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AACR-AstraZeneca Cancer Research Fellowships   

The AACR-AstraZeneca Cancer Research Fellowships represent a joint effort to encourage and support mentored young investigators to conduct cancer research and to establish a successful career path in this field. The research proposed for funding must have direct applicability to lung cancer, immuno-oncology research, hematology research, or DNA damage repair pathways in ovarian cancer and may be basic, translational, clinical, or epidemiological in nature.

2018 Grantees

AACR-AstraZeneca Lymphoma Research Fellowship

Elodie Bal, PhDElodie Bal, PhD
Postdoctoral Fellow
Columbia University in the City of New York
New York, New York
headshot_1 line spacerNon-coding regulatory mutations in Diffuse large B-cell lymphoma

Scientific Statement of Reseach
Diffuse large B-cell lymphoma (DLBCL) remains incurable in ~40% of patients. Coding-genome sequencing efforts identified several genes/pathways altered in this disease, including new therapeutic targets. However, the non-coding genome of DLBCL remains unexplored despite emerging evidence indicating the occurrence of recurrent mutations contributing to tumorigenesis in other tumor types. This project aims at identifying the landscape of functional non-coding mutations deregulating gene expression in DLBCL. Preliminary analysis indicates that the AID-mediated aberrant somatic hypermutation mechanism, which involves  >50% of DLBCL, specifically recognizes gene-body enhancers/superenhancers (E/SE) of multiple proto-oncogenes, suggesting that this process can cause extensive gene deregulation. Using whole-genome sequencing and RNA-seq analysis of DLBCL cells, she will identify non-coding mutations that lead to E/SE dysregulation, as documented by ChIP-seq of histone modification marks. Candidate lesions will be functionally dissected for their specific effect on gene transcription. The results of this project are expected to identify novel mechanisms of DLBCL pathogenesis, thus revealing novel targets for therapeutic intervention.

Biography
Dr. Elodie Bal completed her PhD in Genetics at the Paris Descartes University, Imagine Institute of Genetic Diseases in 2016. Her PhD work focused on the identification of mutations in enhancers leading to tumor suppressor gene deregulation and aberrant activation of the Hedgehog pathway in inherited and sporadic basal cell carcinomas. In 2017, she joined the laboratory of Professor Riccardo Dalla-Favera at the Institute for Cancer Genetics, Columbia University, as a postdoctoral fellow to work on the identification of non-coding regulatory mutations in Diffuse large B-cell lymphoma.

Achnowledgement of Support
I sincerely thank the grant review committee for selecting me as a recipient for the AACR Lymphoma Reseach Fellowship. This award will allow me to beneficiate of the expertise of my mentors and support my research training and career development in lymphoma research.

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AACR-AstraZeneca Ovarian Cancer Research Fellowship

Sergey Karakashev, PhDSergey Karakashev, PhD
Postdoctoral Fellow
The Wistar Institute
Philadelphia, Pennsylvania
headshot spacer_1 lineEZH2 inhibition sensitizes CARM1-positive ovarian cancer to PARP inhibitors

Scientific Statement of Research
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer-related deaths. EOC is a genetically heterogeneous disease, and it is imperative to develop novel therapeutic strategies in a personalized manner. Coactivator-associated arginine methyltransferase 1 (CARM1) regulates the activity of multiple epigenetic factors such as an oncogene EZH2. Notably, CARM1 is overexpressed in EOC and its overexpression is associated with poor survival. Our data suggest that CARM1 negatively regulates non-homologous end-joining (NHEJ) in EZH2-dependent manner. NHEJ is an error-prone DNA repair pathway and its inactivation results in decreased sensitivity to PARP inhibitors. Therefore, it is critically important to understand the mechanism underling CARM1-mediated regulation of NHEJ. This study will lay a critical foundation to establish the use of a combination of EZH2 and PARP inhibitors in CARM1-expressing EOCs. PARP inhibitors are FDA-approved, and EZH2 inhibitors are in clinical development. Thus these findings will have an immediate impact on EOC patients.

Biography
Dr. Sergey Karakashev is currently a postdoctoral fellow in the laboratory of Dr. Rugang Zhang at the Wistar Institute in Philadelphia. He received his Master’s degree from Russian State Medical University in Moscow. Sergey started working on cancer research as a PhD student at Drexel University College of Medicine with Dr. Mauricio Reginato. After obtaining his PhD degree Sergey has joined the laboratory of Dr. Rugang Zhang where he is focusing on the role of epigenetics in the development of ovarian cancer and how anticancer drugs targeting epigenetic factors can be used to develop novel therapeutic strategies.

Acknowledgement of Support
I am honored to accept the 2018 AACR-AstraZeneca Ovarian Cancer Research Fellowship.  This fellowship will provide an extraordinary support to my research and will help us to develop novel therapeutic strategies for ovarian cancer patients. It will also help me to achieve my goal to become an independent investigator.

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AACR-AstraZeneca Lung Cancer Research Fellowships

Zhenfang Du, PhDZhenfang Du, PhD
Postdoctoral Fellow
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee 
headshot 1 line spacerNovel and therapeutically actionable EGFR rearrangements in lung cancer

Scientific Statement of Research
The prospective identification and rational therapeutic targeting of genomic alterations has revolutionized the treatments of cancer patients. It has been shown that patients whose tumors harbor activating mutations within the EGFR tyrosine kinase domain exhibit favorable clinical responses with EGFR tyrosine kinase inhibitor (TKIs) therapy compared to standard chemotherapy. Recently, the Lovly lab has identified three novel EGFR alterations in patients with lung cancer, including EGFR exon 18-25 kinase domain duplication (EGFR-KDD), EGFR-RAD51 fusion, and an EGFR transmembrane domain mutation. In this project, Dr. Du will utilize structural and computational modeling with various biochemical, molecular, and cell based assays to elucidate the exact mechanism underlying the effects of these EGFR alterations on EGF receptor biology. In addition, Dr. Du will focus on the identification of targeted agents and therapeutic strategies to maximally inhibit these alterations.

Biography
Dr. Du received his BSc degree in biotechnology from Fuzhou University, China in 2008. He obtained his MSc degree in medical genetics from Zhejiang University, China in 2012. He then completed his PhD in cancer epigenetics at The Chinese University of Hong Kong in 2016. After that, he joined in the laboratory of Christine M. Lovly, MD, PhD at Vanderbilt-Ingram Cancer Center as a postdoctoral fellow, where he is focusing on the identification of novel molecular cohorts of lung cancer with EGFR alterations.

Acknowledgement of Support
The 2018 AACR-AstraZeneca Fellowship in Lung Cancer Research will provide me with a solid foundation upon which to build my future career as a translational investigator, studying novel EGFR alterations in patient tumor samples. My goal for these studies is to have direct patient impact and to inform future drug development for agents targeting the EGF receptor.

Sushi Kumar, PhDSushil Kumar, PhD
Postdoctoral Research Fellow
Dana-Farber Cancer Institute
Boston, Massachusetts
headshot_1 line spacerCARM1 as an epigenetic target for lung cancer immunotherapy

Scientific Statement of Research
Cancer immunotherapy has shown convincingly beneficial results in lung cancer in recent studies. It has also been appreciated in immune checkpoint blockade studies that T cell infiltration frequency, distribution and location into tumor have predictive value for tumor progression and overall survival of patients. However, in lung cancer and other solid tumors, tumor infiltrating T cells are dysfunctional due to immunosuppressive tumor microenvironment. Recent studies indicate a role for epigenetic regulation in T cell dysfunction, wherein massive epigenetic changes occur in tumor infiltrating T cells. In this project, Dr. Kumar proposes to identify the regulators of tumor infiltrating CD8 T cells in lung cancer that suppress T cell function. These epigenetic factors could have therapeutic relevance in lung cancer. Dr. Kumar will use the novel in vivo CRISPR/Cas9 based CD8 T cell screening to identify the epigenetic regulators and pathway mediating genes. Identification of the epigenetic regulators that may increase the efficacy of current immune checkpoint blockade regimens such as PD-1 and CTLA-4 in lung cancer.

Biography
Dr. Kumar is a post-doctoral fellow in the department of cancer immunology and virology of Dana-Farber Cancer Institute at Harvard University. He received his bachelor’s and master’s degrees in biotechnology from Bangalore University (India) in 2007 and 2009 respectively. He served as a lecturer in department of applied genetics for almost two years. In 2011, he joined Graduate School of Biomedical Sciences of Rutgers University for doctoral studies in Dr. Raymond Birge’s lab, where he studied the role of adaptor proteins and oncogenes in cancer progression via rewiring of cellular signaling and modulation of immune evasion. In 2017, he joined Dr. Kai Wucherpfennig’s lab where he is currently investigating the role of epigenetic modulators of T cell dysfunction in the context of lung cancer.

Acknowledgement of Support
I am honored to be selected for the AACR-AstraZeneca Lung Cancer Research fellowship this year. I wish to thank the AACR for this grant. This fellowship comes as an encouragement to continue my research on epigenetic regulation of T cell dysfunction in tumors and also as a mean to facilitate my progress into an independent investigator in this field under the guidance of my mentor Dr. Kai Wucherpfennig.

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AACR-AstraZeneca Lymphoma Research Fellowship

Sydney Lu, MDSydney Lu, MD
Postdoctoral Research Fellow
Memorial Sloan Kettering Institute for Cancer Research
New York, New York
headshot_1 line spacerUnderstanding and targeting SF3B1 mutations in CLL

Scientific Statement of Research
Recurrent mutations of the mRNA splicing factor SF3B1 occur in 10-15% of chronic lymphocytic leukemia (CLL) patients and confer an alteration of function but it is not clear how they functionally contribute to CLL development. Recently we have found that SF3B1 mutations in vivo promote lymphomagenesis driven by MYC, producing a phenotype more aggressive than that of MYC expression alone. This provides the first preclinical model where SF3B1 mutations impart a robust biologic advantage as well as a model for evaluating therapies aimed at targeted SF3B1-mutant CLL cells. This model also provides an opportunity to evaluate the effects of MYC on RNA splicing, alone and in the context of mutant SF3B1. We will use these models and patient primary samples to understand the biological and mechanistic enrichment of SF3B1 mutations in CLL and evaluate a series of novel pharmacologic approaches with preferential effects on SF3B1-mutant CLL cells.

Biography
Sydney attended Dartmouth College where he received a BA in Chemistry and Biology. He received his PhD from the Memorial Sloan-Kettering division of the Weill Cornell Graduate School of Medical Sciences, where he worked under Dr. Marcel van den Brink, studying mouse models of hematopoietic stem cell transplant and mechanisms of graft-versus-host-disease and post-transplant immune reconstitution. He received his MD from Stanford University School of Medicine and completed a residency in internal medicine at New York Presbyterian-Cornell. He is currently a hematology / medical oncology fellow at Memorial Sloan-Kettering Cancer Center doing research in the laboratory of Dr. Omar Abdel-Wahab.

Acknowledgement of Support
The AACR-AstraZeneca Lymphoma Research Fellowship is a truly tremendous honor. As the first research support of my academic career, it is invaluable both for the proposed studies, and in helping me establish a track record for future grants as I make the critical transition from fellowship to independent research.

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AACR-AstraZeneca Immuno-oncology Research Fellowship

Naiara Martinez-Velez, PhDNaiara Martinez-Velez, PhD
Postdoctoral Researcher
Clínica Universidad de Navarra
Pamplona, Spain
headshot_1 line spacerImmuno-modulation mediated by virotherapy in osteosarcoma

Scientific Statement of Research
Osteosarcoma is the most common non-hematological pediatric bone cancer and is usually diagnosed during puberty. Despite surgical resection and chemotherapy treatment, the survival rate of patients with osteosarcoma reaches only 60-70%, and is decreased to 30% in patients with metastatic disease of the lungs. Oncolytic adenoviruses have emerged as a potent tool in the fight against different tumors. Besides selective destruction of cancer cells, adenoviral infection triggers lymphocyte infiltration in the tumor, leading to an enhancement of the anti-tumor immune response. However, the tumor mass is usually associated with an immunosuppressive environment that hampers the anti-tumor response. A new oncolytic virus, encoding a T-cell activator transgene, alone or in combination with immunomodulatory antibodies would enhance antitumor response.  Dr. Martinez-Velez expects to provide enough preclinical rationale for an innovative clinical trial for osteosarcoma patients, based on local delivery of oncolytic viruses with the capacity of awakening the immune system.

Biography
Naiara Martinez-Velez earned her B.S. degree in Biological Sciences from the University of Salamanca in Spain. She received her M.S. and Ph.D. degrees from the University of Navarra in Spain. Her doctoral thesis research is focused on the use of oncolytic adenoviruses as immune modulators for the treatment of solid pediatric tumors. Specifically, she has tested this new therapy in preclinical studies for osteosarcoma and DIPGs (diffuse intrinsic pontine gliomas). In addition, she has participated in the development of murine models to model the DIPG disease. In particular, she is interested in understanding the immunological changes occurring upon virotherapy with the goal of designing new therapies for these pediatric solid tumors.

Acknowledgement of Support
The AACR Immuno-oncology Research Fellowship provides an extraordinary opportunity to develop my professional career as a scientist in osteosarcoma research, an area where the development of new therapies is much needed. I am truly honored to be a recipient of this prestigious award and I hope to contribute in the future in the field of immune-oncology.

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AACR-AstraZeneca Immuno-oncology Research Fellowship

Robert M. Samstein, MD, PhDRobert M. Samstein, MD, PhD
Resident
Memorial Sloan Kettering Institute for Cancer Research
New York, New York
headshot_1 line spacerImmunogenicity of homologous recombination repair defects

Scientific Statement of Research
The introduction of immune checkpoint inhibitors (ICI) has dramatically changed the treatment landscape of metastatic cancer. However, only a minority of patients respond, emphasizing the need for predictive biomarkers. Mismatch repair deficiency was recently approved as a pan-cancer FDA indication for immunotherapy. We hypothesize that an analogous DNA repair deficiency, defects in homologous recombination (HRD), may result in improved response to immunotherapy. This proposal aims to test this hypothesis using orthogonal datasets as well as preclinical studies. An institutional retrospective database will be utilized to assess for an improvement in survival after immunotherapy in HRD tumors. Additionally, a preclinical syngeneic breast cancer tumor model will be developed to study isogenic introduction of HR-deficiency using CRISPR-Cas9 genome editing and its effect on immunogenicity and response to PD-1 blockade. These studies will demonstrate a clear role for HRD as a predictive biomarker and pave the way for prospective clinical trials.

Biography
Robert Samstein completed his undergraduate studies in biomedical engineering and economics at Yale University followed by joining the Tri-Institutional MD-PhD Program of Weill Cornell Medical College, The Rockefeller University, and Memorial Sloan Kettering. He conducted his doctoral thesis on the study of studied immune regulation mediated by regulatory T cells and their biology and function with preeminent immunologist Alexander Rudensky. He completed a transitional year internship at Memorial Sloan Kettering Cancer Center before joining the Radiation Oncology residency program where he is currently in the Holman research pathway.

Acknowledgement of Support
This award will provide the necessary resources to conduct the experiments described and hopefully advance our understanding of the anti-tumor immune response and how it can be modulated.  In addition, this grant will promote my career development as a physician scientist, conducting translational research to ultimately improve patient care.

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2017 Grantees

AACR-AstraZeneca Fellowship in Immuno-oncology Research

Peran_90x110.jpgIvana Peran, PhD
Postdoctoral Fellow
Georgetown University
Washington, D.C.
The role of cadherin-11 in immunomodulation of pancreatic adenocarcinoma

Scientific Statement of Research
Pancreatic ductal adenocarcinoma (PDAC) is a desmoplastic disease with abundant fibrotic stroma containing activated pancreatic stellate cells (PSCs). As existing  therapies that target the epithelial component of PDAC do not improve overall survival, targeting tumor-stroma crosstalk and interaction with the immune system is gaining attention as a therapeutic strategy. Inflammatory cells can modulate cancer microenvironment through PSCs by both immunosuppressive and immunostimulatory activities. Depleting the PSCs affects both activities and is just as likely to promote PDAC as inhibit it. Therefore, Dr. Peran proposes to attenuate PDAC progression in immunocompetent transgenic mouse model by targeting an important molecular component of activated PSCs, without depleting the stromal compartment, and shift the PSC/immune system toward an immunostimulatory response against cancer. Upon the treatment, identified immunomodulatory components are going to be used as targets to potentiate chemo- and immunotherapy.

Biography
Ivana Peran is a postdoctoral fellow at the Lombardi Comprehensive Cancer Center. Ivana graduated from the University of Zagreb with an engineering degree in molecular biology in 2008. As a Fulbright Science and Technology Scholar, Ivana pursued her doctoral degree in tumor biology by working on treatment response markers and new therapies in pancreatic cancer. She received her PhD degree from Georgetown University in 2014. Currently, her project is focused on the role of activated stellate cells in immunomodulation of pancreatic ductal adenocarcinoma and identifying new combination therapy strategies based on immune-related components.

Acknowledgement of Support
The 2017 AACR-AstraZeneca Fellowship in Immuno-oncology Research is of extraordinary importance to understand the involvement of immunomodulatory components in pancreatic cancer progression. Once translated into the clinic, this research will lead to better treatment options for cancer patients. I am truly honored for this opportunity to make advancements in the immuno-oncology field.

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AACR-AstraZeneca Fellowship in Lung Cancer Research

Dardaei_90x110.jpgLeila Dardaei, PhD
Postdoctoral Research Fellow
Massachusetts General Hospital
Boston, Massachusetts
Overcoming acquired drug resistance in ALK fusion-positive lung cancers

Scientific Statement of Research
The vast majority of ALK-rearranged NSCLCs initially respond to small molecule ALK inhibitors but resistance invariably develops and limits the efficacy of these inhibitors in the clinic. The major classes of resistance are on-target genetic alterations and activation of bypass signaling pathways. The highly potent and selective third generation ALK inhibitor lorlatinib is active against all known secondary ALK kinase domain mutations that confer resistance to first and second generation ALK inhibitor therapies. However, lorlatinib fails to suppress growth of resistant cells with activated bypass signaling pathways which are detected in ~50 percent of cancers. Thus, there is an urgent need to develop new treatments for this subset of patients who develop ALK-independent resistance mechanisms and are resistant to all known ALK inhibitors. In this project, Dr. Dardaei will utilize a unique panel of patient-derived cell lines and patient-derived xenograft mouse models developed from MGH patients who developed resistance to ALK inhibitors. She will perform complementary synthetic lethal pooled shRNA screens and high-throughput combination drug screens to elucidate ALK-independent resistant mechanisms and identify effective ALK inhibitor combination therapies to overcome them.

Biography
Dr. Dardaei received her BSc degree in microbiology from Alzahra University, Iran in 2005. She obtained her MSc degree in molecular genetics from Tarbiat Modares University, Iran in 2008. She then completed her PhD in molecular medicine with a focus on molecular oncology and human genetics at the University of Milan, Italy in 2013. As a PhD student in Professor Francesco Blasi’s laboratory at IFOM in Milan, she developed a project centered on the concept of competition between oncogenes and tumor suppressors in solid and hematological malignancies. In 2014, she joined the laboratory of Dr. Engelman and recently Dr. Hata at the MGH Cancer Center as a postdoctoral research fellow, where she is currently studying targeted therapy and drug resistance in lung cancer and pursuing clinically relevant questions in the field.

Acknowledgement of Support
The 2017 AACR-AstraZeneca Fellowship in Lung Cancer Research will provide critical funding to support my research training and career development, and enable me to compete for additional funding from foundation and government funding sources. The knowledge, skills, research experience and scientific insight gained from this project will facilitate my career development towards becoming an independent investigator and help move the field of molecular targeted cancer therapy forward by studying basis of acquired resistance to targeted therapies and develop novel therapeutic strategies for cancer.

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 AACR-AstraZeneca Ovarian Cancer Research Fellowship

He_90x110.jpgYizhou J. He, PhD
Postdoctoral Fellow
Dana-Farber Cancer Institute
Boston, Massachusetts
Investigation of PARP inhibitor resistance in BRCA1-mutant ovarian tumors

Scientific Statement of Research
Ovarian cancer is the fifth leading cause of mortality in women and the most lethal of all gynecologic tumors. PARP inhibitors (PARPi) have emerged as potent antitumor agents against BRCA1/2 mutated ovarian tumors and were very recently FDA approved. However, a number of resistance mechanisms are emerging in patients being treated with PARPi. Dr. He has undertaken a systematic genome-wide investigation of the underlying cause of PARPi resistance using novel gene-editing (CRISPR) technology, and has identified genes and pathways whose loss make patients resistant to PARPi. Dr. He proposes a multi-pronged approach of investigating the molecular mechanism of resistance in cell–based assays and close examination of these genes/pathways in tumors from ovarian cancer patients that are resistant to PARPi. The goal is to define genetic alterations that drive resistance to PARP inhibitors and that will serve as the basis for rational approach to novel drug development.

Biography
Dr. He received his bachelor’s degree at Nanchang University (China) studying bio-engineering and computer science. In 2001, he came to the United States to work as a computational biology research assistant in Dr. Yue Xiong’s laboratory at UNC-Chapel Hill. In 2006, He joined graduate school at UNC-Chapel Hill mentored by Dr. Yanping Zhang studying the mechanism of genomic instability caused by altered p53 function. In 2014, he joined Dr. Dipanjan Chowdhury’s lab in the radiation oncology department at the Dana-Farber Cancer Institute. His current work focuses on exploring resistance mechanisms to chemotherapy in BRCA-mutant ovarian cancer using genome-wide CRISPR screen.

Acknowledgement of Support
I am honored to be selected for the AACR-AstraZeneca fellowship this year. This is an excellent opportunity to advance our understanding into the multifactorial chemotherapeutic response in BCRA mutated ovarian cancer, towards ultimately adapting therapeutic approaches personalized to each patient’s genome.

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