State: Massachusetts

Funded by the Stewart J. Rahr Foundation PCF Challenge Award: 

co-funded by The Prostate Cancer Foundation and

the 2016 V Foundation Wine Celebration Fund a Need

Nearly all patients with metastatic castration resistant prostate cancer (mCRPC) develop resistance to androgen targeting agents and ultimately succumb to their disease. Recent discoveries by our group and others have demonstrated that a significant proportion of these patients harbor somatic or germline genomic defects in DNA repair defects, and targeting this genomically defined subset with therapies affecting this pathway may impact patient care. The goal of this project is to definitively characterize the genomic and functional landscape of DNA repair defects in mCRPC, clinically test the hypothesis that tumors harboring DNA repair defects preferentially benefit from immune checkpoint blockade, and explore innovative strategies to augment the efficacy of these agents through genomic and preclinical approaches. The project described herein is the first to comprehensively bridge the DNA repair and immuno-oncology fields to directly impact patients with advanced prostate cancer. We propose an integrated strategy that leverages advances in clinical genomics, trial design, and preclinical modeling methodology pioneered by our team. Furthermore, our proposal will be the first to specifically enable immune checkpoint blockade treatment strategies for mCRPC. In summary, this project will catalyze our understanding of how DNA repair defects impact advanced prostate cancer, and how deep knowledge about these events may enable clinical development of a transformative new class of immunotherapies that are greatly needed for advanced prostate cancer patients.

V Scholar Plus Award- extended funding for exceptional V Scholars

Most cancers occur more often in males than in females. We don’t understand why. It isn’t explained by differences in cigarette smoking, for example. Males have two different “sex chromosomes,” called X and Y. Females have two copies of X, but no Y. We think that the X and Y chromosomes influence cancer risk and might explain why some cancers are more frequent in men. We studied cancer cells and were surprised to find that some patients had an excess of mutations in genes that “live” on the X chromosome. 100% of those patients were men. In this study, we will look at mutations on X and Y from thousands of patients with many types of cancer. Differences between men and women could explain some of the disparity in cancer incidence between the sexes. These findings may be relevant in cancers that are more frequent in men, including leukemia, brain tumors, kidney cancer, and bladder cancer. In addition, we will study these genes in the laboratory, comparing male and female cells. We will ask how sex differences in mutations on the X chromosome contribute to cancer. We hope that our research discovers new ways to prevent or treat cancer. Specifically, we want to understand why men and women might have different rates of developing cancer. This work might lead us to consider that men and women with the same type of tumor might best be treated differently.

Support for the Liposarcoma Genome Project was funded by

Alex Gould and Friends in memory of Kathryn Gould.

Liposarcoma Genome Project –
Liposarcoma is the most common type of cancer that arises in soft tissue.  These tumors often present as low grade tumors initially, but a subset of patients will experience recurrence of a higher grade tumor.  Those patients who recur with higher grade tumors do poorly.  Therefore, our research focuses on understanding these high grade tumors.  We will explore the genetic changes between the low grade and high grade tumors in order to understand the molecular features that underlie high grade transformation.  We will begin by sequencing gene mutations in these tumors and surveying gene activity in each tumor type (Aim 1).   Mechanisms that govern which genes are on and off frequently involve how the DNA is packaged and structurally arranged in the cell.  Therefore, we will characterize the packaging (chromatin) and structure (topology) of the genomic DNA in these tumors (Aim 2).  By elucidating mechanisms by which tumor cells alter gene expression, we will better understand the genes and pathways that sustain them.  Finally, we will develop models of these tumors (Aim 3).  We can use these models to test driver genes and candidate therapeutic targets identified in our study.  We believe that our interdisciplinary team of clinicians and scientists is poised to complete the proposed aims, which should yield important insights into liposarcoma biology and guide future clinical strategies.