Targeting PRMT5 in MTAP-Loss Melanoma
Abstract
Background: Cancer is driven by either the loss of a tumor suppressor or the gain of an oncogene. The CDKN2A/B locus is a tumor suppressor region that is deleted in roughly 20% of all cancer types and up to 30% in melanoma. Melanoma patients bearing deletion of this locus exhibit poor clinical outcome and resistance to currently available treatment, highlighting an unmet need to develop effective therapeutic approaches for these patients. Importantly, when the CDKN2A/B locus is deleted in cancer there is very often (80% of cases) also a deletion of closely linked metabolic enzyme called methylthioadenosine phosphorylase (MTAP), which is referred to as collateral lethality. Given that MTAP is the enzyme responsible for producing a metabolite called methylthioadenosine (MTA), MTA levels are much higher in MTAP-null tumors than those in normal tissues. Recently, MTA has been shown to be a nature inhibitor for protein arginine methyltransferase 5 (PRMT5), an enzyme with critical roles in cancer development via regulating protein modification. Therefore, CDKN2A/B/MTA-null tumors display a unique vulnerability to PRMT5 inhibitors (PRMT5i). Since then, there have been numerous efforts by Pharma and Biotech to develop PRMT5i, and there are at least 20 different types of PRMT5i. The efficacy of the first-generation inhibitors for cancer treatment was not impressive, likely due to the difficulty in establishing a therapeutic window. To address this issue, several companies (Mirati, Tango, and Amgen) have developed second-generation inhibitors, which only suppress the enzymatic activity of PRMT5 in presence of high MTA levels. Preliminary data from our groups show that these new inhibitors are exquisitely selective for MTAP-null tumors. In this manner, PRMT5 is total inhibited in the cancer cells that harbor the CDKN2A/B/MTA-deletion, while the normal cells remain untouched by these inhibitors, thus generating a very large and safe therapeutic window. It is important to note that MTA can also be secreted by MTAP-null tumors, which has been linked to a cold tumor-immune phenotype. Thus, we are dealing with two independent biological functions for elevated MTA levels in these cancer cells and their microenvironment: (1) The unique vulnerability (to PRMT5 inhibition) and (2) resistance (to immunotherapy). We expect that second-generation PRMT5 inhibitors will reduce tumor size, and as a consequence of this atrophy, the PRMT5i-treated tumors will also reduce the amount of secreted MTA, which in turn will sensitize the tumors to immunotherapy. Melanoma Research Program Focus Areas Addressed: (1) Identify how the tumor microenvironment impacts tumor initiation, response to therapy. (2) Delineate the molecular pathways that influence metastatic spread and recurrence. Rationale, Objective, and Aims: We hypothesize that by selectively inhibiting PRMT5 in MTAP-loss cells with high MTA, tumor volume will be reduced, resulting in the tumor microenvironment harboring low MTA and consequently becoming responsive to immunotherapy. Our objective is to develop a comprehensive plan to definitively evaluate the therapeutic potential of PRMT5 inhibitors (PRMT5i) with different mechanisms of action, alone and in combination with immunotherapeutic for MTAP-null melanomas. These goals will be achieved by the following Aims. Aim 1: Develop melanoma mouse and cell models of MTAP loss to understand its impact on melanoma development and to better evaluate treatment efficacy. Aim 2: Determine antitumor activity of PRMT5i in combination with immunotherapy in MTAP-loss melanoma. Aim 3: Identify therapeutic targets for MTAP-loss melanoma that have developed PRMT5i resistance. The Following Melanoma Patients Will Be Helped by This Proposal: Second-generation PRMT5 inhibitors specifically target a cancer cell vulnerability that occurs because of MTAP loss. This MTAP-null genotype accounts for roughly 30% of melanomas. Th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310826
Entities
People
- Weiyi Peng
Organizations
- United States Army
- University of Houston