Identification of Collateral Lethal Targets in Prostate Cancer
Abstract
Prostate cancer is the second most common cancer among men in the United States, with more than 191,000 new cases estimated to occur in 2020. It is also the second leading cause of cancer death in American men, behind only lung cancer. An estimated 1 in 41 men will die of prostate cancer this year. Up to 40% of advanced prostate cancers sustain loss of the tumor suppressor gene PTEN, which correlates with poorer prognosis and a higher occurrence of metastasis. When cancer cells sustain deletion of PTEN, the neighboring genes of the PTEN locus are invariably co-deleted. We surmised that these “passenger deletions” may confer cancer cell-specific vulnerabilities if the passenger-deleted gene encodes a cell essential function. We further reasoned that cancer cells survive these passenger deletions due to the presence of functionally redundant co-expressed paralogs residing elsewhere in the genome and capable of sustaining these essential functions. We hypothesized that specific genetic or pharmacological inhibition of the non-deleted paralogs would represent a cancer-specific vulnerability to PTEN-deleted prostate cancers with relevant passenger deletions, yet spare normal cells with intact genomes. PTEN-null prostate cancers often sustain loss of the neighboring gene, PAPSS2. Along with its paralog, PAPSS1, these genes are the only ones that encode the synthetases central to sulfation by generating the sulfate-donor for many proteins and small molecules involved in myriad cell functions. Our preliminary data show that PAPSS1 depletion induces cancer cell death in PAPSS2-deleted cells and, thus, suggests that PAPSS1 is a novel druggable target for PTEN-null prostate cancers harboring PAPSS2 deletion. The known crystal structure of PAPSS1 enables structural analysis of PAPSS1 and our virtual screening for selective PAPSS1 inhibitors using our large chemical libraries. The top inhibitors emerging from multiple rounds of selection via computer simulation are then funneled into cell-based assays testing for their inhibitory effects on PAPSS1 biochemical activity as well as on cancer cell growth and survival in PAPSS2 wild-type versus deleted prostate cancer cells. The top drug candidates validated in these in vitro systems are then enlisted into tumor studies in vivo with the goal of prioritizing those compounds with desired biological activity and drug characteristics that would justify a medicinal chemistry campaign and IND-enabling studies. Beyond this flagship PAPSS program, we will perform whole-genome screens using a powerful tool (enCas12a) to identify additional targets related to the other co-deleted genes in the PTEN locus. Although beyond the scope of this grant, any confirmed targets from these screens would similarly be enlisted into in-depth validation and drug discovery efforts for cancers harboring specific passenger mutations. We believe that this proposed research will significantly increase the pool of novel drug targets for prostate cancer patients, thereby addressing PCRP’s overarching challenge to develop treatments that improve outcomes for men with lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110766
Entities
People
- Ronald A. DePinho
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army