Department of Medicine, Division of Oncology, Stanford University, USA
Tumor-targeting monoclonal antibody (mAb) therapy has changed the natural history of patients with B cell lymphomas, breast cancer, and colorectal and head and neck cancers, respectively. Despite their promise, response rates are suboptimal at less than 25%, highlighting the need to enhance mAb activity. Natural killer (NK) cells are important effector cells mediating antibody dependent cell-mediated cytotoxicity (ADCC), a primary antitumor mechanism of action of mAbs. Approaches that specifically augment NK cell function can thus complement and enhance mAb therapy. The costimulatory molecule CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to tumor cells bound by their tumor-targeting mAb, including rituximab-coated-CD20-expressing lymphoma, trastuzumab-coated, HER2-expressing breast cancer, and cetuximab-coated, EGFR-expressing head and neck and colorectal cancercell lines. Furthermore, activation of CD137 with an agonistic mAb(anti-CD137) enhanced NK cell degranulation and cytotoxicity. In multiple murine syngeneic and xenograft models, combined tumor-targeting mAband anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving mAb therapy, the level of CD137 on circulating NK cells increased post mAb infusions. This sequential antibody strategy, combining a tumor-targeting mAb with anti-CD137 to activate the host innate immune system, may improve the therapeutic effects of tumor-targeting mAbs and is now being investigated in clinical trials.
Biography:
Dr. Amani Makkouk is a postdoctoral fellow in Dr. Holbrook Kohrtʼs lab at Stanford University. She studies novel strategies to potentiate the immune responses of tumor-targeting monoclonal antibodies through immunomodulation of natural killer cells. Dr. Makkouk was trained as a pharmacist and has a Masters degree in microbiology and immunology and a Masters degree in health physics. She obtained her PhD in immunology from the University of Iowa under the mentorship of Dr. George Weiner. Her doctoral thesis focused on devising a framework for combining agents for in situ immunization using biodegradable microparticles and immunomodulatory antibodies.
Verschuren Centre, Cape Breton University, Canada
Recent advances in nanotechnologies have generated revolutionary impact on modern drug delivery and cancer treatment. Due to the complexity of cancers, multifunctional drug delivery platform that combines the advanced properties of different materials for combinatory treatment are highly demanded. However, these platforms are difficult to be built-up because the materials and therapeutic agents often have diverse properties.
Herein, I will report the progress we have made in designing and fabrication of multifunctional nano- and micro-drug delivery systems (DDSs). For the micro-DDSs, the microfluidic emulsion droplet technique was employed to fabricate microparticle platforms containing DNA structures for gene delivery, gold nanorods for photothermal treatment, and magnetic nanoparticles for imaging. For nanoparticle platforms, multiple chemotherapeutics such as doxorubicin and cisplatin were encapsulated in liposome/gold nano-shells. DNA aptamers were attached to the nanoshell surfaces to stabilize the particles and target the cancer cells. These platforms were tested in cellular models to demonstrate their efficacy in targeted drug delivery, photothermal release, and radiation enhancement.
Biography:
As Research Chair in Applied Nanotechnology in Verschuren Centre at Cape Breton University, Dr. Shine (Xu) Zhang developing and applying nanotechnology to address the emerging healthand environmental issues. His research focuses on interfacing biomolecules to various nanostructured materials for cancer diagnostics and treatment. Dr. Zhang graduated from the University of Waterloo with a PhD degree in Chemistry. He finished his postdoctoral training in nanotechnology at Waterloo Institute for Nanotechnology and the School of Engineering and Applied Science at Harvard University.
1School of Biotechnology, JiangNan University, China
2School of Science, JiangNan University, China
Breast cancer is highly heterogeneous. The subtypes defined using immunohistochemistry markers and gene expression profilings (GEP) are related but not equivalent, with inter-connections under investigated. We revealed a set of diff-genes, containing 1015 mRNAs and 69 miRNAs, which characterize the immunohistochemistry-defined breast tumor subtypes at the GEP level. We further reduced the dimension of this gene set to remove redundancy or noisy information. Using hierarchical clustering and nearest-to-center principle, we identified 119 mRNAs and 20 miRNAs best explaining breast tumor heterogeneity with the most succinct number of genes. The final signature panelcontains the 119 mRNAs, whose superiority over diff-genes was replicated in two independent public datasets. The comparison of our signature with two pioneering signatures, the Sorlieʼssignature and PAM50, suggests a novel marker, FOXA1, in breast cancer classification. Subtype-specific feature genes are reported to characterize each immunohistochemistry-defined subgroup. Pathway and network analysis reveal the critical roles of Notch signalings in [ER+|PR+] HER2- and cell cycle in [ER+|PR+]HER2+ tumors. Our study reveals the primary differences among the four immunohistochemistry-defined breast tumors at the mRNA and miRNA expression levels, and proposes a novel signature for breast tumor subtyping given gene expression data.
Biography:
Dr. Xiaofeng Dai, Ph.D., now is an Associate Professor at the National Engineering Laboratory for Cereal Fermentation Technology, School of Biotechnology, JiangNan University, China. She has master degrees both in Molecular Biology and Bioinformatics, and two doctoral degrees, one in Computational System Biology, and one in Quantitative Methods in Economics. Currently Dr. Daiʼ researches focus on breast cancer subtyping and heterogeneity, cancer stem cell signaling network and its association with immune response in basal breast cancer. She has published 15 SCI papers as the first author in reputed journals.
Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, China
The combination of dendritic cells (DCs) with cytokine-induced killer cells (CIKs) can induce the anti-tumor immune response and radiotherapy may promote the activity. The purpose of this study is to explore the efficacy of DCs/CIKs combined with thoracic radiotherapy (TRT) for patients with advanced non-small-cell lung cancer (NSCLC). The eligibility criteria were as follows: at least 18 years of age; a life expectancy of more than 3 months; performance status (PS) 0-2; ≥2 cycles of previous chemotherapy and at least one measurable lesion. In control group, TRT alone was given at 2 Gy per fraction, 5 fractions per week to a total dose of 60-66 Gy. In treatment group, in addition to the TRT regimens mentioned above, patients received a weekly autologous DC injection for four successive weeks starting from the 6th fraction of irradiation, and CIK infusion for four continuous days from day 11. Finally, 82 patients with advanced NSCLC from 2012–2014 were enrolled, with 21 in treatment group and 61 in control group. There was no significant difference in the gender, age, clinical stage and the total dose of radiotherapy between the two groups (P > 0.05). The median progress-free survival (mPFS) in treatment group was longer than in control group (330 days vs 233 days, hazard ratio 0.51, 95% CI 0.27-1.0, P < 0.05), and the objective response rate (ORR) of treatment group (47.6%) was significantly higher compared with control group (24.6%, P < 0.05). There was no significant difference in disease control rate (DCR) and median overall survival (mOS) between the two groups (P > 0.05). The side effects in treatment group were mild and there were not any treatment-related deaths. In conclusion, DCs/CIKs combined TRT had higher response rate and significant improvement in PFS compared with TRT alone in advanced NSCLC.
Biography:
Jian-Guo Sun received his PhD in oncology in 2004 from Third Military Medical University, China. He was a visiting scholar in the Department of Radiation Oncology, Stanford University. He has been a physician and an oncology researcher and published more than 20 articles in international journals. His current research focuses on the radio resistance and re-growth of lung cancer cells after radiation.
1Department of Otorhinolaryngology-Head&Neck Surgery, Zagazig University, Egypt
2Department of Surgery, Faculty of Medicine, Zagazig University, Egypt
3Department of Surgery, National Cancer Institute, Egypt
4Department of Vascular and Reconstructive Surgery, National Cancer Institute, Egypt
This study aimed to evaluate the operative outcomes of using gastric pull-up (GPU), pectoralis major myocutaneous flap (PMMF), and jejunal free flap (JFF) to reconstruct the hypopharynx after resection of hypopharyngeal and cervical esophageal carcinoma.
Patients and Methods: Records of 104 patients who underwent resection of carcinoma of the hypopharynx and cervical esophagus were reviewed to determine the indications for radical resection, location, and stage of the primary tumor, gross and pathological surgical resection margins, operative complications, morbidity, and mortality. Reconstruction was performed using the GPU for group (1) (n = 33), PMMF for group (2) (n = 34), and JFF for group (3) (n = 37).
Results: The hypopharynx was the most common primary tumor site for group (2) and group (3) whereas group (1) had lesions more frequently in the cervical esophagus. The overall postoperative morbidity rate was 20.2 % with a perioperative mortality rate of 6.7 % and there was no significant difference between the three groups. There was no graft necrosis in group (1) compared to 5.9 % in group (2) and 5.4 % in group (3). Pulmonary complications occurred commonly (30.3 %) in group (1) compared to 11.8 % in group (2) and 10.8 % in group (3) The overall 3 years survival rate was 67.3 % and there was no significant difference between the three groups.
Conclusion: The outcomes of the three techniques are equally successful when used appropriately. The nature of the defect indicates the method of reconstruction. For short reconstruction above the thoracic inlet, PMMF or JFF are equally effective and in tumors requiring total esophagectomy, GPA is indicated.
Biography:
Professor Alaa Eldin Elfeky is a professor of Otorhinolaryngology and Head&Neck surgery, Faculty of Medicine, Zagazig University, Egypt. He obtained his MD in ORL-HNS from the University of Zagazig, Egypt in 1990. Prof. Elfeky is the main supervisor for more than 50 theses of Master and Doctor Degree. He was in the board of evaluation of more than 50 theses of Master and Doctor Degree in all Universities of Egypt. He is in the board of Egyptian Society of Surgical Oncology since 2000 and he is the president of Delta Society of Otorhinolaryngology-Head and Neck Surgery, Egypt since 2010. He wrote a book of “Essentials of Otorhinolaryngology” in 1997. He is a member of the Egyptian promotion committee for professors and assistant professors since 2013. He is the founder and senior of the Head and Neck Surgery Unit in ORL Department Zagazig University since 2000.
1IRST-IRCCS, Italy
2University of Ancona Italy
3University of Cagliari, Italy
4University of Modena, Italy
We evaluated a systemic immune-inflammation index (SII) based on lymphocyte, neutrophil and platelet counts and explored its prognostic value in patients with advanced hepatocellular carcinoma treated with sorafenib. Neutrophils promote the secretion of circulating growth factors such as VEGF and proteases, while lymphocytes play a crucial role in tumor defense by inducing cytotoxic cell death and inhibiting tumor cell proliferation and migration, thereby dictating the hostʼs immune response to malignancy. Several inflammation and immune-based prognostic scores have been developed to predict survival and recurrence, e.g. lymphocyte count, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio.
Experimental Design: Ninety-seven patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib were available for our analysis. Lymphocyte, neutrophil and platelet counts were measured before the beginning of treatment. Prediction accuracy was evaluated by receiver operating characteristic analysis (ROC).
Results: An optimal cutoff of 360 for the SII stratified patients into high (≥360) or low SII (<360) groups in the training cohort. Univariate and multivariate analyses revealed that SII was an independent predictor of overall survival and relapse-free survival, and a prognostic marker for advanced HCC patients treated with sorafenib. Patients with SII < 360 had a better outcome than those with SII > 360; median PFS 3.9 months (95%CI 2.8-6.2) vs. 2.6 months (95%CI 1.8-3.3) (p 0.026) and median OS 13.9 months (95%CI 5.7-22.8) vs. 5.6 months (95%CI 3.2-10.4) (p=0.024), respectively.
Conclusion: In our study, the SII was a powerful prognostic indicator of poor outcome in patients with advanced HCC treated with sorafenib. The fact that it is calculated from the results of a routine blood test makes it a potentially useful strategy to assess prognosis in patients with advanced HCC.
School of Nutritional Sciences Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel
Obesity is a key risk factor for the development of colon cancer; however, the endocrine/paracrine/metabolic networks mediating this connection are poorly understood. Our goal was to explore the metabolic networks and molecular signaling pathways linking obesity, adipose tissue and colon cancer. Using in-vivo experiments, we found that mice fed a high-fat diet (HFD) and injected with MC38 colon cancer cells develop significantly larger tumors than their counterparts fed a normal diet. In in vitro assays, human colon cancer cells were exposed to conditioned media (CM) from cultured human adipose tissue fragments of obese vs. non-obese subjects. Oxygen consumption rate (OCR, =mitochondrial respiration) and extracellular acidification rate (ECAR, =glycolytic respiration) were examined vis-à-vis cell viability and expression of related genes and proteins. CM from obese (vs. non-obese) subjects decreased OCR and gene expression of mitochondrial proteins without affecting cell viability or expression of glycolytic enzymes. Similar changes could be recapitulated by incubating cells with leptin, whereas, leptin-receptor specific antagonist inhibited the reduced OCR induced by conditioned media from obese subjects.
Additional in vitro experiments, murine colon cancer cells exposed to CM from the adipose tissue of HFD-fed mice demonstrated significantly lower OCR. In addition, these colon cancer cells exposed to CM prepared from the visceral fat of HFD-fed mice or to leptin showed downregulated expression of mitochondrial genes. Additionally, we found a close link between the fat adipose tissue and cancer development and demonstrated that this effect is mediated by the JNK/STAT3-signaling pathway. We conclude that obese adipose tissue alters the metabolic networks of colon cancer cells, impinging directly on their metabolism and malignant stage. These results highlight a putative novel mechanism for obesity-associated risk of gastrointestinal malignancies, and suggest potential new therapeutic avenues.
Biography:
Betty Schwartz is a full professor in the School of Nutritional Sciences Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment at The Hebrew University of Jerusalem, Israel. Cancer is one of the leading causes of death in the Western world including Israel. The role of diet in modulating cancer risk is a well-accepted concept, and natural compounds which have been proven safe over time and easily accessible through the diet represent ideal candidates as chemopreventive agents for the effective reduction of cancer-related morbidity and mortality. Her laboratory has searched for numerous agents present in foods that can act as chemopreventive agents and exert their activity on multiple signal transduction, transcriptional regulation and activation of several apoptotic cascades in various tumor cells and animal models of colorectal cancer or associated colon cancer (induced by inflammation of the bowel). Natural agents such as lycopene, isoflavones, allicin, omega-3 fatty acids, glucans, specific proteins etc. have been shown by us to possess chemopreventive potential. Her personal and collaborative research utilizes molecular and chemical biology approaches, including in vivo animal and even human studies to ask well as hypothesis-driven strategies, to interrogate cancer biology, identify and validate new cancer targets, discover and develop chemical, molecular tools to identify nutrients acting on these targets, identify predictive and mechanism of action.
Second Military Medical University, China
Background: The benefit of adjuvant therapy (AT) for gallbladder cancer (GBC) is unclearas evidenced by conflicting results from nonrandomized studies. Here we aimed to perform a meta-analysis to determine the impact of AT on overall survival (OS).
Methods: We used data from MEDLINE, EMBASE and the Cochrane Collaboration Library and published between October 1967 and October 2014. Studiesthat evaluated AT compared with curative-intent surgery alone for resected GBC were included. Subgroup analyses of benefit based on node status, margins status, and American Joint Committee on Cancer (AJCC) staging were prespecified. Data were weighted and pooled using random-effect modeling.
Results: Ten retrospective studies involving 3,191 patients were analyzed. There was a nonsignificant improvement inOS with AT compared with surgery alone (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.56–1.03). A significant improvement was observed in OS with chemotherapy (CT) compared with surgery alone (HR, 0.42; 95% CI, 0.22–0.80) by sensitivity analysis. The greatest benefit for AT was also observed in those with R1 disease (HR, 0.33; 95% CI, 0.19–0.59), LN-positive disease (HR, 0.71; 95% CI, 0.63–0.81), and AJCC staging meeting or exceeding tumor Stage II(HR, 0.45; 95% CI, 0.26–0.79), but not in those with LN-negative or R0 disease.
Conclusion: Our results strongly support the use of CT as an AT in GBC. Moreover, patients with node positivity, margin positivity, or non–stage I disease are more likely to benefit from AT.
Biography:
Bin Wang has graduated from Chinese PLA Second Military Medical University and received M.D. He is an attending physician of department of oncology, Changhai Hospital, the Second Military Medical University of China. He is also a China GCP alliance youth committee member. His major interest is in diagnosis and treatment of malignancy. His research area is mainly in basic and clinical of tumor immunity. He is also in charge of a basic research of China National Natural Science Foundation on immune therapy of breast cancer (NO. 81472479).
Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, South Africa
Traditional plant based system of medicine or herbal medicine is an important part of the health care system in most of the countries. Rubus is one of the important genera with significant pharmacological activities. Aim of this study is to focus the importance of Rubus fairholmianus in the pharmaceutical industry for the development of cost-effective drugs for cancer treatment. The in vivo antitumor, pharmacological and antioxidant properties of this plant encouraged authors to study the in vitro anticancer activities. Morphological examination of MCF-7 cells after 24 h treatment with Rubus fairholmianus methanolic sub-fraction (RFM) was observed by inverted microscopy. The cell viability was determined by trypan blue dye exclusion assay. The CellTiter-Glo1 luminescent ATP assay carried out to estimate the proliferation rates by measuring cellular ATP levels. The release of LDH is a measure of cell membrane damage to the cells after RFM treatment and it was measured by CytoTox961 Assay. The Annexin V-FITC apoptosis detection kit was used to distinguish the apoptotic and non-apoptotic cells using flow cytometry. The morphological features of RFM treated cells showed the decreased cell numbers and induction of apoptosis. The viability of treated cells decreased considerably in a dose dependant manner. Viability of untreated cells was 95.8% whereas the treated cells showed 80.52, 71.98 and 56.72% for 5, 10 and 20 µg/ml, concentrations. The increased ATP level of untreated cells depicts the higher energetic level. The RFM treated cells resulted a substantial decrease (p<0.001) in cellular proliferation. The treatments activated a higher release of LDH and showed an increase in LDH levels significantly. The population of apoptotic cells increased with increase in concentration of RFM. The RFM treated cells showed an increase in the percentages of early and late apoptotic cells. The non-apoptotic or necrotic cells concentration in the treated groups found to be very low. In the untreated groups; the population of early and late apoptotic cells were less. When MCF-7 cells were treated with RFM, the apoptotic population increased concurrently and induced a decrease in the viable cell (Annexin V-/PI-) population. This is the first evidence about the in vitro antiproliferative activity of RFM on MCF-7 human breast cancer cells. Further work is wanted to characterise the bioactive compounds responsible for the cell death. Due to the apoptosis inducing properties of this extract, it can be considered as an effective adjuvant therapeutic agent after the clinical trials.
Biography:
Dr. Blassan P George is a postdoctoral research fellow, doing research in photodynamic therapy of cancer at Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, South Africa since July 2014 under the supervision of Prof. Heidi Abrahamse. His interests include phyto-pharmacological evaluation of berries collected from Western Ghats with special reference to cancer. He has completed the anticancer activities of Rubus species in breast, colorectal, lung cancer and melanoma cells and the results have been published and presented in international accredited journals and conferences. Currently he engaged in testing the phototoxic activities of Rubus extracts and the coupled phthalocyanine photosensitizers on breast cancer cells. He received PhD degree in Biotechnology from Bharathiar University, India.
Department of Radiation Oncology, Amrita Institute of Medical Sciences, Kerala
Introduction: Head and neck malignancies account for about 30% of all malignancies in India. Treatment of head and neck malignancies has always been challenging and radiation remains the mainstay, be it in primary, adjuvant or palliative settings. Sophisticated aggressive approaches have translated to acceptable loco-regional controls, but loco-regional recurrences and second malignancies in the treated areas are also on the increase, the incidence being 30%-50% and 20% respectively. This poses a further challenge and the armamentarium includes surgery, chemotherapeutic agents, targeted therapies and also reirradiation. Advanced state-of-the-art technologies in the field of re-radiation have shown a ray of hope in the otherwise bleak scenario.
Aim: Analysis of patients treated with re-radiation was done with a view to look into clinical outcome and toxicity profile in recurrent and second primary malignancies in head and neck region.
Materials and Methods: Data of patients re-irradiated were retrieved form the electronic medical records and planning systems and was analysed. Factors like, site, stage of disease, intent and technique of treatment, gross tumour volume, cumulative dose achieved, interval between treatments, toxicities and details of hospitalization were looked into.
Results: Re-radiation was offered either as a radical or as an adjuvant option. Both intensity modulated radiotherapy and 3 dimensional conformal radiotherapy, were used. Median cumulative dose achieved was 116 Gy. Major acute toxicity encountered was grade III mucositis. Acute myelo-toxicities were not observed. Age, performance status and interval between initial and reradiation were found to be important prognostic factors influencing overall survival and treatment related morbidity.
Conclusion: Advent of modern techniques has made re-irradiation technically feasible, achieving predictable loco-regional control and overall survival with acceptable toxicity profiles, as proved by GORTEC trials. Though long term follow-up data is wanting, re-irradiation is a viable option in selected patients and requires dedicated and diligent care.
Biography:
Dr. Chelakkot Govindalayathil Prameela completed her post-graduation in Radiation Oncology from Manipal Academy of Higher Education, India. She has 17 years of experience as Radiation Oncologist. She presently is an Associate Professor, in the Department of Radiation Oncology, at Amrita Institute of Medical Sciences, Kochi, Kerala, India. She is interested in Head and Neck and thoracic oncology and Female health care. She has international and national presentations on breast, stomach, vagina, and head and neck malignancies. She is involved in works on androgen receptors in breast cancer, dysphagia aspiration-related structures in head and neck radiation, and in gynaecological malignancies.
1Leibniz Institute of Age Research, Fritz Lipmann Institute, Germany
2Institute of Neural Information Processing, Ulm University, Germany
3Department of Gastroenterology, Ulm University, Germany
4Department of Urology, Ulm University, Germany
In humans and mice, most autosomal monosomies and trisomies are not compatible with organismal survival. It was shown that aneuploidy impairs cellular proliferation, survival, and spontaneous immortalization. In contrast, aneuploidy is a hallmark of cancer cells indicating that aneuploidy survival mechanisms must exist in cancer cells. We used a genome-wide, stable iRNA screening and identified a large set of gene knockdowns with a novel role in aneuploidy induction strongly associating with recurrent gene mutations in human cancers. In mouse hematopoietic stem cells in vivo and in primary human cell cultures, aneuploidy inducing gene knockdowns result in telomere replication stress, premature senescence, or stem cell depletion. These aneuploidy-induced checkpoints were abrogated by endogenous expression of telomerase in stem cells and by up-regulating telomerase in primary human cells. We show, that aneuploidy inducing gene knockdowns replace the requirement of iatrogenic introduction of oncogenic Ras for the malignant transformation of human cells. Current studies focus on elucidating the mechanisms that induce telomere replication stress in response to aneuploidy and the mechanism how telomerase suppresses aneuploidy-induced senescence.
Center for Complexity & Biosystems and Department of Bioscience, University of Milan, Italy
Cancer progression in humans is difficult to infer because we do not routinely sample patients at multiple stages of their disease. The identification of cancer stem cell (CSC) subpopulations inside tumors opens a new perspective on cancer development, since it implies that tumors can only be eradicated by targeting CSCs. Several markers have been proposed in the literature to identify CSCs both in breast and melanoma but no consensus has been reached, leading to the hypothesis that the CSC phenotype might be dynamically switched. Herein we provide quantitative evidence of CSCs in melanoma discussing the complex network regulating their biological functions.
Biography:
Caterina La Porta is a Research associate professor of General Pathology at University of Milan, visiting scientist in many university and institutes, she is group leader of the Molecular Oncology Laboratory at the University of Milan and co-founder of the Center for Complexity & Biosystems at the same University. The focus of her group is to understand cancer progression and related mechanical properties. The group is also investigating the mechanisms underlining neurodegenerative pathologies.
1The Swiss Institute for Experimental Cancer Research (ISREC), Switzerland
2The Institute of Chemical Sciences & Engineering (ISIC-SB-EPFL), Switzerland
3Department of Molecular, Cell and Developmental Biology; University of California, USA
4The Swiss Cancer Center Lausanne (SCCL), Swiss Federal Institute of Technology Lausanne, Switzerland
Although anti-angiogenic therapy has demonstrable efficacy in mouse models of cancer and in certain types of human cancer, responses are typically transitory, followed by resumption of malignant progression that limits survival benefit. Unconventional modes of evasive/adaptive resistance underlay the eventual failures of anti-angiogenic therapy. Functionally established resistance mechanisms include revascularization mediated by alternative pro-angiogenic signals, protection by peri-vascular macrophages and monocytes, and normal vessel cooption via heightened local invasion and distant metastasis. All three mechanisms have been documented in the prototypical RIP-Tag2 mouse model of multistep tumorigenesis, in which the angiogenic switch is a discrete step in the pathway to invasive pancreatic neuroendocrine cancer. New results to be presented identify a fourth mode of adaptive resistance to potent anti-angiogenic therapy in this model: metabolic adaptation, whereby cancer cells adopt distinctive metabolic states, such that they can be alternatively fueled by glucose or lactate, in a form of metabolic symbiosis.
Biography:
Elizabeth Allen received a BS in biology, and an MS/PhD in Human Genetics at the University of Michigan. She worked as part of the Sharpiroʼs team that cloned the steroid sulfatase gene, and performed structure-function studies of the in von Willebrand Factor protein in the Ginsburg lab. Her postdoctoral research in the Fuchs lab involved engineering mouse models with desmosomal mutations in order to potentially identify associated human skin diseases. She became a staff scientist at Stanford University, where she worked with the Yang lab to help identify the role of the proteasome in Giant Axonal Neuropathy. She joined the Hanahan group at UCSF and EPFL to use mouse PanNET models to investigate the mechanisms of resistance to antiangiogenic therapy.
King Abdulaziz University, Saudi Arabia
Colorectal cancer (CRC) is common worldwide. The high prevalence of the disease raises concerns about how CRC influences the health-related quality of life (QoL). To explore the impact of physiological symptoms and complications of CRC on patientsʼ QoL, we conducted a cross-sectional survey using the FACT-C self-report instrument. The chi-square test was used to compare qualitative data. We found that pain was reported by most of the patients (n = 31; 77.5 %). Furthermore, male patients were more likely to complain of pain “mostly” as compared with females. We found no significant differences between genders regarding general health-related questions. A greater proportion of male patients often complained of abdominal cramps, weight loss, and diarrhea. More than half of the patients (n = 26; 65 %) reported having a good appetite; a greater proportion of males reported having a good appetite “mostly”. Social and psychological qualities of life were not significantly different between male and female patients. Male and female patients did not differ in their report of disease acceptance and ability to enjoy life. No difference was also found between genders regarding contentment with QoL or ability to sleep well. Furthermore, there were no differences between genders regarding job fulfillment. Our results add to the growing body of knowledge about the effect of CRC on QoL. Importantly, the differences in self-reported pain and appetite between male and female patients in our study suggest the importance of gender-based treatments in improving patientsʼ QoL.
Department of Clinical Laboratory, Nanjing Medical University Cancer Hospital & Jiangsu Cancer Hospital, China
The UHRF1 protein is pivotal for DNA methylation and heterochromatin formation, leading to decreased expressions of tumor suppressor genes and contributing to tumorigenesis. However, the factors that modulate UHRF1 expression incolorectal cancer (CRC) remain unclear. Here we showed that, compared with corresponding normal tissues, UHRF1 was upregulated and microRNA-9 (miR-9) was down regulated in CRC tissues. The expression of UHRF1 was inversely correlated with overall survival rates of patients with CRC. Over expression of miR-9 in CRC cell lines significantly attenuated CRC cell proliferation and promoted cell apoptosis. The expression of UHRF1 was markedly reduced in pre-miR-9 transfected CRC cells. Using luciferase reporter assay, we confirmed that miR-9 was a direct upstream regulator of UHRF1. Finally, analysis of miR-9 and UHRF1 levels in human CRC tissues revealed that expression of miR-9 was inversely correlated with UHRF1 expression. Collectively, our results offer in vitro validation of the concept that miR-9 could repress the expression of UHRF1, and function as a tumor-suppressive micro RNA in CRC. It may serve as a prognostic and therapeutic marker for CRC for diagnosis and a gene target for therapy.
Biography:
Feng Yan is the vice director of Department of Clinical Laboratory in Nanjing Medical University Cancer Hospital & Jiangsu Cancer Hospital. The research works focus on the bioanalytical chemistry in laboratory medical diagnostics. She has published more than 42 papers in reputed journals.
Hacettepe University Faculty of Nursing, Turkey
The purpose of this study was to investigate the effect of home care service on the sexual satisfaction of patients with gynecologic cancer. Sexual health and sexual satisfaction was greatly affected in patients with gynecological cancer depending on the disease and its treatments. Prospective randomized case control study. This study was conducted with 70 patients, of whom 35 patients were in the intervention and 35 patients were in the control group. Data were collected using An Interview Questionnaire, Home Visit Monitoring Questionnaire and Golombok Rust Inventory of Sexual Satisfaction. The intervention group patients were provided with the nursing care service through hospital and home visits (1st and 12th weeks) within the framework of a specifically developed nursing care plans. The control group was monitored without any intervention through the hospital routine protocols (1st and 12th weeks). Data were evaluated using Chi square, McNemarʼs, independent t test and one-way ANOVA tests. It was found that, within the 12-week post-discharge monitoring period as compared with the time before treatment, patients within the intervention group (those receiving home care services) experienced fewer sexual problems as compared to the control group (patients not receiving home care services). This study found home care services to be efficient in improving the sexual health and sexual satisfaction of patients with gynecological cancer.
Biography:
Dr. Fusun Terzioglu graduated in first place from Hacettepe University in 1989. She won the İhsan Dogramacı Superior Merit Award and Science Incentive Award. She earned her pilotʼs license from Republic of Turkey Ministry of Transport. She studied about counselling on assisted reproductive techniques at Liverpool Womenʼs Hospital Reproductive Medicine Unit in United Kingdom on the British Council Research Scholarship. She earned a certificate in management and leadership in nursing. She is an active member of Thematic Network leadership work group. She studied as a research scholar at Kent State University College of Nursing in 2006 for 3 months. In 2007, she worked on a project named “Development of Leadership Skills in Nursing Doctoral Students” at University of Michigan Faculty of Nursing on an international research scholarship which was supported by International Network for Doctoral Education in Nursing (INDEN) and Sigma Theta Tau and provided to only three people around the world every year. She worked as a research assistant at Hacettepe University School of Nursing in the Maternity and Womenʼs Health Nursing Division from 1990 to 1997. She was promoted to assistant professor in 1998, associate professor in 2006 and professor in 2012. She worked as a Co-Head of Nursing Department, Erasmus Department Coordinator, Head of Strategic Planning Group and board member of Hacettepe University Womenʼs Research and Implementation Center (HUWRICH) between 2009 and 2011. Her interest subjects are sexuality and reproductive health and management and leadership. She is member of national and international nurseʼs organizations such as INDEN and Sigma Theta Tau. She has been working as a Director of Nursing Services at Hacettepe University Hospitals since September 2012 and Founding Dean of Faculty of Nursing between 2012-2013. She has published more than 50 papers, 15 grant projects, eight books as an editor and author, and 90 presentations in the national and international congresses. She is also invited speaker in more than 60 congress and symposium.
School of Pharmaceutical Sciences, Tsinghua University, China
Cancer metastasis is the major cause of more than 90% death with tumor related diseases. Therefore, successful clinical cancer treatment is optimal for combination of chemotherapy and immunotherapy. We previously designed and synthesized a conjugate of MDP and paclitaxel that not only retains its cytotoxicity against most tumor cell lines but also has immune enhancing capacity in vitro. Further experiments indicated this conjugate is powerless to prevent metastasis of Lewis lung carcinoma (LLC) in mice, which may be caused by its consistent ability to induce inflammatory cytokines, especially TNF-α(Li et al., Glycoconjugate Journal, 2008, 25: 415–25). Conmutaxol, a conjugate (MTC-220) of paclitaxel and muramyl dipeptideʼs analog, was further demonstrated in mice to prevent both tumor growth via releasing paclitaxel in vivo and tumor metastasis through suppressing myeloid derived suppressor cell accumulation in the spleen and bone marrow of tumor-bearing mice, and repressing inflammatory cytokines in tumor tissue (Ma et al., J. Med. Chem. 2011, 54, 2767–77). Recent studies revealed that Conmutaxol was highly absorbed by tumor tissue of mice and further increased the paclitaxelʼs concentration in murine tumor tissue that degraded from Conmutaxol. Mechanism investigation indicated that Conmutaxol inhibits NOD1 and NOD2 mediated NK-κB and MAPKs signaling in HEK-293 cells, THP-1 cells and human PBMCs-derived macrophages. Compare to paclitaxel, Conmutaxol significantly reduced the serum level of VEGF-D and MCP-1 in tumor bearing mice, which suggests that VEGF-D and MCP-1 may act as direct biomarkers of Conmutaxel treatment. Finally, Conmutaxol was prepared in large scale by a hybrid protocol of solid-phase synthesis of peptide and solution-phase conjugation of peptide and paclitaxel. Conmutaxolis formulated into a pair of bottles, whereas one contains lyophilized 50mg MTC-220 powder and another one fills with 10mL dissolving solvent by using solutol HS15 as a nonionic solubilizer. It is recommended for patient utilization with final 1mg/mL concentration in saline via intravenous injection. Injectable Conmutaxol is currently submitted to China Food and Drug Administration (CFDA) for phase I clinical trial approve.
Biography:
Gang LIU, Ph.D., Professor of Medicinal Chemistry, graduated from Beijing Medical University in 1994. He then moved to Beijing Institute of Pharmacology and Toxicology for his two years postdoctoral fellowship. He joined Dr. Kit Lamʼs lab in University of California at Davis from 1998 to 2000 as postdoctoral fellow and senior scientist. From 2000, he received a full professor position and Chair of department of synthetic medicinal chemistry in Institute of Materia Medica (IMM), Peking Union Medical College (PUMC) until 2011. Since 2011, he took a position of full professor and dept Chair in School of Pharmaceutical Sciences, Tsinghua University. Prof. Gang LIUʼs lab is currently interested in drug discovery and development with phenotype screening technology and novel target identification for cancer treatment and chronic infectious diseases, including HBV, HIV, and mycobacterium tuberculosis.
Council for Scientific and Industrial Research, South Africa
South African plants were evaluated for their anti-cancer properties and plant samples were collected throughout South Africa. Voucher specimensweredeposited and identified at the South African National Biodiversity Institute. Plant extractswere preparedand screened for in vitro anti-cancer activity against a panel of three human cell lines (breast MCF7, renalTK10 and melanoma UACC62) at the Council for Scientific and Industrial Research. Plant extracts that exhibited anti-cancer activity against thesethree human cell lines were screened by the NCI against sixty human cancer cell lines organized intosub-panels representing leukaemia, melanoma, cancer of the lung, colon, kidney, ovary, central nervoussystem, breast and prostate. More than 7500 plant extracts were screened for in vitro anticancer activity over the last 15 years. Hits were classifiedinto four categories based on their total growth inhibition of the cell lines. A hit rate of 5.9% wasobtained for extracts which showed activity and thesewere screened by the NCI against a panelof sixty human cancer cell lines. The extracts of plant species with limited published information for theiranticancer properties were subjected to bioassay-guided fractionation and the active constituents isolated and identified. Although the extracts of the plantswere randomly selected, 68% of these plant species whichwere hits in the screening programme are reported to be used medicinally.
Biography:
Prof. Gerda Fouche has been involved in natural product research for the last eighteen years as Organic Chemist at the Council for Scientific and Industrial Research in South Africa. Experience includes management and collaboration of projects with multi-disciplinary research teams at international and national research institutes, universities, government departments and private companies. The research projects are aimed at the discovery and development of drug/herbal leads from the biodiversity of South Africa. These projects involve scientific validation of medicinal plants, through interactions with owners of indigenous knowledge and purification, isolation and structure elucidation of active constituents from these plants in various therapeutic areas such as asthma, cancer, inflammation, benign prostatic hyperplasia, erectile dysfunction, oxidative stress, Alzheimer etc. She has presented at national and international conferences and workshops and has published more than 30 articles in peer-reviewed journals and has 6 international patents to her credit.
Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), India
Background: Benzo(a)pyrene (B(a)P) is a well-known carcinogen present in an environment. Its main source is tobacco smoke, forest fire and automobile exhaust. Extract of Acacia catechu (L.f.) willd bark has shown various pharmacological properties including anti-inflammatory, antioxidant, anti-lipid peroxidative, anti-hyperglycemic and protect against DNA strand breaks.
Purpose: The purpose of this study was to investigate the protective effects of methanolic extract of the bark of Acacia catechu (L.f.) willd (MEBA) against B(a)P induced oxidative stress, inflammation, and apoptosis.
Study design: Thirty male Swiss albino mice were randomly allocated into five groups having six animals in each group. MEBA was given orally once daily for seven consecutive days at the doses of 200 and 400 mg/kg body weight in the distilled water. On day 7, a single dose of B(a)P was given orally in the corn oil at the dose of 125 mg/kg body weight.
Methods: After 24 hours of last treatment, mice were sacrificed then toxicity markers (lipid peroxidation, lactate dehydrogenase and xanthine oxidase activity), antioxidant enzymes activities (catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase glutathione-S-transferase and quinone reductase) and reduced glutathione content were measured by different methods. Expression of NF-kB, COX-2, TNF-α, p53, Bax, Caspase-3 and bcl-2 were measured by Immunohistochemistry and histopathology also was done.
Results: Pretreatment with MEBA significantly attenuated B(a)P-induced induced lipid peroxidation, lactate dehydrogenase activity, xanthine oxidase activity, glutathione depletion, decrease in antioxidant enzymes (catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase glutathione-S-transferase and quinone reductase) activities. MEBA also attenuated expression of NF-kB, COX-2, TNF-α, p53, Bax, Caspase-3, and bcl-2. Histological results further confirmed the protective role of MEBA against B(a)P-induced lung toxicity.
Conclusion: The data of the present study showed that MEBA successfully suppresses B(a)P induced lungs damage by ameliorating oxidative stress, inflammation, and apoptotic responses.
Biography:
Sarwat Sultana is an Associate Professor in the Department of Medical Elementology & Toxicology at Jamia Hamdard (Hamdard University), India. She has 25 years of research experience in Cancer Biology. Her research specialization is Metabolic basis of chemical carcinogenesis, correlation of alteration in DNA with cancer induction. Targeting the molecular mechanism and elucidation of their plausible role in induction of carcinogenesis. She is a member and life member of several societies of Toxicology. She has 189 papers published in International Journals of high repute.
1Institute of Stem Cell Biology and Regenerative Medicine, Stanford, USA
2Department of Neurosurgery, Division of Pediatric neurosurgery, Stanford, USA
Background: Pediatric brain tumors are the leading cause of morbidity and mortality among pediatric malignancies. Limited current therapeutic approaches as well as their long-lasting side effects are emerging concerns in pediatric neuro-oncology, calling for urgent need to develop new treatments. Blocking CD47- SIRPα interaction using CD47 antibodies has proven to be effective in treatment of various types of cancers though multiple translational studies. Here, we show the efficacy and safety of Humanized anti-CD47 against various types of pediatric brain tumors.
Methods: CD47 expression levels were assessed in freshly isolated surgical tissue and post-mortemsamples from different pediatric brain tumor types: Diffuse Intrinsic Pontine Glioma, Medulloblastoma, Glioblastoma, Oligodendroglioma, Atypical TeratoidRhabdoid Tumor, and Primitive Neuroectodermal Tumor. We assessed blockade of CD47-SIRPα interactions via humanized anti-CD47 monoclonal antibody (huanti-CD47Ab) treatment both in vitro with tumor phagocytosis assays and in vivo with orthotopicxenograft tumor models derived from human primary tumor cells. We next tested the therapeutic dose and antibody penetration through blood brain barrier. Finally, we performed toxicity studies, in vitro and in vivo, to assess the off-target effect of humanized anti-CD47 antibodyon normal neural stem cells.
Results: In vitro studies showed that tumor cells were phagocytized significantly higher by macrophages in the presence of huanti-CD47Ab. Further in vivo studies using patient derived xenograft models revealed significant regression and subsequent durable therapeutic response in treated mice compared to control group. Our safety studies revealed that huanti-CD47Ab selectively target tumor cells with negligible effect on normal neural cells.
Conclusion: Huanti-CD47Ab results in effective therapeutic response infive deadly malignant pediatric brain tumors. Huanti-CD47Ab induced phagocytosis of brain tumor cells by macrophages, and induced tumor regression and prolonged survival in tumor-bearing mice. These results provide important preclinical data in support of Phase I clinical trial of huanti-CD47Ab in the treatment of pediatric patients withsuch malignancies.
Biography:
Sharareh Gholamin is a postdoctoral fellow at Institute of Stem Cell Biology and Regenerative Medicine and Department of Neurosurgery at Stanford University, USA. Over the last four years, she was leading the project, developing humanized anti-CD47 antibody treatment as a potentially safe and effective treatment for patients with pediatric brain tumors. She can confidently say that this study came to be the first and the most comprehensive pre-clinical analysis of a monoclonal antibody, both in safety and efficacy, against various malignant pediatric brain tumors. The study is currently under review in Nature Medicine journal. In continuation of a presented study, her current focus is optimizing combinational immunotherapy approach to treat various pediatric brain tumors in preclinical setting. She do believe that immunotherapy will be a promising move towardfighting various type of cancer and brain tumors, indeed, are not exceptions.
CEO, apceth GmbH & Co. KG, Germany
Autologous gmMSC product Agenmestencel-T shows inherent ability to target tumors and express the therapeutic transgene HSV-TK under the control of the RANTES promoter in situ. Intravenously administered gmMSC migrate to tumors, where the promoter drives HSV-TK enzyme expression. Subsequently prodrug ganciclovir is administered intravenously. In tumors HSV-TK metabolizes ganciclovir to a cytotoxic product, which is taken up by tumor cells via gap junctions.
The phase I/II clinical trial TREAT-ME 1 was designed based on in vivo efficacy data and proof-of-concept in mice. In the completed phase I part, 6 advanced-stage gastrointestinal adenocarcinoma patients were treated: 3 CRC, 2 pancreatic, 1 CCC. gmMSC were administered in a low (3 patients; 0.5x106 cells/kg-BW/week) or a high (3 patients; 106 cells/kg-BW/week) dose per week for 3 weeks, each followed by ganciclovir administration on days 3, 4 and 5.
The treatment was safe and tolerable in all patients. No related adverse or serious adverse events with CTC-AE grade 3-5 toxicity and no signs of clinically significant negative trends were recorded. The results indicate a decline of elevated liver enzymes and cholestasis parameters, due to the liver involvement, in chronological correlation to the therapy. The effect was not sustained after end of the treatment and might require repeated doses. According to RECIST (1.1) 4/6 patients showed stable disease at 3 months follow-up, 2/6 progressive disease. 1/6 was in sustained SD (>5 months). 2/6 patients had stable clinical condition. This is the first reported clinical trial with gmMSC and the first report of MSC application in oncology. It shows that gmMSC are a viable, safe and promising therapeutic modality. The currently running phase II part evaluates the safety, tolerability and efficacy of Agenmestencel-T in 10 patients. A new phase I trial will start in 2016 to evaluate the use of donor-derived allogeneic gmMSC for tumor therapy.
Biography:
Dr. Günther has more than 20 years of experience in clinical hematology and oncology and worked for 6 years as QP, head of quality control and medical director at a public German stem cell/cord blood bank. Here she worked in the field of stem cell and tissue procurement, donor testing, characterization of cell products, and their application to the patient. She was especially involved in the clinical development and licensing of a cord blood product for the use in malignant diseases. In 2008 Dr. Günther joined apceth as the companyʼs managing director.
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