Identification and Characterization of Novel Targetable Mechanisms Associated with Homologous Recombination Repair Defects in mCRPC Patients
Abstract
In the United States, approximately 1 man in 9 will be diagnosed with prostate cancer (PC) during his lifetime. PC is the most commonly diagnosed cancer among men in the United States. There will be an estimated 164,690 new cases of PC, resulting in approximately 29,430 deaths, in 2018. Men with PC that recurs after local therapy (surgery or radiation therapy) frequently undergo androgen deprivation therapy, also known as hormone therapy. This treatment initially causes tumor reduction and relief of symptoms (if they are present), but frequently the cancer becomes resistant to this treatment and the drugs no longer work. Once the cancer is able to grow despite androgen deprivation therapy, it has transitioned into a more aggressive form called castration-resistant prostate cancer and may eventually spread beyond the prostate, developing into metastatic castration-resistant prostate cancer (mCRPC), which is the lethal form of the disease. DNA integrity is essential for healthy normal growth of cells. DNA damage repair (DDR) genes help maintain DNA integrity, and we have found that alterations in these genes are present in a substantial subset of men who develop mCRPC. Also, the frequency of these alterations is significantly higher in men whose cancer is limited to the prostate, but considered high-risk. This observation has wide-ranging implications for men with PC. For instance, aberrations in DDR genes and genes and proteins affected by DDR genes, whether inherited or acquired over the lifetime or during cancer treatment, could be used to identify men with the highest risk of developing mCRPC and to personalize their therapy. Decades ago, scientists demonstrated that cancer cells with DDR alterations are hypersensitive to drugs that inhibit the protein poly (ADP-Ribose) polymerase (known as PARP). These findings led to the approval of PARP-inhibiting drugs for patients with a number of cancers and, recently, to approval of a PARP inhibitor for men with mCRPC with DDR alterations. Although PARP inhibition shows significant promise, lasting responses are rare and resistance occurs frequently. Therefore, identifying mechanisms of resistance to PARP inhibition and developing therapeutic strategies to overcome them, or developing strategies by combining PARP inhibition with other agents, are of utmost importance. Recently we discovered that BRCA2 (a DDR gene) is deleted along with a nearby gene, RB1, in almost 60% of tumors in men with mCRPC, and that this co-deletion is associated with therapy resistance and a worse prognosis. Building on these data, we have also identified increased activity of the gene WNK1 as a direct consequence of BRCA2-RB1 co-deletion. We have also observed significant activity of SRC and related genes in patients with BRCA2 deletion. We think that inhibiting WNK1 or SRC alone or in combination with PARP inhibition is a promising therapeutic strategy for men with mCRPC and DDR alterations and can potentially increase the efficacy of PARP inhibition. Additionally, we will use two approaches to identify human kinases, enzymes that are known to be involved in resistance to cancer drugs, which could be responsible for resistance to PARP inhibition. Successful identification of such kinases will provide us with new targets for drug development and help us formulate new strategies to overcome resistance to PARP inhibition. Applicability of the Research: This study is likely to advance the understanding the role of DDR genes in the progression of PC from local to metastatic, an issue of the highest importance for men with PC and one of the most challenging areas of prostate cancer research. We expect that the success of our current proposal will allow us to develop new therapeutic strategies for PC patients who harbor DDR alterations and do not respond to existing therapies. Also, this approach could be beneficial for PC patients who test positive for inherited BRCA2 mutations (~5%
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910470
Entities
People
- Philip W. Kantoff
Organizations
- Sloan-Kettering Institute
- United States Army