The AACR-AstraZeneca Stimulating Therapeutic Advances through Research Training (START) Grants represent an exciting initiative to encourage and support collaboration between academia and industry. The combined academic and industry training provided through this program will be invaluable to young investigators, allowing them to attain a comprehensive research experience.  Projects have direct applicability to cancer with a specific focus on DNA Damage Response (DDR) pathways.

2019 grantees

Research
Deficiencies in certain DNA double strand break repair (DSBR) pathways can make cancers susceptible to other pathway inhibitors. For example, PARP inhibitors have proven successful in treating homologous recombination deficient (HRD) cancers. Currently used assays are unable to fully capture the pathway choices cells make to repair damaged DNA. Dr. Hussain is using the CRISPR-Cas9 system and next generation sequencing platforms to develop an assay that can simultaneously measure usage of major DSBR pathways in any live cell.

Biography
Dr. Hussain received his PhD in pharmacology at UT Health San Antonio, where he identified RPS6KB1 as a novel target for overcoming prostate cancer radioresistance. He is currently a research fellow at Memorial Sloan Kettering Cancer Center, developing an assay to detect double strand break repair pathway choice in cancer.

Acknowledgement of Support
It is an honor to be awarded the AACR-Astra Zeneca START Grant. This grant gives me a unique opportunity to use resources from both MSKCC and AstraZeneca to enable effective translation of our research from bench to bedside.

Research
An emerging therapeutic strategy for metastatic castration-resistant prostate cancer involves targeting the epigenetic modulator EZH2. Utilizing a genome wide CRISPR screening approach, Dr. Shah has discovered that the DNA damage response (DDR) pathway, which has frequent germline mutations in prostate cancer, plays an integral role in EZH2 inhibitor sensitivity and response. He is set to determine the role and mechanism of the DDR pathway in EZH2 inhibitor sensitivity, discover biomarkers of response, and uncover synergistic combination therapies, including co-treatment with PARP inhibitors.

Biography
Dr. Shah completed his PhD at Memorial Sloan Kettering Cancer Center in New York City. Dr. Shah joined the Dana-Farber Cancer Institute as an oncology fellow, where his current research is focused on discovering novel therapeutic approaches for advanced stages of prostate cancer.

Acknowledgement of Support
I am extremely honored and thankful to be awarded the AACR-AstraZeneca START Grant. This fellowship will give me the opportunity to carry out my proposed research and will ultimately allow for the development of improved treatment strategies for prostate cancer patients. This fellowship will also be instrumental in helping me develop my career as an independent clinical cancer research scientist.

2018 grantees

Research
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 has been identifying synergistic combinations of specific DNA damage response inhibitors with PARPi in Ewing sarcoma to overcome PARPi resistance. She is also developing a deep-learning framework to predict the response of BRCA-like cancers to drug combinations based on genome-wide molecular profiles.

Biography
Dr. Gorthi received her PhD in cellular and structural biology from UT Health San Antonio, where she identified altered transcription, R-loops, and BRCA1 function in Ewing sarcoma. She is a postdoctoral fellow at UT Health San Antonio, where she is developing machine-learning based frameworks for predicting drug efficacy and evaluating synergistic drug combinations in pediatric cancers.

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.

Research
2-Hydroxyglutarate (2HG) is an oncometabolite induced by neomorphic mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes. IDH1/2 mutant tumors are defective in homologous recombination (HR) repair, rendering them exquisitely sensitive to PARP inhibitors. Overproduction of other oncometabolites, fumarate and succinate, block HR via a mechanism similar to that observed with 2HG. Dr. Sule has been performing a combined genetic and small molecule screen for other nodes in key DNA Damage Response pathways that can be targeted in oncometabolite-producing tumors.

Biography
Dr. Sule completed her PhD at 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. She is currently a postdoctoral associate in the Department of Therapeutic Radiology at Yale University, 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.