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AACR-AstraZeneca 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.

2019 Grantees

AACR-AstraZeneca Breast Cancer Research Fellowship

Panday_ArvindArvind Panday, PhD
Postdoctoral Fellow
Beth Israel Deaconess Medical Center
Boston, Massachusetts
spacerTherapeutic potential of FANCM for BRCA1-linked breast cancer

Scientific Statement of Research
The focus of Dr. Panday’s research is to understand the mechanism that prevents genomic instability and associated BRCA1 mutated breast cancer. Primary cells lacking BRCA1 respond to the Tus/Ter replication fork barrier by forming small tandem duplications (TDs). Intriguingly, breast cancers lacking BRCA1 similarly acquire large numbers of small TDs. Dr. Panday’s preliminary data show that stalled fork motor protein-FANCM (product of the Fanconi anemia [FA] group M gene) acts synergistically with BRCA1 to suppress TDs. He discovered a novel synthetic lethal interaction between BRCA1 and FANCM loss in primary mouse ES cells. He proposes to dissect the mechanism of TD formation and homologous recombination at stalled fork using FANCM as a genetic probe and to determine whether FANCM is an actionable "druggable" target for therapy of BRCA1-linked breast cancer.

Biography
Dr. Panday completed his PhD in biological sciences under the supervision of Dr. Anne Grove at the Louisiana State University. During his thesis he uncovered a novel linker histone-like function of yeast, HMO1, showing that this unusual high mobility group protein stabilizes chromatin and is evicted along with core histones in preparation for DNA repair. Dr. Panday is a currently a research fellow in the laboratory of Dr. Ralph Scully at Beth Israel Deaconess Medical Center, Harvard Medical School. His major goal is to understand the mechanism of genomic instability and associated breast cancer.

Acknowledgment of Support
I am extremely honored to be awarded the AACR Breast Cancer fellowship. I sincerely thank the grant review committee for selecting me as a recipient for this grant. This fellowship will allow me to carry out the proposed research and establish a track record for future grants as I make the critical transition from fellow to independent scientist.

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AACR-AstraZeneca Breast Cancer Research Fellowship

Vlahakis_AriadneAriadne Vlahakis, PhD
Postdoctoral Fellow
University of California, San Francisco
San Francisco, California
spacerNBR1 mediated selective autophagy in pro-metastatic adhesion signaling

Scientific Statement of Research
The proposed research examines the role of selective autophagy during breast cancer metastasis. Autophagy is a catabolic recycling process that promotes tumor fitness, though the role of selective autophagy during metastasis is unclear. This proposal builds upon previous and preliminary evidence linking the selective autophagy adaptor NBR1 to pro-metastatic signaling events, including focal adhesion turnover, migration, and metastatic colonization. The objective is to understand, with molecular detail, the link between NBR1 mediated selective autophagy and pro-metastatic adhesion signaling in promoting breast cancer metastasis. To achieve this, the proposed research couples cutting-edge proximity-based biotinylation proteomics and human cell biology with in-vivo breast cancer models to 1) dissect the role of selective autophagy in metastatic adhesion signaling, 2) identify novel and cancer-relevant NBR1 targets in human mammary epithelia, and 3) assess the physiological relevance of NBR1 signaling to breast cancer metastasis in-vivo.

Biography
Dr. Vlahakis is a postdoctoral fellow in Dr. Jayanta Debnath’s laboratory at UCSF. Her research interests lie in understanding how metastatic cells fine-tune cancer relevant stress responses, such as autophagy, to adapt to changing environments. Her interest in cancer-related cell biology began during her PhD at UC Davis, where she published several first author studies uncovering a novel role for the rapamycin insensitive TOR Complex 2 (TORC2) signaling pathway in promoting autophagy. Her postdoctoral research seeks to understand, with molecular detail, the role of selective autophagy in regulating pro-metastatic adhesion signaling in the context of breast cancer metastasis.

Acknowledgement of Support
Receiving the AACR postdoctoral fellowship fuels within me an immense sense of dedication and honor in continuing my career in cancer research. It significantly poises me for success as I strive to one day become an independent investigator, by providing merit to my dedication and training in cancer research.

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AACR-AstraZeneca Immuno-oncology Research Fellowship

Peters_BrandilynBrandilyn A. Peters, PhD
Postdoctoral Fellow
New York University School of Medicine
New York, New York
spacerThe lung microbiome, peripheral immunity, and lung cancer recurrence

Scientific Statement of Research
Early stage non-small cell lung cancer (NSCLC) patients typically undergo tumor resection without adjuvant therapy and have good survival rates. Yet 8-32 percent of curatively resected stage I NSCLC patients die within five years of diagnosis, and there is no established method for identifying patients at high risk for recurrence. The objectives of this project are to relate the lung microbiome to recurrence-free survival and peripheral immune gene expression and to identify lung bacterial biomarkers which can improve the performance of a recurrence prediction model. The central hypothesis is that lung bacteria play a role in lung cancer recurrence and this role is mediated by effects of lung microbiota on the immune environment. Identification of these biomarkers may enhance survival for lung cancer patients by identifying patients with poorer prognosis who may benefit from increased surveillance or adjuvant therapy and by potentially identifying bacterial targets for therapy.

Biography
Dr. Peters received her PhD in environmental health sciences in 2015 from Columbia University, where she studied nutritional interventions to mitigate exposure to inorganic arsenic, a Group 1 human carcinogen. She subsequently began her postdoctoral training in microbiome research under the mentorship of Dr. Jiyoung Ahn in the Division of Epidemiology, Department of Population Health at NYU School of Medicine. As a postdoctoral fellow, Dr. Peters studies the role of the human microbiome in chronic diseases, including cancer.

Acknowledgement of Support
Receiving an AACR-AstraZeneca Immuno-oncology Research Fellowship is a great honor and important step forward in my career. This support will allow me to conduct independent research and develop a successful career in microbiome and cancer research, while enabling me to work towards discovery of microbiome-based approaches to improve cancer survival.

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AACR-AstraZeneca Immuno-oncology Research Fellowship

Jiang_ZhouZhou Jiang, PhD
Postdoctoral Fellow
University of Texas MD Anderson Cancer Center
Houston, Texas
spacerOvercoming anti-PD-1/PD-L1 resistance in triple-negative breast cancer

Scientific Statement of Research
Half of patients with triple-negative-breast-cancer (TNBC) do not respond to TNBC front-line therapy, and the disease eventually relapses with metastasis, leading to poor overall survival. Because TNBC exhibits higher levels of PD-L1 expression, tumor-infiltrating lymphocytes, and tumor mutant burden compared with other breast cancer subtypes, it likely responds better to immunotherapy. Numerous immunotherapy clinical trials for TNBC are ongoing and have demonstrated tremendous achievements. However, response rates are still far from satisfactory, as only about 10-20 percent of patients are responsive due to anti-PD-1/PD-L1 resistance and inadequate biomarkers for patient selection. Through non-biased methods, receptor tyrosine kinase Tyro3 has been identified as a major contributor to anti-PD-1/PD-L1 resistance. Results show Tyro3 could serve as a biomarker of anti-PD1/PD-L1 resistance and as a therapeutic target to overcome resistance.

Biography
Dr. Jiang is a postdoctoral fellow at the University of Texas MD Anderson Cancer Center. He received his PhD in December 2017 from Wuhan University, China, where he investigated the role of innate immunity in inflammatory diseases. In 2018, he joined Dr. Mien-Chie Hung’s lab at MD Anderson Cancer Center. His current research focus is the resistance mechanisms of anti-PD1/PD-L1 therapy and the identification of new biomarkers to predict resistance. He is also interested in studying new immunotherapy targets and looking for innovative therapeutic strategies by immune checkpoint antibodies and drugs conjugation.

Acknowledgement of Support
This fellowship will not only support my ongoing project but also promote my career development as a translational scientist in the cancer immunotherapy field. I sincerely appreciate AstraZeneca and the AACR for this fellowship opportunity. It is my great honor to receive this funding support.

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AACR-AstraZeneca Lung Cancer Research Fellowship

Jen_JayuJayu Jen, PhD
Postdoctoral Fellow
New York University
New York, New York
spacerPIK3C3 is a haploinsufficient tumor suppressor gene in lung cancer

Scientific Statement of Research
Analysis of genomic sequencing of lung adenocarcinoma (LUAD) reveals rare mutations in, and 47 percent heterozygous deletion of, PIK3C3, which encodes the Class III PI3K hVPS34. hVPS34 plays an important role in regulating autophagy, endocytosis, and mTOR, but its potential role in oncogenesis has not been explored. Preliminary results suggest that decreased autophagy mediated by heterozygous mutation or deletion of Pik3c3 promotes lung cancer progression in vitro and in vivo. Moreover, extensive macrophage infiltration was observed in autophagy deficient LUAD, suggesting that impaired autophagy might modulate the LUAD microenvironment. By combining transgenic mouse models, in vitro spheroid cultures, and systems-based analysis, such as RNA-seq and multiplex flow cytometry, Dr. Jen aims to determine the underlying mechanism by which Pik3c3 haploinsufficiency promotes lung cancer progression and microenvironment modulation. This study may shed new light on lung cancer therapy and provide a biomarker for patients who might fare worse with autophagy inhibition.

Biography
Dr. Jen received her PhD in 2015 at National Cheng Kung University in Tainan, Taiwan. Her PhD studies focused on transcription dysregulation in lung cancer progression. In 2017 she joined the laboratory of Dr. Benjamin Neel at NYU Langone Health Perlmutter Cancer Center in New York as a postdoctoral fellow. She is now working on autophagy deficiency-mediated transcription dysregulation and tumor microenvironment in lung cancer.

Acknowledgement of Support
It is my great honor to be selected for a 2019 AACR-AstraZeneca Lung Cancer Research Fellowship. This fellowship will provide support allowing me to complete my current study on autophagy deficiency-mediated lung cancer progression. More importantly, this fellowship will be a solid foundation to build up my academic career.

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AACR-AstraZeneca Lung Cancer Research Fellowship

Vaughan_CatherineCatherine Vaughan, PhD
Postdoctoral Fellow
Virginia Commonwealth University
Richmond, Virginia
spacerNovel targeting of lung cancer

Scientific Statement of Research
p53 is mutated in 69 percent of lung cancers. Most p53 mutations are single amino acid changes instilling gain-of-function (GOF) phenotypes, making GOF p53 a therapeutic target. Unique DNA sequences were found that complex with specific transcription factors (TFs) and GOF p53 and are needed for GOF p53-mediated transactivation. These sequences are referred to as GOF p53 response elements (RE). Using one such RE, a novel custom promoter was built that is specifically activated by mutant p53 and unaffected by wild-type p53. This promoter provides a tool to express proteins that tag the fate of cells with GOF p53. An RE induced suicide gene, herpes simplex virus 1 thymidine kinase, kills cancer cells with GOF p53, having no effect on cells lacking GOF p53. Dr. Vaughan plans to develop the RE driven synthetic promoter to specifically target mutant p53-expressing lung cancer cells with suicide gene expression as a therapeutic strategy.

Biography
Dr. Vaughan is a postdoctoral fellow at Virginia Commonwealth University (VCU). She completed her BS in 2008 and her PhD in integrated life sciences in 2015 from Dr. Sumitra Deb’s laboratory at VCU. Her PhD work used ChIP-sequencing and transcription factor analysis to explore how p53 transactivates its target genes. She has since been in Dr. Deb’s lab exploring unique GOF p53 response elements (RE). She intends to utilize the REs to specifically target cancer cells expressing GOF p53. She plans to continue her career in cancer research by developing new and effective strategies to cure cancer.

Acknowledgement of Support
I am honored to receive the AACR-AstraZeneca Lung Cancer Research Fellowship. This opportunity supports a project that proposes to design strategies to specifically eliminate cancer cells with gain of function mutant p53. Since p53 is mutated in a large number of lung cancer patients, the impact will be huge. 

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AACR-AstraZeneca Lymphoma Research Fellowship

Steen_ChloeChloé B. Steen, PhD
Postdoctoral Scholar
Stanford University
Stanford, California
spacerCellular determinants of adverse risk in follicular lymphoma

Scientific Statement of Research
Follicular lymphoma (FL) is an indolent lymphoma that is generally considered incurable. Patients may experience multiple relapses, and some undergo transformation to an aggressive form of the disease that is associated with poor outcome. Currently, the most predictive indicator of overall survival in FL is time to first relapse. Patients who progress within 24 months after treatment induction have poor overall survival. Dr. Steen hypothesizes that tumor cellular heterogeneity underlies variation in clinical outcomes, including early relapse and transformation. To address this hypothesis, CIBERSORTx, a digital cytometry framework that leverages single-cell RNA-sequencing for large-scale tissue dissection of bulk tumor transcriptomes, was recently developed. Applying this framework to FL will allow Dr. Steen to interrogate numerous cell subsets for their associations with early progression and transformation to aggressive disease. If successful, this work will improve understanding of FL biology and reveal new candidates for the identification of biomarkers and therapeutic targets.

Biography
Dr. Steen graduated from the University of Oslo, Norway, with a BSc and MSc in molecular biology. She was first exposed to the field of lymphoma research as an undergraduate while working in the lab of Professor Jan Delabie. She did her PhD work in computational biology at the University of Oslo under the mentorship of Profesoor Ole Christian Lingjærde, where she investigated the transcriptomics of transformation in follicular lymphoma. She is now a postdoc at Stanford University, where she has joined the labs of Drs. Ash Alizadeh and Aaron Newman, and studies the cellular heterogeneity of lymphomas.

Acknowledgement of Support
Support from the AACR-AstraZeneca Lymphoma Research Fellowship is critical in my development as a young researcher. Hopefully it will also help improve lymphoma patient diagnosis and treatment, as I hope to identify novel drug targets and biomarkers for more personalized medicine.

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AACR-AstraZeneca Lymphoma Research Fellowship

Zlitni_SoumayaSoumaya Zlitni, PhD
Postdoctoral Research Scholar
Stanford University
Palo Alto, California
spacerThe role of the microbiome in transplant outcomes in lymphoma patients

Scientific Statement of Research
The human gastrointestinal tract is inhabited by numerous microbial species known as the gut microbiota. Conditions that alter gut microbiome composition compromise immune functions leading to inflammatory responses of varying severity. Lymphoma patients who receive allogeneic hematopoietic stem cell transplantation (HCT) undergo chemotherapy and radiation and are treated with broad-spectrum antibiotics. Loss in gut microbiome diversity is associated with increased risk of graft-vs-host disease, a pathology where the donor lymphocytes attack the host’s healthy tissues. With the increasing appreciation of the role of the gut microbiome in modulating immunity in transplant populations, novel microbiome-derived immunomodulators will be identified from stool extracts in Hodgkin and non-Hodgkin lymphoma patients during the course of their HCT treatment using a combination of flow cytometry immune assays, shotgun metagenomics, and robust metabolomic analyses. Lead microbes and metabolites will be advanced for preclinical testing, bringing us closer to developing therapeutic strategies to improve lymphoma patient outcomes.

Biography
Dr. Zlitni is a postdoctoral scholar in Dr. Ami Bhatt’s laboratory at Stanford University. She received her PhD in biochemistry from McMaster University in Canada, where her work centered on the discovery and characterization of novel antibacterial inhibitors. Before coming to Stanford, she was a postdoctoral fellow at the University of Toronto, where she developed metabolomic platforms to study the metabolic consequences of chemical and genetic perturbations in bacteria and yeast. She is interested in leveraging her training in microbiology, biochemistry, and metabolism to address questions about complex microbial communities and host-microbiome interactions in states of health and disease.

Acknowledgement of Support
I am honored to be a recipient of the 2019 AACR-AstraZeneca Lymphoma Research Fellowship. This grant will support me during an important stage of my scientific career. I will pursue critical questions in translational microbiome research with great therapeutic potential to help lymphoma patients who undergo bone marrow transplantation.

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AACR-AstraZeneca Ovarian Cancer Research Fellowship

George_ErinErin George, MD
Instructor
University of Pennsylvania
Philadelphia, Pennsylvania
spacerOptimizing DNA damage response inhibitors in Cyclin E high ovarian cancers

Scientific Statement of Research
Cyclin E (CCNE1) is amplified in 25 percent of ovarian cancers. Aberrant Cyclin E expression increases reliance on replication fork protectors and G2/M checkpoint regulators for survival. Two such key kinases are ATR and WEE1. Combined inhibition of these kinases (WEE1i-ATRi) is more effective than chemotherapy in preclinical models. Dr. George hypothesizes that sequential treatment of WEE1i-ATRi will be more tolerable and effective than concomitant and response will be Cyclin E level dependent. First, to identify a feasible yet effective dosing schedule for a clinical trial, she will test various dosing schedules in PDX models with varying Cyclin E levels. Toxicities will be evaluated. Secondly, she will compare mechanisms of action for dosing schedules. Cyclin E levels will be correlated with response. Results will guide the design of a future clinical trial evaluating a new drug combination for women with limited treatment options.

Biography
Dr. George recently finished her gynecologic oncology fellowship and is currently pursuing a career as a physician-scientist under the mentorship of Dr. Fiona Simpkins at the University of Pennsylvania. She obtained her undergraduate degree in biomedical engineering at Columbia University and then continued at that same institution to complete her MD and obstetrics and gynecology residency. Her dedicated year of research during her fellowship intensified her interest in the biology of gynecologic cancers and translational research. Now she is continuing to develop the skills and knowledge she needs to ultimately become an independent investigator in this field.

Acknowledgement of Support
My AACR-AstraZeneca Ovarian Cancer Research Fellowship will support the training elements needed to acquire the additional technical expertise, research experience, and publication record to foster a strong foundation to become on independent investigator. I hope to continue translational research and take our promising findings to clinical trials.

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AACR-AstraZeneca Ovarian Cancer Research Fellowship

Hill_Sarah_JamesSarah James Hill, MD, PhD
Clinical Fellow
Dana-Farber Cancer Institute
Boston, Massachusetts
spacerTargeting fork protection defects in high grade serous ovarian cancer

Scientific Statement of Research
Patients with high grade serous ovarian cancer (HGSC) have limited therapeutic options, and there is no current method of predicting which patients will respond to specific therapies. Dr. Hill has generated growth conditions for HGSC organoids and developed a platform of assays to query the anti-tumor immune response and DNA damage repair capacity of the organoid cultures. Results indicate that a larger number of organoids from tumors both with and without mutations in known DNA damage repair genes harbor stalled replication fork protection defects.  Based on these findings, the goal of this work will be to use HGSC organoids derived in the context of a clinical trial to assess the prevalence and different mechanisms of replication fork protection defects that lead to various therapeutic sensitivities and understand how such defects may be exacerbated to enhance the anti-tumor immune response.

Biography
Dr. Hill earned her MD from Harvard Medical School and PhD in genetics from Harvard University. She also holds an MSc in biochemistry from Oxford University and was a Rhodes Scholar. She is currently a gynecologic pathology fellow at Brigham and Women’s Hospital and a clinical fellow in the laboratory of Dr. Alan D’Andrea at Dana Farber Cancer Institute. Dr. Hill has developed growth conditions for patient-derived organoids from high grade serous ovarian tumors (HGSCs) and is focused on characterizing the DNA damage repair capacity and immune microenvironment of the organoid cultures.

Acknowledgement of Support
My 2019 AACR-AstraZeneca Ovarian Cancer Research Fellowship will allow me to study the DNA damage response in ovarian cancer under an experienced mentor in both fields. It will give me the foundation to build my career as an independent physician scientist and leader in the field of ovarian cancer.

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2018 Grantees

AACR-AstraZeneca Stimulating Therapeutic Advances through Research Training (START) Grant

Gorthi_AparnaAparna Gorthi, PhD
Postdoctoral Fellow
University of Texas Health Science Center at San Antonio
San Antonio, Texas
spacer_1-lineIdentifying modifiers of PARP1 inhibitor sensitivity in BRCA-like tumors

Scientific Statement of Research
Cytotoxic chemotherapies are often used effectively in cancer treatment. However, associated collateral toxicity and long-term health issues have driven development of targeted therapies that take advantage of tumor-specific genetic aberrations. Unfortunately, like classic chemotherapeutics, these strategies suffer from acquired resistance. BRCA-like tumors display functional loss of BRCA1/2, impaired homologous recombination, and synthetic lethality with PARP inhibitors (PARPi). However, single agent PARPi failed in clinical trials of pre-treated Ewing sarcoma patients, an aggressive BRCA-like pediatric cancer. Dr. Gorthi will work to identify synergistic combinations of specific DNA damage response inhibitors with PARPi in Ewing sarcoma to overcome PARPi resistance. She also aims to develop a deep-learning framework to predict the response of BRCA-like cancers to drug combinations based on genome-wide molecular profiles. Dr. Gorthi expects to establish in silico models to prioritize drug combinations for in vitro screening and functional validation in pre-clinical models to accelerate bench-to-bedside translational science.

Biography
Dr. Aparna Gorthi is a postdoctoral fellow at UT Health San Antonio with Dr. Yidong Chen and Dr. Alex Bishop, developing machine-learning based frameworks for predicting drug efficacy and evaluating synergistic drug combinations in pediatric cancers. She received her PhD in cellular and structural biology from UTHSA in Dr. Bishop’s laboratory, where she identified altered transcription, R-loops, and BRCA1 function in Ewing sarcoma. She has a bachelor’s in computer science and received her master’s in bioengineering from the Indian Institute of Technology Kanpur. Dr. Gorthi has also worked as a bioinformatician at Philips Research analyzing epigenetic data.

Acknowledgement of Support
It is my distinct honor to receive the AACR-AstraZeneca START Grant. This support enables me to combine experimental and computational approaches towards advancing therapeutic options for pediatric and BRCA-like cancers. The unique exposure provided in academia and industry will also facilitate my career progression to becoming an independent translational scientist.

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AACR-AstraZeneca Stimulating Therapeutic Advances through Research Training (START) Grant

Sule_AmritaAmrita Sule, PhD
Postdoctoral Associate
Yale University
New Haven, Connecticut
spacer_1-lineTargeting oncometabolite-producing cancers with DNA repair inhibitors

Scientific Statement of Research
2-Hydroxyglutarate (2HG) has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG) dependent dioxygenases. 2HG is an oncometabolite induced by neomorphic mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes that encode Krebs cycle enzymes. IDH1/2 mutations were first identified in gliomas and subsequently have been found in multiple other tumor types. IDH1/2 mutant tumors are defective in Homologous recombination (HR) repair, which renders them exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Additionally, overproduction of fumarate (Hereditary Leiomyomatosis and Renal Cell Cancer) and succinate (Hereditary Paraganglioma-Pheochromocytoma) block HR via a mechanism similar to that observed with 2HG. This pathway can therefore be exploited with DNA repair inhibitors for therapeutic gain. Dr. Sule proposes to perform a combined genetic and small molecule screen for other nodes in key DNA Damage Response (DDR) pathways that can be targeted in oncometabolite-producing tumors for a therapeutic gain.

Biography
Dr. Amrita Sule is currently a postdoctoral associate in the Department of Therapeutic Radiology at Yale University. She completed her bachelor’s (2008) and master’s (2010) in life sciences at the University of Mumbai, India. She completed her PhD in 2017 from Dr. Kristoffer Valerie’s lab in Virginia Commonwealth University, where her work focused on a molecular interaction between protein phosphatase 2A and ATM kinase and its effect on DNA damage response. In 2018 she joined Dr. Ranjit Bindra’s laboratory as a postdoctoral associate where she is investigating potential DNA repair targets in oncometabolite producing cancers.

Acknowledgement of Support
I am extremely honored to be awarded the AACR-AstraZeneca fellowship this year. This fellowship will allow me to carry out the proposed research and identify novel targets in the DNA repair pathway. This fellowship will also be instrumental in helping me develop my career as an independent investigator.

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AACR-AstraZeneca-MedImmune Clinical Immuno-oncology Training Fellowship

Sheth_SiddarthSiddarth H. Sheth, DO, MPH
Clinical Fellow
University of North Carolina
Chapel Hill, North Carolina

Biography
Dr. Siddharth (Sid) Sheth is a third-year medical oncology fellow at the University of North Carolina at Chapel Hill. Prior to this fellowship, he completed medical school at Lake Erie College of Medicine and internal medicine residency at the University of Pittsburgh Medical Center. Dr. Sheth has clinical and research interests in head and neck cancer. Dr. Sheth is fully committed to a career as a clinician-scientist and hopes to improve patient outcomes through clinical trials and translational research.

Acknowledgement of Support
I am thrilled to advance my understanding of immuno-oncology (IO) drug and biomarker development, and participation in industry sponsored clinical trials. Importantly, this unique fellowship at AstraZeneca/MedImmune’s headquarters will expose me to promising IO agents in the developmental pipeline. I hope to develop an early-phase clinical trial concept that integrates novel combination IO strategies.

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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 percent 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 percent 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 benefit from 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 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.

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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 postdoctoral 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 the 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 percent 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 percent, and is decreased to 30 percent 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 BS degree in biological sciences from the University of Salamanca in Spain. She received her MS and PhD 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 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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