inhibit tumor recurrence, Antibodies continuously produced a lasting immune response to inhibit tumor recurrence.

This presentation will detail our clinical trial and basic studies based on the development of combinatorial immunotherapeutic strategies that act synergistically to enhance immune-mediated tumor killing aimed at addressing mechanisms of tumor resistance for several tumor types. We will discuss the novel combinations of HER-2 and PD-1 vaccines.

Dr. Kaumaya is Professor of Medicine in Department of Ob/Gyn at the OSU Wexner Medical Center and the James Comprehensive Cancer Center. Dr Kaumaya is internationally recognized as an expert in the fields of vaccine research with emphasis on peptide vaccines for cancer, viral diseases as well as peptide therapy for autoimmune diseases. He conducts research in the areas of tumor immunology, mechanisms of tumor cell-immune cell interactions, and immune mechanisms. The laboratory functions as an integrated translational research program with the goal of designing and developing new immunotherapies and immunologic strategies for cancer treatment and prevention. He is an inventor on several issued and pending patents for Peptide Vaccines and Therapeutic Technologies.

Translation of Laboratory Research Findings towards Cancer Risk Assessments from Environmental Chemicals

David W. Hein

Department of Pharmacology & Toxicology and James Graham Brown Cancer Center, University of Louisville, USA

Human epidemiological studies associating chemical exposures to cancer risk often are inconsistently validated across studies. Examples include the effect of smoking on cancer etiology other than the lung, such as urinary bladder and breast. Research findings from the laboratory have improved the understanding of arylamine carcinogen metabolism leading to improved design and interpretation of human molecular epidemiology investigations. Laboratory studies that infer and test biological plausibility, including cancer risks modified by differential metabolism of arylamine carcinogens in rapid and slow arylamine N-acetyltransferase (NAT2) acetylators, have been critical for investigating the role of smoking in the etiology of human cancers. These concepts will be explored with an example of a cancer in which the role of smoking has largely been validated (urinary bladder cancer) and an example where a consensus for the role of smoking remains to be achieved (breast cancer).

Dr. Hein serves as Peter K. Knoefel Endowed Chair of Pharmacology, Professor and Chairman of the Department of Pharmacology & Toxicology, and Distinguished University Scholar at the University of Louisville (USA). His research program includes studies of the molecular epidemiology of cancer susceptibility, pharmacogenetics, genomics, personalized medicine, and functional genomics. He has coauthored over 240 peer-reviewed journal articles and book chapters, 75 published gene sequences, and over 600 abstracts. The publications have over 13,000 citations with an h-index 58. He has served as principal investigator/co-investigator/mentor on over 75 research grants and contracts totaling over $50 million dollars.

Epidemiology and the Etiology of HPV Induced Cervical cancer: A Cohort Study in Eastern Uttar Pradesh, India

Jagat Kumar Roy, Shikha Srivastava, Biswa Pratim Das Purkayastha and Anand Prakash

Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, India

Apart from the numerous risk factors associated, HPV alone accounts for more than 95% of cervical cancer. Epidemiological studies in 2424 women in eastern Uttar Pradesh from differing socio-demographic strata showed HPV16 to be most prevalent (63.7%) strain, followed by HPV 31(6.7%). Focusing on the role of host cellular factors during tumourigenesis, identified transcription factors, BRN3A and WWOX, to be differentially expressed in a number of other tumours. Analysis of HPV positive cell lines shows that BRN3A does not interact with activated HIPK2, undergoes positive auto-regulation and remains unaltered in presence of cisplatin. Screening of sensory enhancer region of BRN3A led to the identification of a novel SNP at 60163379 A>G, with the frequency of G allele being 8.73%. Silencing of BRN3A in cervical cancer cell lines led to down-regulation of the factors instrumental in the process of angiogenesis, viz., VEGF, HIF-1α, ANGPT2 and FGF-2. This brings to light the involvement of the oncoprotein, BRN3A, in neovascularization process in uterine cervix cancer cells. However, the transcription factor WWOX, showed a significantly decreased protein level despite its elevated transcript levels. Taken together, our study opens up further avenues in the exploration of HPV induced cervical carcinogenesis to delineate the interacting partners of HPV.

Jagat Kumar Roy is a Professor of Zoology in Banaras Hindu University teaching Genetics and Developmental Biology. In research front, lab has shown involvement of Rab11, a small G-protein, in membrane morphogenesis and differentiation in Drosophila. Also a new tumour suppressor function has been assigned to Dcp2 in Drosophila besides its function of decapping of mRNA. Epidemiology of HPV in human cervix cancer and in understanding the role of some of the cellular factors in HPV induced cervical cancer is in progress. 13 students dis Ph D from the lab and 49 publications came including a small paper in Nature.

Personalized Therapy in Oncology: Progress, Challenges and Opportunities

Sherry A. Bradford

AccuTheranostics Inc., USA

Despite significant increases in the numbers of people surviving cancer, there yet exists a vast rift in the number who die each year despite treatment. It remains one of the most challenging diseases to treat, in part, due to the heterogeneity of the malady.

Most cancers originate as a single cell, and thus monoclonal in origin, however, due to innate genetic instability of subsequent cell generations, new characteristics create a heterogenic disease well-defined by genetic clonal expansion epigenetic changes.

However, tumors cells are not the only contributors to tumor heterogeneity. There exists a reciprocal and dynamic interaction between the microenvironment constituents, such as infiltrating cells, and juxtapositoned matrices and cells, to produce a distinct individualistic tumor phenotype.

The clinical relevance is that this tumor heterogeneity contributes significantly to the efficacy of drug therapy and therefore imparts considerable inter-individual variation in pharmacotherapy and clinical response to a myriad of medications. Thus, this divergence underscores the necessity to personalize therapeutic regimens.

This oration, tersely, but-to-the-point, edifies the progress, challenges and opportunities for personalized medicine in oncology.

Dr. Sherry Bradford attended undergraduate school at SUNY at Buffalo and was awarded a full tuition scholarship to pursue her PhD graduate degree (Biochemistry) from the University of Buffalo/ Roswell Park Cancer Institute Division of SUNY at Buffalo School of Medical and Biomedical Sciences.
During her clinical laboratory vocation, she was solicited by the Chief of Surgery at Millard Fillmore Hospital, Buffalo, NY, to direct the Surgical Research laboratory. There she successfully led the research on the use of human microvascular umbilical cord endothelium for lining stents. She was further awarded the “1st Place - Award for Excellence in Research” from the American Federation for Clinical Research, and the “1st Place - Award for Excellence in Research” – SUNY at Buffalo, Roswell Park Cancer Institute Research Forum.
In 2008, Dr Bradford and colleagues form AccuTheranostics and the idea of Oncology Personalized Medicine (PM) based on the specific patientʼs own biochemical and genetic profile to administer personized treatment regimens. An in vitro chemosensitivity test on tumor cells, using flow cytometric methodologies, was developed and is currently being evaluated by the NYS-DOH for clinical utility. At present, the research division of AccuTheranostics is in the throngs of developing at least 3 novel PM assays for translation into clinical status.
Dr. Bradford sits on the EDITORIAL BOARD of the International Journal of Medical and Health Sciences Research; on the EDITORIAL BOARD of Insights in Cancer Research, Editorial Board Member (Editor-in-Chief) for the Scientific Federation of Oncology & Cancer: Editorial Board Member of the Journal of Biomolecular Research and Therapy; and has authored and co-authored a number of scientific peer-reviewed manuscripts.
She is also a member of many professional organizations including (but not limited to): International Metabolic Cancer Group, AACR, ASCO, and GLIFCA.
Shehas been and will be an invited speaker at various domestic and international scientific meetings including:Invited Speaker: Proceedings of the 6th Intʼl Conf on Frontiers of Polymers and Adv Materials, Recife, Brazil, March 2001; Key Note Speaker: Cancer Science 3rd World Congress Oct. 21, 2013 – San Francisco, CA; Plenary Speaker, Cancer Science 4th World Congress: Valencia, Spain, Sept. 1-3, 2015;International Expert and Key Note Speaker: INDOGLOBAL HEALTHCARE SUMMIT & EXPO 2014, Hyderabad, India from July 23-26, 2015;Key Note Speaker: Dubai, United Arab Emirates, Aug 27-29, 2015; Keynote Speaker Gynecologic Oncology, May 19-21, 2016, San Antonio, Tx. This Year (2017) Keynote Speaker in Rome, Portugal, Dubai, Chicago, San Francisco and Philadelphia.
Dr. Bradford also holds one patent: U.S. Patent No. 6485714, Published Patent - Serial No./Application No. 10/340,858, and 3 – patents pending (2017).

A Clinical and Morphological Rationale for Lateral Neck Lymph Node Dissections in Children and Adolescents with Papillary Thyroid Carcinoma

Mikhail Fridman1*, Olga Krasko2, Alfred King-yin Lam3 and Sviatlana Mankovskaya4

1Republican Centre for Thyroid Tumors, Belarus
2United Institute of Informatics Problems, National Academy of Sciences of Belarus, Belarus
3School of Medicine and Menzies Health Institute Queensland, Griffith University, Australia
4Institute of Physiology (S.M.), National Academy of Sciences of Belarus, Belarus

Background: In Belarus with many papillary thyroid carcinoma (PTC) cases developedin patients because of the post-Chernobyl irradiation the need for prophylactic dissections of the central and lateral compartments of the neck is never questioned. As a result, we collected hundreds of PTC cases in children and adolescents that provide excellent information on the real initial extent of the disease, subsequent treatment and follow-up.

Aims: To identify factors associated with nodal disease (and the degree of their involvement) and to predict the risk of recurrent/persistent disease in this cohort of patients using clinical and morphological characteristics of the primary thyroid tumour and its lymph-node metastases in the central compartment of the neck.

Material and Methods: All the patients aged <19 years old at presentation with PTC who were treated with total thyroidectomy and lymph nodes dissections (in the central and lateral compartments of the neck) according to the extent of disease at the time of diagnosis (n = 509).

Results: The metastatic ratio index (MRI) was an independent variable that potentially influence the decision to carry out lateral lymph nodes compartment surgery in addition to routinely performed central lymph nodes dissection. A nomogram with excellent discriminatory ability and accuracy in predicting probability of ipsi or bi-lateral nodal disease was created. Clinical and pathological characteristics associated with relapse were identified.

Conclusion: The results of our study allowed us to supplement and refine the algorithms proposed by specialists of the American Thyroid Association.

Dr. Mikhail Fridman works at the Minsk Municipal Clinical Hospital for Oncology, Republican Centre for Thyroid Tumors (2002- present) as the Head of the department of pathology. Successfully passed the exam in immunohistochemistry for mammary gland carcinoma under the auspices of NordiQC (2014), Degree Doctor of Medicine (oncology) was earned in the year 2015 for a research “Papillary thyroid cancer in children and adolescents: diagnosis, treatment, and prognosis”. Took part in conferences under the auspices of European Thyroid Association, American Thyroid Association, International Academy of Digital Pathology, International Academy of Pathology and World Congress on thyroid Cancerin the form of abstracts, posters and oral presentations.

Body-Mind Interventions for Cancer Patients: Methodological Reflections

Adriaan Visser, Netherlands

Objective: Methodological analysis on the content, results and limitations of three body-mind interventions for cancer patients.

Methods: A secondary analysis of the research designs, patient characteristics, evaluation, and effects of three body-mind interventions for cancer patients: haptotherapy (N= 57) and two studies applying relaxing face massage (N=34 and 79). Different experimental designs have been applied. A variety of well-being effect measures were used.

Result: The three appreciated interventions showed limited effects after controlling for confounding factors. The drop-out, differences in severity of cancer, the use of other complementary approaches, and response shift may have affected the found effects.

Conclusions: Body-mind interventions require more methodological reflections to develop attractive and effective interventions for cancer patients. Attention need to be paid to measuring short term effects, practically fitting research designs, and response shift.

Practice Implications: Body-mind approaches are needed to compensate the lack of attention to intentionally body contact of cancer patients during illness and treatment. Body-mind interventions should be intensive, repeated and not too short. The implementation of effective body-mind interventions requires attention to several organizational factors in the health care.

Adriaan Visser (1941), PhD, studied social psychology at the Free University, Amsterdam (NL). The published thesis (1984) was on the methodology of the measurement of patient satisfaction. Worked the rest of his life mostly as health psychologist, engaged in education of university and high school students (psychology, medical, nursing), research in health care, implementation of health care changes, writing, and editing. Nearly 100 grants have been awarded and a lot articles published on patient education, organization of health care, dental care, diabetes, fibromialgie, psychosocial cancer care, breast cancer, prostate cancer, palliative care, aging, family planning, psycho-neuroimmunology (PNI), depression, mindfulness, complementary medicine, and spirituality.

Isolation, Identification of a Flavonoid and Antitumor Activity in Lung Cancer

Rafael Silva1, Ricardo Damián1 and Ana Laura Luna2

1Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City
2CentroInterdiciplinario de Ciencias de la Salud, Instituto Politécnico Nacional, Mexico City

The use of Traditional Medicine in Mexico is an economic and affordable alternative. There are several species used to treat different disease such as Annona muricate, commonly know as Guanabana that is used for different diseases as anticonvulsant, antiparasitic, antimalarial, hepatoprotective, antidiabetic, etc. It has been reported that various parts of the plant have antiproliferative activity in diferent cancer cells lines, so in this work the objective was to study the anticancer activity of Annona muricate skin in vitro in A549 cell lines of lung cancer. An ethanolic crude extract was prepared from the Guanabana skin. The crude extract was subjected to preliminary chemical tests, to know the chemical content of the extract and was subjected to several chromatographic techniques using different stationary and mobile phases. Biological tests were carry out using lung cancer cells A549usin Paclitaxel as a positive control. From the ethanolic extract was isolated a flavonoid that was identified by nuclear magnetic resonance as 2-(4ʼhydroxyphenil)-5,7—dihydroxy-chromone. The results of the activity. The results of the activity on the viability of the lung cells cancer showed that a 300 µg/mL induces a cytotocyc action in the A549 cell line presenting a similar effect to the drug Paclitaxel which is a broad spectrum anticancer compound.

Rafael Silva Torres has completed his PhD. From Escuela Nacional de Ciencias Biológicas of National Polytecnic Institute and abroad studies M. Phil of Medicinal Chemistry from Loughborough University of Technology Great Britain and sabbatical year from Museum Nacional DʼHistoire Naturelle Paris France. He has been working on lung, cervical and breast cancer since 2008. He is membership of American Association of Pharmaceutical Scientists and American Chemical Society. He is investigating the antitumor properties of medicinal plants such as: Sedum praealtum DC. Stenocereus griseus an Annona muricate.

Psychological Risk Factors for Cancer?

Shulamith Kreitler

Affiliation School of Psychological Sciences, Tel-Aviv University and Psychooncology Research Center, Sheba Medical Center, Israel

The talk will present a theoretical and methodological approach to defining the nature and role of psychological factors as risk factors for cancer diseases. The approach assumes that psychological risk factors are one kind of risk factors functioning in the presence of other kinds of risk factors affecting the chances for the occurrence and course of disease in the presence of a pathogen which is of a physical nature. A psychological methodology based on the cognitive orientation theory will be described for identifying relevant psychological risk factors for diseases and validating them. These factors are beliefs of four kinds (about oneself, about others and reality, about rules and norms, and about goals and wishes) referring to particular individually-shaped meanings. Two studies will be presented, one describing the cognitive orientation cluster characteristic of breast cancer, the other describing the impact of a cognitive orientation cluster on the duration of disease-free interval in three cancer diagnoses.

Shulamith Kreitler is a full professor of psychology at Tel Aviv University since 1986, and has worked at Princeton, Harvard and Yale Universities. She is a certified clinical psychologist and health psychologist. She has established (in 1993) the unit of psychooncology at the Tel Aviv Medical Center and (in 2007) the Center for Psychooncology Research at the Sheba Medical Center, Tel-Hashomer and functions as its director. Her major publications are in cognition, personality, and psychooncology. She has developed a new approach to meaning, and for predicting and changing psychological risk factors for chronic diseases

Cancer Metastasis and Interctions with Bone Micoenvironment

Razi Vago

Avram and Stella Goldstein-Goren, Department of Biotechnology Engineering, Ben Gurion University of the Negev, Israel

Solid cancers originating in the breast, prostate, and lung tend to metastasize to bone. Once deployed in bone these tumor cells harness this microenvironment, shift to a quiescent mode or initiate a vicious cycle that often leads bone destruction and gain an increased tumorigenicity by mechanisms which are not yet fully understood. Here we introduce a new three-dimensional model which closely resembles a living natural bone that can be used to study cellular and molecular cues in bone tumors and metastasis. Using this model we showed that the mineral phase may have an important role on cellular characteristics of mesenchymal stem cells (MSCʼs) and toumor cells. We also revealed that interactions with MSCʼs increased migration and invasion capacities along with fibrosarcomas (FS) and osteosarcomas (OS) proliferation. Moreover, we showed that via regulation of pathways such Wnt, cadherins, Notch and their downstream target genes such as c-Myc, these capacities were further enhanced when accommodated with the bone like biolattice and directly interacted with the MSCs. We also suggest that progression in OS aggressiveness can also can be attributed to a transition in Wnt signaling from canonical to noncanonical pathways, which is intensified in presence of MSCs. We suggest these kind of tumor promoting interactions may be found in the natural and tumorigenic bone microenvironment. New insights on the interplay between these signaling cues and their effects tumor progression will be discussed. A better understanding of the molecular signaling mechanisms involved in the tumor development and bone metastasis may contribute to development of new cancer therapies.

Prof. Vago earned his Ph.D. from the Department of Life Science, Bar-Ilan University. He was later gained an Australian Institute of Marine Science Post Doctoral Fellow award. In 2000 he took a part in the foundation of the Department Biotechnology Engineering at Ben-Gurion University. He is a recipient of the Koret Foundation Grant Award for 1998 and 1999, and the Israeli Ministry of Science Grant Award and fellowship (1999-2000). In last six years Prof. Vago is the Head of the Avram and Stella Goldstain-Goren Department of Biotechnology Engineering. The research in his laboratory combines bioengineering and basic approaches for studying biology and bioengineering of mesenchymal stem cells on one hand and their role in development and metastasis of cancer on the other.