Departments of Oncology and Radiology,
Johns Hopkins University School of Medicine, USA
Further clinical optimization of the dose, route, vaccine composition, and use of immunoadjuvants could greatly benefit from clinical imaging approaches that can interrogate the biological fate of cells repeatedly and non-invasively without the need for obtaining biopsies. By pre-labeling DCs with superparamagnetic iron oxide nanoparticles as an MRI contrast agent, it is not only possible to follow their migration to nearby lymph nodes, but also to verify if the injections have been performed accurately. Surprisingly, in our first clinical DC MRI cell tracking study, we showed that the target lymph node was routinely misinjected in 50% of stage IV melanoma patients.
A different kind of cancer vaccine developed at our institute is GVAX, which consists of lethally irradiated tumor cells engineered to secrete GM-CSF. By pre-labeling GVAX with SPIO, we developed “magnetovaccination” as a novel MRI technique to monitor serially over time DC antigen capture and subsequent homing to draining lymph nodes. Using magneto GVAX and MRI for serially monitoring the afferent arm of the immune response (DCs), and bioluminescent imaging (BLI) for monitoring the efferent arm (T cells), we applied dual-mode imaging to better understand the time course of antigen capture, lymph node delivery, and clonal T cell expansion. Depending on the timing of administration, toll-like-receptor (TLR) agonists either reduced or enhanced antigen capture and delivery to the lymph nodes. The lack of antigen delivery to lymph nodes was consistent with the lack of T cell BLI signal in the lymph nodes. In those cases, a massive extranodal T cell proliferation occurred in the liver and spleen. Our studies show how dual-mode imaging can be used to evaluate and optimize combinatorial cancer vaccines.
Biography:
Dr. Jeff W. M. Bulte is a Professor in the Johns Hopkins Departments of Radiology, Oncology, Biomedical Engineering, and Chemical & Biomolecular Engineering. He serves as the Director of Cellular Imaging at the Johns Hopkins Institute for Cell Engineering. He specializes in molecular and cellular imaging.
Dr. Bulte has pioneered methods to label cells magnetically, making them visible by magnetic resonance imaging (MRI). His team is developing MRI cell tracking techniques, reporter genes and immunoprotective semi-permeable microcapsules detectable by MRI, computed tomography, ultrasound, and bioluminescent imaging.
Dr. Bulte received his undergraduate degree in biology and masters in medical biology from the Free University of Amsterdam in The Netherlands. He earned his Ph.D. in medicine summa cum laude from the University of Groningen in the Netherlands in 1991. He subsequently spent 10 years with the National Institutes of Health, first as a postdoctoral fellow and then a staff scientist in the Laboratory of Diagnostic Radiology Research. Dr. Bulte joined the Johns Hopkins faculty as an Assistant Professor in 2001, became an Associate Professor in 2002, and a Professor in 2006.
1Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, USA
23J Biotech, Beijing, P. R. China
3California Nanosystems Institute, University of California at Los Angeles, USA
4Cancer Institute, Chinese Academy of Medical Sciences, P. R. China
5Department of Chemistry, University of California at Los Angeles, USA
6Department of Biomedical Engineering, School of Engineering, University of California at Los Angeles, USA
7Department of Integrative Biology and Physiology, University of California at Los Angeles, USA
The hallmark of cancer is the invasive and metastatic nature of the disease. Cancer cell invasion and metastasis are partly regulated by altered cytoskeletal structures that result from the complex interplay of activation/inactivation of multiple signaling pathways regulating these cellular events, which can occur at either the genetic or epigenetic level. Thus, attempts to accurately assess these physiologically relevant mechanical properties of cancer cells using single, or even multiple marker profiles at the DNA, RNA, or protein level, may not be effective. Recently we showed that cancer cell mechanical properties, or mechanotypic biomarkers, including cell elasticity and deformability can be directly and accurately measured by state of the art, label-free technologies at the single cell level. These mechanical properties of cells can be a marker for cancer cell behavior including invasion, metastasis, and drug response. We developed an approach that uses mechanotypic profiling to complement morphological and molecular analyses, a process called “Nanocytology” which collectively enable robust and high throughput measurements and can potentially be implemented even in resources poor areas. The nanocytology approach combined with targeted delivery of nanoparticles with molecular-tailored anti-cancer agents may provide a more effective alternative for cancer detection and management.
Biography:
Dr. Rao is a tenured full professor of pathology and epidemiology at University of California at Los Angeles (UCLA). He is the chief of Cytopathology, the ex-director of gynecological pathology, the director of international telepathology, and the medical director of cytotechnology school. He is a fellow of College of American Pathologist (FCAP), Fellow of Academy of Translational Medicine (FacdTM), Member of Jonsson Comprehensive Cancer Center, a Member of California Nanosystem Institute, aGuangji Scholar and visiting professor at Zhejiang University, and elected-recipient of Thousand-Talent Program, China. He has over 150 peer-reviewed publicationsand been a speaker for over 150 meetings and occasions locally, nationally and internationally for variety topics including cancer biomarkers, screen and prevention, cytology, pathology, and nanotechnology. His notable accomplishments include established the first-ever international Telepathology program, investigated mechanisms of cytoskeletal actin remodeling in cancer development and progression, and studied cellular nano-mechanical profiling as a biomarker for cancer.
Hollings Cancer Center/Medical University of South Carolina, USA
In response to oncogenic insult, human cells were induced to express a family of MHC I-chain related molecules A and B (MICA and MICB, generally termed MIC) on the surface which serve as the ligands for the activating immune receptor NKG2D expressed by all human NK, CD8 T, NKT, and subsets of gδ T cells. Theoretically, engagement of NKG2D by tumor cell surface MIC is deemed to signal and provoke the immune system to eliminate transformed cells. Clinically, almost all advanced tumors in cancer patients produce soluble MIC through proteolytic shedding mediated by metalloproteases, or by release in exosomes derived from the cell membrane. Tumor-derived sMIC is known to be highly immune suppressive and profoundly insults the immune system by downregulating receptor NKG2D expression on effector NK and T cells, driving the expansion of tumor-favoring myeloid suppression cells, skewing macrophages into alternatively activated phenotypes, and perturbing NK cell peripheral maintenance. High levels of serum sMIC significantly correlate with advanced diseases of many types of cancer. These observations clearly endorse sMIC to be a cancer immune therapeutic target. However, due to mice lack homologues to human MIC, this concept was not proven until our recent studies. Using a “humanized” MIC-transgenic spontaneous mouse model which recapitulates the NKG2D-mediatedonco-immune dynamics of human cancer patients, we show that neutralizing circulating sMIC with a first-in-field non-blocking antibody B10 that does not block the interaction of MIC with NKG2D revamps endogenous innate and antigen-specific CD8 T cell responses. We show that therapy with the non-blocking sMIC-neutralizing antibody results in effectively debulk of primary tumor and elimination of metastasis, with no observed toxicity. Furthermore, we show that clearing sMIC with the first-in-class neutralizing antibody B10 also enhanced the efficacy of other cancer immunotherapeutic modalities, such as immune checkpoint blockade or adoptive cell-based therapy pre-clinically. Our study has launched a new avenue of cancer immunotherapy which can be readily translated into clinical trials.
Biography:
Dr. Jennifer Wu received her Ph. D from the University of British Columbia and post-doc training at the Fred Hutchinson Cancer Research Center. Later Dr. Wu joined the Faculty of Medicine at the University of Washington and tenured as an Associate Professor. In 2011, she accepted the faculty appointment at the Medical University of South Carolina and became a member of Hollings Cancer Center Cancer Immunology Program. Dr. Wuʼs research focuses on understanding how cancer cells disable the immune system with the ultimate goal to develop effective immunotherapy of cancer. Her work was the first to shown that tumors shed NKG2D ligand sMIC to perturb the maintenance of tumor-killing NK cells and to facilitate tumor metastasis. Her research team then developed a first-in-class sMIC-neutralizing immunostimulatory antibody and subsequently demonstrated that antibody targeting sMIC refuels and revamps endogenous innate and adoptive anti-tumor responses. Her findings were extensively published in Nature, Journal of Clinical investigations, Clinical Cancer Research, Oncotarget, OncoImmunology etc. Dr. Wuʼs research team has continuously received research support from NIH, DOD, and the first-in-field cancer immunology challenge award from Prostate Cancer Foundation. Dr. Wu has served as the elected Chair of Cancer Immunology in the Federation of Clinical Immunology Society, editorial board of an array of cancer immunology-related Journals, and grant review Study Sections at NIH and DOD.
1Vancouver Prostate Centre, Canada
2University of British Columbia, Canada
Prostate cancer is a heterogeneous disease and the major clinical challenge has long been in recognition and targeting of the most aggressive disease. Recently, new classification method for prostate cancer described three novel subtypes, PCS1, PCS2 and PCS3 from which PCS1 was identified as the most aggressive and lethal subtype that correlated with poor survival. However, there are no specific molecular targets or therapeutics available for this subtype in the clinic.
To investigate whether our recently generated castration and Enzalutamide (ENZ) resistant prostate cancer cell line models display any of the newly characterized prostate cancer subtypes, we performed gene expression analyses and analysed the expression of the subset specific genes in our cells. Surprisingly, the results showed that ‘androgen receptor (AR)-indifferentʼ 42DENZR and 42FENZR cells displayed PCS1 signature whereas the AR-driven, ENZ resistant 49BENZR, 49DENZR and 49FENZR cells were categorized as PCR2 subtype. The results were also confirmed by gene set enrichment analyses. These results indicate thatmolecular features in PCS1-like 42DENZR and 42FENZR cells can be utilized to study novel targets and therapeutics for PCS1. Next, we utilized the gene expression data from the PCS1 subtype and PCS1-like cells and identified forkhead box M1 inhibitor Thiostrepton as the most enriched compound reversing all three signatures. These results suggest Thiostrepton as a novel PCS1 targeting agent. Moreover, the results reveal that targeting forkhead box M1 is a potential novel strategy to target the most lethal subtype of prostate cancer.
In conclusion, the results revealed that our AR-indifferent Enzalutamide resistant prostate cancer cells model the most aggressive and lethal prostate cancer subtype PCS1. These results also indicate that elucidating the molecular mechanisms that govern aggressive cell phenotypes, and establishing their importance in prostate disease progression, may guide clinical evaluation of compounds targeting PCS1 subtype associated with ENZ and castration resistant prostate cancer to improve current standard of care.
Biography:
US Department of Defense and Prostate Cancer Canada Fellow Kirsi Ketola, PhD, is a molecular biochemist and prostate cancer researcher at the University of British Columbia and Vancouver Prostate Centre. She has expertise in cancer systems biology, precision medicine and drug discovery and her current research interests include utilizing the ‘knowledge of the omicsʼ in designing novel treatment options for cancer and to repurpose drugs for personalized cancer treatment. Her projects specially focus on the mechanisms of castration and Enzalutamide resistance and development of novel targeted agents for adaptive response to therapy in advanced and lethal prostate cancer. She has published several peer-reviewed publications related to these areas.
The University of Texas MD Anderson Cancer Center, USA
Therapeutic resistance is the primary factor that limits the effectiveness of current therapies for solid tumors. Strategies for overcoming this resistance should readily translate into improved outcomes. This concept is particularly relevant for overcoming resistance to ionizing radiation, which is currently the only potentially curative nonsurgical approach for most solid tumors. Therapeutic delivery of synthetic microRNAs (miRNAs) that mimic endogenous tumor suppressor miRNAs has emerged as a promising approach for treating cancer. MiRNAs target multiple cellular processes and thus in theory can have broader effects beyond current approaches that are limited to targeting single aspects of a cellular pathway. The ability to inhibit oncogenic miRNAs or replace them with tumor suppressor miRNAs may complement traditional treatments such as chemotherapy and radiation. However, the role of miRNAs in mediating resistance to radiotherapy is poorly understood. Therefore, the ultimate goal is to assess the potential applicability of miRNA delivery in combination with radiation therapy. Furthermore, the immune-modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. We previously found that immunomodulatory miRNAs, such as miR-200 and miR-34a, can overcome resistance to radiation. We next generated a preclinical tumor model resistant to radiation and immunotherapy and identified upregulation of miRNAs as an underlying mechanism by which some tumors do not respond to immunotherapy. Our future goal is to validate these findings on our ongoing clinical studies.
Biography:
Maria Angelica received her masterʼs and Ph.D degree from University of Sao Paulo, Brazil, in 2009. She completed part of her thesis at Dr. George Calin laboratory at MD Anderson, where she devoted her thesis to understanding the roles of noncoding RNAs, including microRNAs, in the molecular mechanisms underlying tumor progression. She joined Dr. Welshʼs lab as a postdoctoral fellow in 2011 and was appointed Instructor at the Department of Radiation Oncology in 2015. Dr. Cortezʼs long-term career goal is to discovery novel therapeutic strategies to target immunotherapy resistant lung and breast cancer cells. Her current projects include: 1) understanding the mechanisms by which tumors evade the immune system, and 2) exploring the interaction between radiation and immunotherapies for the treatment of lung cancer.
University of Texas MD Anderson Cancer Center, USA
Lung metastasis constitutes the main cause of death in patients with osteosarcoma (OS). Despite aggressive chemotherapy and successful control of primary tumor, survival has remained stagnant for the past 20 years.
We demonstrated that Fas plays an important role in the metastatic potential of OS. We hypothesized that Fas is an early defense mechanism to clear invading tumor cells to the lung. Constitutive FasL in the lung microenvironment allows Fas positive tumor cells to get cleared while Fas negative cells survive and give rise to the tumor. Treatment of OS lung metastases with aerosol Gemcitabine or liposomal 9-Nitrocamptothecin upregulates Fas expression and causes tumor regression. Blocking the Fas pathway decreases aerosol therapeutic efficacy. In the absence of FasL in the lung, therapeutic effect of aerosolized therapy is completely abolished. These results demonstrate the importance of an intact Fas pathway in the therapeutic efficacy of these agents. A phase I trial of aerosol Gemcitabine will be initiated at MD Anderson.
Despite the significant therapeutic efficacy of aerosolized therapy, a subset of cells failed to respond to GCB resulting in persistent small isolated lung metastases. Autophagy, a catabolic process involved in cellular homeostasis, can either be protective or promote cell death. Our in vitro and in vivo studies demonstrated that autophagyplays a role in OSresponse to GCB. GCB induces autophagy in several different OS cell lines including the human LM7 and CCH-OS-D. Blocking autophagy using Hydroxychloroquine and/or the downregulation of Beclin 1increased the sensitivity of LM7 cells to GCB but decreased the sensitivity of CCH-OS-D cells. This dual role of autophagy has been described in other tumor types. However, predicting whether blocking autophagy will increase or decrease drug-sensitivity has not been described. We found that the induction of phosphorylated heat shock protein 27 (pHsp27) following drug exposure with camptothecin or GCB correlated with the role of autophagy in drug sensitivity. Blocking autophagy in cells whose pHsp27 was increased following chemotherapy resulted in enhanced drug sensitivity whereas blocking autophagy in cells where pHsp27 was decreased resulted in reduced drug sensitivity. In conclusion, induction of pHsp27 following chemotherapy predicts whether blocking autophagy will increase or decrease drug sensitivity.
Understanding the molecular pathways and characteristics that determine how autophagy contributes to drug-induced resistance or responsewill allow translational studies incorporating autophagy inhibitors or autophagy stimulators into specific treatment regimens using either chemotherapy, pathway specific blocking agents or immunotherapy.
Biography:
Dr. Nancy Gordon was born and raised in Caracas, Venezuela. She received her MD title in 1993. In 1995, she moved to the United States. She completed her Residency in Pediatrics at Driscoll Childrenʼs Hospital, Corpus Christi, TX in 2001 and her Hematology/Oncology fellowship at UT MD Anderson Cancer Center in 2005. In 2009 she completed three years of a post-doctoral fellowship. Thereafter she became an Instructor and 6 months later an Assistant Professor. Dr. Gordon is an established investigator at MD Anderson whose main focus has been in understanding the biology of bone tumors, specifically Osteosarcoma and the microenvironment as well as mechanisms implicated in tumor cells resistance to chemotherapy. More recently Dr. Gordon has been studying the process of autophagy and its implications in tumor response to therapy.
1Louisiana State University Health Sciences Center, USA
2Neuroendocrine Tumor Program, Ochsner Medical Center – Kenner, USA
Background: Neuroendocrine tumors (NETs) are rare neoplasms. Our group has treated over 2,000 NET patients and has performed over 1,000 surgical cytoreductive procedures.
Study Design: Records of 834 NET patients who underwent surgical cytoreduction at our institution were reviewed. Demographic information, intraoperative findings, extent of disease, complications, and survival rates werecalculated.
Results: 800 patients underwent 1,001 cytoreductive surgeries. Sixty-five percent had small bowel primaries.138 patients presented with an unknown primary site, which was localized intraoperatively in 89% of these cases. The intraoperative complication rate was 9%. The incidence of intraoperative carcinoid crisis was 1%. Mean operative time was 368 ± 146 minutes. Mean hospital stay was 9 ± 10 days. Minor postoperative complications occurred following 43% of procedures and major postoperative complications were noted after 19% of procedures. The 30-day postoperative mortality rate was 2%. Median overall survival (OS)for pancreatic NETs was 124 months. The 5-, 10- and 20-year OS for pancreatic NETs were 67%, 51% and 36%, respectively. The life expectancy difference [between OS and actuarial survival (AS)] after surgical cytoreduction for pancreatic NETs was 16.6 years. Median OS for small bowel NETs was 161 months. The 5-, 10- and 20-year OS for small bowel NETs were 84%, 67% and 31%, respectively. The life expectancy difference after surgical cytoreduction for small bowel NETs was 11.7 years.
Conclusion:Surgical cytoreduction in NET patients has low morbidity and mortality rates and results in prolonged survival. We believe that surgical cytoreduction should play a major role in the care of patients with NETs.
Biography:
Dr. J. Philip Boudreaux is a Professor of Surgery at Louisiana State University Health Science Center School of Medicine in New Orleans, Louisiana. He attended medical school at LSUHSC – New Orleans and completed his internship at St. Jude Childrenʼs Research Hospital in Memphis, Tennessee. He completed his residency in General Surgery at Charity Hospital in New Orleans and has completed fellowships in Pediatric Surgery and in Organ Transplantation Immunology. Dr. Boudreaux is board certified in Surgery and Surgical Critical Care and holds a specialty certificate in Transplant Immunology. He currently practices at Ochsner Medical Center in Kenner, Louisiana where he has served as chairman of the Department of Surgery since 2009. Dr. Boudreaux was appointed as the Director of Liver, Pancreas, and Kidney Transplant Services at the Transplant Institute of New Orleans in 1997 and has served on the Board of Directors for the Louisiana Organ Procurement Agency since 1990. His group, the New Orleans Louisiana Neuroendocrine Tumor Specialists (NOLANETS), is a multidisciplinary team specializing in the treatment and management of neuroendocrine tumors (NETs). The NOLANETS team has treated over 2,000 NETs patients to date and performed over 1,000 surgical cytoreductions on patients with NETs.
Department of Radiation Oncology, Amrita School of Medicine, Kochi. Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Amrita University, India
Purpose: Radiation therapy to the post mastectomy chest wall is traditionally done with a tangent pair or with a few different energy electrons. We describe our experience in delivering post-mastectomy chest wall radiotherapy using a single electron beam.
Methods: The medical records of patients with breast cancer treated with post-mastectomy radiotherapy from January 2005 to December 2015 were retrospectively analyzed.
Results: A total of 718 patients received adjuvant post-mastectomy radiation therapy. There were 8 male patients. 588 patients (81.9%) had a locally advanced breast cancer (T3-4, any N, M0; or T1-2, N2-3, M0). Of these, 117 patients (19.89%) had had neoadjuvant chemotherapy followed by mastectomy. All patients received radiation therapy to the chest wall using electron energies of 6-12MeV. The most common energy used was 8MeV, prescribed most commonly to the 85% isodose line. All of them received radiation to axilla and supra-clavicular fossa (SCF) as per the institutional protocol. Unless clinically enlarged, the internal mammary chain was not intentionally included in the CTV although the area did receive 40-60% of the prescription dose. 159 patients received hypofractionated radiation therapy according to the START B protocol and the rest were treated with the standard dose of 50Gy in 25 fractions. At the time of analysis, 412 patients were alive with a median follow up of 70.8 months (range 12-130 months). The 5-year local control was 95.5%. The 5-year recurrence rates in the chest wall, supraclavicular node, axilla, and internal mammary chain were 1.7%, 2.1%, 2.8%, and 0%, respectively. Treatment related toxicity was low, with the incidence of symptomatic pneumonitis being 0%. Grade I skin reaction was seen uniformly. Grade II skin reaction rate was 6.3%. Grade I skin changes persisted even on follow up.
Conclusions: Single electron beam radiation therapy can be easily incorporated into clinical practice and is associated with excellent local control and very low toxicity.
Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
The incidence of HCC is much higher in males than in females and the underlying mechanism is thought to be associated with female hormones. However, the role of ERa and ERa36 signaling in hepatocellular carcinoma (HCC) remain largely known. In this study, we examined ERa and ERa36 in three cohorts, which included: (i) primary HCC patients (N = 76, cohort P), (ii) secondary HCC from metastatic colorectal cancer (mCRC) (N = 32, cohort S), and (iii) HCC from The Cancer Genome Atlas (TCGA) (N = 121). Our data showed that WtERa was downregulated and that ERa36 was upregulated in tumor tissues in both cohort P and TCGA data set. ERa36 was downregulated in tumor tissues in cohort S. In cohort P, wtERa was differentially expressed in gender (P< 0.000), age (P= 0.004), tumor number (P= 0.043), tumor size (P=0.002), intrahepatic recurrence (P = 0.054). ERa36 was unequally expressed in different non-tumor liver status (P=0.040). WtERa was negatively associated with overall survival (OS) and disease free survival (DFS) in cohort P. Compared with non-tumor tissues, the expression of ERa36 was increased in primary HCC but decreased in secondary HCC, showing opposite expression patterns of ERa36 between primary HCC and secondary HCC. Collectively, Primary HCC is associated with the decreased WtERa but increased ERa36. The expression pattern of ERa36 is different between primary HCC and secondary HCC, as the former with the increased ERa36 but the latter with the decreased ERa36. Therefore, the expression of ERa36 may be used to differentiate the primary HCC and the secondary one. (Acknowledgement: Jian Zhang, Jianwei Ren, Charing CN Chong, and Paul BS Lai contributed to this study. The study was supported by Direct grant Ref No 4054222 from the Chinese University of Hong Kong).
Biography:
George G Chen is a professor in the Department of Surgery, Director of Surgical Research Laboratories, Faculty of Medicine, the Chinese University of Hong Kong, China. He has extensive experience in cancer research. He has authored or co-authored more than 190 papers and has written a number of books or book chapters.
*President Foundation T. & L. de Beaumont Bonelli for cancer research, Italy
Department of Oncology and Hematology, University Cancer Center, Hamburg, Germany
Lung and bronchus cancers are still one of the most common cancers worldwide, and the estimated numbers of new cases and deaths are more than 2.2 and 1.5 million respectively in the United States in 2013. Despite multi-model treatment strategies, including surgery, radiotherapy, chemotherapy and targeted therapy are used, the death rate of lung cancer is still the first leading cause of cancer-related death both in the World and in the America. The 5-year survival rate of lung cancer, predominantly NSCLC, remains as low as 15%. Therefore, improvements in diagnostics (marker associated with different degrees of malignancy and the consequent clinical behaviour of lung tumors) and treatments are urgently needed. Serological markers such as CEA, NSE (neuron-specific enolase) and Cyfra 21-1 are included in the diagnosis and management of lung cancer, but their diagnostic and prognostic value is still being debated and currently the usefulness of tumor associated antigenic biomarkers in the care of patients with lung cancer is limited. Panel of markers has gained widespread acceptance as a diagnostic test, as a prognostic indicator, or as a monitor of the treatment response. In fact, no useful marker for the screening of asymptomatic patients has been identified to date. Ideally, a biomarker should have one strategy of potentially increase both sensitivity and specificity parameters combining several biomarkers into a prognostic panel. Identification of lung cancer-specific biomarkers, together with other noninvasive methods, may allow for much needed further refinement of lung cancer screening to reduce mortality.
Biography:
Giulio Tarro graduated from Medicine School, Naples University (1962). Research Associate, Division of Virology and Cancer Research, Childrenʼs Hospital (1965-1968), Assistant Professor of Research Pediatrics, College Medicine (1968-1969), Cincinnati University, Ohio. Oncological Virology Professor, Naples University (1972-1985). Chief Division Virology (1973-2003), Head Department Diagnostic Laboratories, (2003-2006). D. Cotugno Hospital for Infectious Diseases, Naples; Emeritus, 2006 -. Since 2007 Chairman Committee of Biotechnologies and VirusSphere, World Academy Biomedical Technologies, UNESCO, Adjunct Professor Department Biology, Temple University, College of Science and Technology, Philadelphia, recipient of the Sbarro Health Research Organization lifetime achievement award (2010). President Foundation de Beaumont Bonelli for Cancer Research. His basic researches have been concerned with antigens induced early during the replication cycle of human herpesviruses. Another study has involved the identification, isolation and characterization of specific virus-induced tumour antigens, which were the “finger-prints” left behind in human cancer. Achievements include patents in field; discovery of Respiratory Syncytial Virus in infant deaths in Naples and of tumor liberated protein as a tumor associated antigen, 55 kilodalton protein overexpressed in lung tumors and other epithelial adenocarcinomas.
International Integrative Medicine, Italy
Thanks to the discoveries of psychoneuroendocrinoimmunology, we now know that every psychological state is mediated by a specific neurochemical condition and every neurochemical change in turn influences psychological status. We can now identify three different levels of neurochemical mediation of the psychological states: neurotransmission, neuromodulation, and the psychoneuromodulation. Neurotransmission is composed of five main neural pathways, noradrenaline, acetylcholine, dopamine, serotonin, and histamine; neuromodulation; and the psychoneuromodulation. We have performed several clinical studies in an attempt to correlate the psychological status of cancer patients with the immune alterations characteristic of the clinical history of neoplastic disease. We have studied the immunologic status by evaluating cytokine blood levels and the lymphocyte subpopulation; the psychological status was assessed by the Ror-schachʼs test; and spiritual status was evaluated by a previously published test to explore spiritual faith. These preliminary psychological studies seem to suggest that a pre-treatment analysis of psychological and spiritual status may predict the efficacy of both chemotherapy and immunotherapy in advanced cancer patients
Biography:
Dr. Giusy Messina was born in 1980. She took her graduate degree (US master equivalent) in Clinical Psychology from the University of Milan (Università degli studi di Milano-Bicocca) in 2004. She is specialized in Psychotherapy from the School of Medicine of the University of Milan. She is working in the clinic with patients and her research area is Psychoneuroendocrinoimmunology (PNEI) and her main research focus is the relation between the psychic condition and the psychoneuroimmunologic of cancer patients using the projective Rorschachʼs test. Dr. Messina is author of more than 100 scientific publications on international and Italian journals. She is enrolled as apprentice in the Psychiatry Clinic of the Major Hospital of Milan (Ospedale Maggiore-Policlinico). She is Associate Member of IPOS (International Psycho-Oncology Society) and of WPA (World Psychiatric Association). She is also a rewiever of Journal of Research in Medical Sciences, Oncology and Tumour. Currently is PhD in Psychology at University of Studies in Bergamo.
Biology Department, College of Science, UAE University, UAE
Liver cancer is the second most common cause of cancer-related death worldwide. Prognosis of liver cancer is usually poor and leads to limited therapeutic options. Therefore, novel approachesto restrainsuch a diseaseare much needed. Saffron and its active constituents were reported to have antioxidant, anti-inflammatory, and anti-tumor properties. The aim of this study was to investigate chemopreventive action of crocin, one of the promising active constituents of saffron, against diethylnitrosamine (DEN)-induced liver cancer in rats, and the possiblemechanisms by which crocin exerts its anti-tumor effects. Findings reported herein demonstrated the anti-proliferative and pro-apoptotic properties of crocin when administrated in DEN-treated rats. Additionally, crocin exhibited anti-inflammatory properties that inhibited NF-kB, among other inflammatory markers. According to our network analysis, NF-kB was identified as a regulatory hub, and therefore, a candidate therapeutic drug target. Together, these findings nominates crocin as a candidate chemopreventive and therapeutic agent against HCC.
Biography:
Amr Amin has completed his PhD at University of Illinois at Chicago, and received a post-doctoral training in the field of molecular genetics at the University of Pennsylvania School of Medicine. He started his academic career at UAE University where he serves now as a Full Professor of Cell Biology. Amrʼs research focuses on ways to control cancer, particularly liver cancer. He published many research articles and reviews and serves as reviewer and as an editorial member of many specialized peer-reviewed journals. He is also a member of many specialized societies and the sole recipient of many national and international scientific awards.
1Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Science, Poland
2Pharmaceutical Research Institute, Poland
Characteristic abnormality in leukemic cells is the blockade at an early stage of their development and failure of differentiation into functional mature cells. Many studies, including those performed in our laboratory confirm that 1,25(OH)2D3 (calcitriol) and its analogue PRI-2191 induce differentiation and inhibits proliferation of leukemia cells. There is considerable body of evidence that leukemia and lymphoma cells can be suitable candidates for chemoprevention or differentiation therapy with vitamin D. Growing evidence suggest that microRNAs have an important role in the development of chemosensitivity or chemoresistance in different types of cancers. This phenomenon take place through miRNAs interaction with messenger RNAs (mRNA) and the transcriptional and post-transcriptional regulation of their expression. The biological actions of calcitriol are mediated by vitamin D receptor (VDR) and its intracellular concentrations is determined by CYP24 enzyme. It is known that VDR is regulated by miR-27b. What more, calcitriol itself influences on miRNA from miR-32 and miR-181 family, which regulates expression of proteins like p21, p27 and Bim responsible for important cell processes. The aim of our work was to study the role of miRNA in anticancer activity of calcitriol and PRI-2191 towards human leukemia and lymphoma cells. In our experiments we identified the expression of miRNA in cell after calcitriol and its analogue treatment. We measured the expression of factors which are responsible for differentiation of cells on mRNA and protein level. We conclude that microRNA (miR-27b, miR-32, miR-181a and miR-181b) may regulates crucial molecules engaged in differentiation process of human leukemia and lymphoma cells after exposure to calcitriol and PRI-2191.
Biography:
Justyna Trynda is PhD student at Institute of Immunology and Experimental Therapy, Polish Academy of Science. She has completed her M.Sc. of Biology at University of Agriculture in Wroclaw and also Molecular Biology at Jagiellonian University in Krakow. She has published 3 papers as coauthor in reputed journals and presented results of her research on a national and international conferences.
Member of the Brazilian Society SBACV, Brazil
Background: Changes in the ovariesʼ and the testiclesʼ phenotypes are associated to an increase in the risk of cancer and venous thrombosis. Varicocele and ovarian varicose veins can change the phenotype of the germinating glands. In this study, we made it our goal to evaluate the prevalence of ovarian varicose veins and varicocele in patients with cancer and venous thrombosis.
Material and Method: 54 patients with cancer and 98 patients in the control group who were diagnosed with venous thrombosis were included in this study. All of these patients were examined through ultrasound with vascular Doppler in order for us to investigate varicocele in men and ovarian varicose veins in women.
Result: Of a total of 14,800 patients, 152 with cancer and venous thrombosis were selected (1.02%). The group with cancer presented a significantly (p = 0.0029) higher proportion of varicose veins (96.3%) next to the germinating glands than the group with venous thrombosis (84.7%). The comparison between the groups with cancer and venous thrombosis was evaluated by the χ2test or the Fisher exact. The significance criteria adopted was the level of 5%.
Conclusion: The group with cancer presented a significantly higher proportion of varicose dilation than the group with venous thrombosis. Varicose veins next to the testicles and the ovaries are associated to oxidative stress, which can change the phenotype of germinating glands, provoking abnormalities in the hypothalamic-pituitary-gonadal axis, interfering in gene mutation in patients with cancer and venous thrombosis.
Department of Radiation Oncology, †Department of Medical Oncology, Amrita School of Medicine, Amrita Institute of Medical Sciences & Research Centre, Kochi. Amrita Vishwa Vidyapeetham, Amrita University, India
Background: Triple negative breast cancer (TNBC) account for 15%-20% of all breast cancers and has relatively poor prognosis with documented 5-year OS of 62%[1]. The poor prognosis is attributed to absence of a definitive target molecule, though recent papers suggest a role for androgen receptors[2]. Chemotherapy and adjuvant radiation remains the standard-of-care. Audit of all cases of TNBC treated at our tertiary cancer care centre was done with intent to analyze the pattern of failure.
Methods: Details of all TNBC patients, treated from January, 2004 to June, 2015 were retrieved from the electronic medical records and were analyzed.
Results: A total of 276 TNBC patients were treated in this 10 year period. Median follow-up was 52.92 months (range: 0.07–149.8 months). Median age of presentation was 50 (range: 25-81). 96.4% of patients had infiltrating duct carcinoma. MRM was offered for 67.4% and BCS for 24.3%. 92% had axillary dissection. Upfront chemotherapy was offered for 18.8%, and adjuvant chemotherapy for 77.2%. 49.6% received adjuvant radiation. Fifty (18.1%) patients had recurrence; 4 local (1.4%), 3 regional (1.1%) and 40 distant (14.5%). Three patients had regional and distant failures. Among the 40 distant metastasis, 12 were brain, 8 skeletal, 4 hepatic, 2 pulmonary and 18 had multi-site. 190 (69%) patients were alive with no disease at last follow up. 5-year overall survival (OS) was 83.7%. Stage was the only significant factor affecting OS. Stage I had 100% 5 year OS, stage II, 88.2%, stage III, 72.4% and stage IV, 53.3% (p - <0.0001). Stage III B which includes all T4 patients had relatively low (50%) 5-year OS (p - 0.003). Median OS for T4 patients was 36.2 months (p - 0.004). 5-year OS in the failure-free group was 94.6%. Those who had failed had a median OS of 39.9 months (p - <0.0001). Among the distant failures, skeletal failures fared better with median OS of 71.7 months, followed by multiple-sites (39.1), pulmonary (36.2), hepatic (28.8), and brain (21.8) (p - <0.0001). 5-year DFS was 77.5%. Median time to failure was 13.56 months (range 0.07-113.17 months). BCS patients showed a trend towards better DFS compared to MRM patients (90.08% vs. 84.1% - p – 0.06).
Conclusions: Failure in TNBC is generally systemic and is approximately 4 times more than loco-regional failures. Irrespective of nodal status T4 lesions fared poorly. Patients with BCS had less failures compared to MRM, probably due to early disease and addition of adjuvant radiation. Contrary to western literature our TNBC patients had better survival: 5-year OS of 62% versus 83.7%. This difference in the pattern of TNBC in our subset of patients needs further evaluation.
Nanjing Medical University, Jiangsu, China
Monoclonal antibody (McAb) is the key tool for cancer immunodiagnosis and immunotherapy. In this study, a cell clone which kept secreting high-titer IgG1-type McAb named NJ001 against human non-small cell lung cancer (NSCLC) cells was obtained. The antigen named SP70 of NSCLC specifically identified by NJ001 was proved to be a protein with the relative molecular mass (Mr) of 70kDa. The results of immunohistochemical staining indicated that NJ001 could positively react to NSCLC, but negatively or weak positively react to human small-cell lung cancer (SCLC), pulmonary pseudotumor and other epithelial tumors. In soft agar assay, the colony formation efficiency in NJ001 groups decreased in a dose-dependent manner. For the concentration of 100 μg/ml, 200 μg/ml and 400 μg/ml, the inhibition ratio of colony formation was 23.4%, 62.5% and 100% respectively. Meanwhile, NJ001 caused significant reduction in tumor volume and tumor weight compared to control mice in lung cancer xenograft model. The tumor growth inhibition ratio in 200 μg, 400 μg and 800 μg NJ001 groups was 10.44%, 37.29% and 44.04%, respectively. NJ001 also led to obvious cytomorphological changes and induced the apoptosis of human lung adenocarcinoma cell line SPCA1 significantly. The newly developed NJ001 selectively reacted to NSCLC and exhibited anti-tumor activity both in vitro and in vivo. SP70 is of great value concerning immunodiagnostics and immunotherapy for NSCLC and holds promise for further research regarding the mechanism underlying tumor progression of NSCLC.
Biography:
Professor Shiyang Pan has studied lung cancer over 20 years, during which time he has found novel biomarkers for NSCLC and authored more than 100 peer-reviewed reports. He has served on the editorial board for the Chinese Journal of Laboratory Medicine. Dr. Pan is the director of the Laboratory Medicine Department of Nanjing Medical University and the National Key Clinical Department of Laboratory Medicine. He is the Chairman of the Jiangsu Society of Laboratory Medicine, and a member of the Standing Committee of Chinese Society of Laboratory Medicine, and he has served on review committees for the NSFC and Health Administration of China.
aDepartment of Radiation Oncology, The Canberra Hospital, Australia
bCentre for Advances in Epidemiology and IT, The Canberra Hospital, Australia
cDepartment of ACT Pathology, The Canberra Hospital, Australia
Introduction: Combined score obtained using Immunohistochemical (IHC) 4 (based on oestrogen and progesterone receptor status, Her2 status and Ki-67 score) plus Clinical Treatment Score (based on nodal status, tumour size, grade and age) is a very promising clinicopathological tool predicting risk of distant recurrence. This study explores the role of the combined score in predicting risk of loco-regional recurrence (LRR) in women who had breast conservation surgery without radiotherapy.
Methods: Patients were selected from the ACT and SENSW BCTG database over a 13 year period. Tumour blocks were retrieved to perform IHC testing on those that were incomplete. Clinical scores were obtained from the database and combined scores were calculated using the appropriate formulae.
Results: Cox regression indicated a significant association between the combined score and the risk of LRR (p=0.03). When the cut-off points as in the original study by Cuzick et al, were applied to the LRR outcome, the incidence of LRR was zero, 20 % and 33.3 % in the low, intermediate and high risk groups respectively (p=0.007).
Conclusions: This is the first study of its kind. The combined score may be used to identify women at negligible risk of LRR in whom adjuvant radiotherapy can be omitted.
Xin Yuan Institute of Medicine and Biotechnology, College of LIfe Sciences Zhejiang Sci-Tech University, China
Cancer stem cells (CSCs), also known as tumor-initiating cells, are highly metastatic, chemo-resistant and tumorigenic, and are critical for cancer development, maintenance and recurrence. Oncolytic adenovirus couldtargetedly kill CSCs and has been acted as a promising anticancer agent. Currently, a novel GP73-regulated oncolytic adenovirus GD55 was constructed to specifically treat liver cancer and exhibited obvious cytotoxicity effect. However, there remains to be confirmed that whether GD55 could effectively eliminate liver CSCs. We first utilized the suspension culture to enrich the liver CSCs-like cells, which acquires the properties of liver CSCs in self-renewal, differentiation, quiescence, chemo-resistance and tumorigenicity. The results indicated that GD55 elicited more significant cytotoxicity and stronger oncolytic effect in liver CSC-like cells compared to common oncolytic virus ZD55. Additionally, GD55 possessed the greater efficacy in suppressing the growth of implanted tumors derived from liver CSC-like cells than ZD55. Furthermore, GD55 induced remarkable apoptosis of liver CSC-like cells in vitro and in vivo, and inhibited the propogation of cells and angiogenesis in xenograft tumor tissues. Thus, GD55 may virtually represent an attractive therapeutic agent for targeting liver CSCs to achieve better clinical outcomes for HCC patients.
Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, USA
Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and are thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here, we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR. B3 inhibited the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. We identified a novel mechanism by which KDM4B activates the transcription of Polo-like kinase 1 (PLK1). B3 blocked the binding of KDM4B to the PLK1 promoter. Our studies suggest a potential mechanism-based therapeutic strategy for PCa and tumors with elevated KDM4B/PLK1 expression.
Biography:
Dr. Zhi-Ping Liu obtained her PhD in Biophysics and post-doctoral training in Molecular Biology at UT Southwestern Medical Center. She is now an associate professor in the department of internal medicine, UT Southwestern. Her research focuses on the transcriptional regulation of genes involved in cancer and cardiovascular diseases.
Department of Pharmaceutical Sciences, Dr. Harisingh Gour Central University, India
The present study was aimed to bring forth a multipronged approach for delivery of synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) using surface modified and integrally designed liposomes. Various liposomes (size ~200 nm)viz. Liposomes (Lip), PEGylated liposomes (PL) and FR-targeted PEGylated liposomes (FPL) were developed using thin film casting technique. In vitro drug release study reflected sustained release kinetics at physiological conditions (37±0.5°C, pH 7.4) where as abrupt dispersal (i.e. more than 90%) of liposomal content within 5 min at simulated tumor conditions (41±1°C, pH 4). These liposomes were studied for haemolytic toxicity studies, ex vivo pharmacodynamics (OVCAR-3 cell lines), florescence microscopy, and pharmacokinetics in ovarian tumor-bearing mice. Ex-vivo and in-vivo studies in tumor bearing mice documented a potentiated anticancer activity of FPL attributed to multifaceted features viz. thermosenstivity, long circulatory nature and targetability. Such multi-modal tactic of nanomedicine can be a promising tool for safe and efficacious drug delivery to tumor site.
Biography:
Ankit Jain completed his B. Pharm. and M. Pharm. from Depart. Pharm. Sci., at Dr. H. S. Gour Central University, India. He is a recipient of valuable scholarships (JRF-UGC and UGC-RFSMS) and rewards (SASS and YJA). He owned number of best paper awards (more than 10) in national and international level seminars. He has published more than 35 international high repute publications (total impact factor above 65) including book chapters. He has been invited to present his research work at ESGO-2013 (Liverpool, UK), and Cancer Science and Therapy-2014 (Chicago, USA) with travel grant supports from DST (New Delhi) and ICMR (New Delhi), respectively. Currently, he is a PhD scholar (CSIR-SRF) under supervision of Prof. Sanjay K. Jain in his native university. His area of research is exploration of smart tactics for targeting cancer using “In/On”fabricated nano carriers.
1Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Science, Poland
2Pharmaceutical Research Institute, Poland
miR-125b is involved in regulation of expression of a number of different genes and therefore this molecule has drown many attentions in cancer research. It was showed that miR-125b may act as an oncogene, since it is up-regulated in different types of cancer, or as tumor suppressor, since it is downregulated in others. miR-125b was shown to be involved in regulation of cell proliferation, apoptosis and differentiation. Among thousands of genes regulated by miR-125b are TP53 and VEGFA. We have shown previously that cisplatin and docetaxel alone or in combinations with tyrosine kinase inhibitors induced up-regulation of p53 expression in A549 lung cancer cells, while only treatment with cisplatin alone or in combination with sunitinib significantly lowered the level of VEGF-A secreted by A549 lung cancer cells. In order to investigate the molecular mechanism responsible for downregulation of VEGF-A in A549 cells treated with different combinations of tested agents we decided to study the impact of such treatment on miR-125b expression to see whether there is a correlation between miR-125b and VEGF-A as well as p53 expression. We found for example that after treatment with imatinib and cisplatin the expression of miR-125b was upregulated in A549 cells, what correlated with lowered VEGF-A protein expression when A549 cells were incubated with cisplatin and with downregulation of TP53 when cells were exposed to imatinib. No changes in miR-125b expression were seen after sunitinib treatment.
Biography:
Ewa Maj has completed her PhD in 2016 from Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Science. She has completed her M.Sc. of Biotechnology from University of Agriculture in Krakow and also M.Sc. of Medical Analytics from Jagiellonian University Medical College in Krakow. She has published about 15 papers as co-author in reputed journals and presented results of her research on a national and international conferences.
1Centennial High School, USA
2Department of Mathematics and Statistics, University of Maryland, USA
Despite a wealth of literature on identifying gene signatures for individual types of cancer, little has been reported regarding the comparison of gene signatures across multiple cancers to identify potential common-cancer gene signatures. We hypothesize that multiple cancers can be triggered and/or regulated by similar gene pathways; additionally, we aim to identify promising gene signatures to aid the diagnostic screening of multiple cancers in a more timely and accurate fashion. The advent of the big data era for cancer functional genomics, powered by high-throughput technologies (such as microarrays) and machine learning, has opened up a new path to study these hypotheses. The goals of this study are: (1) to collect gene signatures for individual cancers and evaluate their predictive ability across multiple cancers; (2) to identify potential common gene pathways for multiple cancers; and (3) to construct a meta-classifier to predict multiple cancers. We utilized 14 publicly available microarray gene expression datasets for a variety of cancers from the NCBI-GEO database. Our machine learning analysis indicated high predictive accuracy among the gene signatures identified from the datasets of breast, mammary gland, endometrial, and female non-smoker lung cancers; the results suggest a promising underlying genetic commonality. We will also present enrichment analysis of the predictive genes and demonstrate the relationship among gene pathways across multiple cancers. Our computational algorithm for the meta-classifier of multiple cancers will be shown at the end.
Biography:
Katie Gao is a junior at Centennial High School in Ellicott City, MD. She has been conducting research internship with Prof. Yi Huang at UMBC. She has always been deeply involved in science and has collected a few accolades along the way, including finishing top 20 at the 2016 National Brain Bee Championship and qualifying for the 2016 National Chemistry Olympiad.
Yi Huang is an Associate Professor at UMBCʼs Department of Mathematics and Statistics. She earned Ph.D in Biostatistics at Johns Hopkins University. Her research specializes in biostatistical methodology development and application in many areas of biomedical and health policy research.
Department of Chemistry and Biochemistry, BioFrontiers Institute, Howard Hughes Medical Institute, University of Colorado Boulder, USA
Epigenetic modifications in gene regulatory regions significantly contribute to the chromatin landscape that favors or disfavors transcriptional activation. One of the most abundant and least understood epigenetic modifications in eukaryotic DNA is methylation of cytosines at C-G dinucleotides (CpG). High levels of methylation in CpG rich gene promoters is typical of silenced genes; in contrast CpG methylation in gene bodies is canonically associated with expressed genes.
Telomerase reverse transcriptase (TERT) is an important oncogene on which 85-90% of all cancers rely for their indefinite replication. Methylation of the CpG island (cg11625005) in the proximal TERT promoter in cancer differs markedly from stem cells and differentiated cells. While normal cells exhibit little or no methylation at this locus, existing studies report that nearly all cancers exhibit significant levels of methylation at this CpG island. In contrast to expectations from other genes, numerous studies report that global demethylating agents such as azacytidine are detrimental to TERT mRNA expression in most cancers. We are working on understanding this confounding observation using a subset of cancer cells that express TERT monoallelically. In these cancers, in a single cell, one allele is active, while other TERT alleles are not expressed. Our data indicate that cancers with both active and silent alleles in the same cell display differential methylation patterns at cg11625005 on the different alleles. Targeted epigenome editing of these loci result in phenotypes that differ from previous reports that utilized global demethylating treatments. We conclude that the consequences of CpG methylation in the TERT promoter may be more complex than existing studies suggest.
Biography:
Dr. Stern was awarded his Ph.D from the University of Sydney in Australia before commencing his postdoctoral training at the The University of Colorado in Boulder in the lab of Dr. Thomas Cech. Dr. Stern is focused on understanding the mechanisms that govern telomerase and telomere biology, in both normal and disease contexts, to identify therapeutic targets for the treatment of cancer, as well as other telomere-based diseases.
University of Texas MD Anderson Cancer Center, USA
Salivary gland carcinoma comprises a variety of histologies with distinct clinical behavior. Given disease rarity, no standard of care systemic therapy exists for patients with recurrent/metastatic disease. We have recently reported that Notch1 mutations define a distinct subgroup of adenoid cystic carcinoma patients with very aggressive disease and potential responsiveness to Notch1 inhibitors. Androgen blockage in salivary duct carcinoma overexpressing androgen receptor and TRK inhibitors in EVT6-NTRK3 fused mammary analogue secretory carcinoma are also promising targeted therapy undergoing clinical investigation and will be discussed.
Biography:
Dr. Ferrarotto received her MD degree and completed her Clinical Residency and Fellowship in São Paulo (Brazil). During her Fellowship at MD Anderson Cancer Center (2012-2014), Dr. Ferrarotto led a translational research project investigating biomarkers that predict sensitivity to Polo-like kinase 1 (PLK1) inhibitors in non-small cell lung cancers. Currently, Dr. Ferrarotto is an Assistant Professor focused on translational and clinical research in the Department of Thoracic/Head and Neck Medical Oncology, with a particular focus on the rarer tumor subtypes. Dr. Ferrarottoʼs work focuses on identifying predictive biomarkers that can be used to select the patients that will benefit the most from targeted therapy and immunotherapy.
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA
Lymphodepleting regimens are employed prior to adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic ‘cytokine sinksʼ. These conditioning modalities, however, are often associated with severe toxicities. We found that miR-155 enabled B16 melanoma-specific CD8+ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T cell responsiveness to limited amounts of homeostatic γc cytokines by restraining the expression of the Akt inhibitor Ship1 and multiple negative regulators of Stat5, such as Socs1 and Ptpn2, resulting in delayed cellular contraction and sustained cytokine production. To translate these findings into new clinical trials, we tested whether the overexpression of miR-155 in human T cells would enhance the antitumor efficacy of CD19-specific chimeric antigen receptor (CD19-CAR) cells against systemic acute lymphoblastic leukemia xenografts. As a safety measure, the suicide gene, inducible caspase 9, was included in the miR-155 construct. We found that miR-155 also augmented the antitumor efficacy of T cells in this xenograft tumor model. Recapitulating our findings in mouse cells, human T lymphocytes overexpressing miR-155 showed increased Stat5 signaling and enhanced survival. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be employed to increase the effectiveness of adoptive immunotherapies in a cell intrinsic manner without the need of life-threatening, lymphodepleting maneuvers.
Biography:
Dr. Yun Ji obtained her Ph.D. from Iowa State University in 2004. Following a postdoctoral fellowship at Georgetown University she joined the National Cancer Institute in 2007. In 2016 Dr. Ji was appointed as a Staff Scientist at the Experimental Transplantation and Immunology Branch in the National Cancer Institute. Dr. Ji is interested in the mechanism of CD8+ T cell development and differentiation. Her research focuses on the identification and characterization of key transcription factors, miRNAs, and epigenetic modulators essential for CD8+ T cell activation, differentiation, and function, with a goal of improving T cell-based immunotherapy against cancer.
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