Targeting the Genetic Determinants of Immune Escape and Immunotherapy Failure in CRPC
Abstract
One in eight men will develop prostate cancer in his lifetime. Though patients with advanced prostate cancer initially respond well to standard-of-care hormone therapy, many will relapse following treatment and develop castration resistant prostate cancer (CRPC), which is deadly and lacking in long-term effective treatments. An alternative approach to treating cancer is to use a class of compounds known as immunotherapies to activate the immune system to attack and kill cancer. Though a class of immunotherapy known as immune checkpoint blockade have been effective in other aggressive cancer types that no longer respond to traditional therapy, these therapies have shown limited efficacy in CRPC due to suppression of the immune system in prostate cancer. Therefore, we need to come up with new strategies to target the tumor and immune system to stop CRPC progression and overcome lethal prostate cancer. There are many types of genetic mutations that occur in prostate cancers that relapse as CRPC. My group has previously shown that some of these genetic mutations can lead to suppression of the immune system and may contribute to immunotherapy failure. The objective of this application is to understand how different genetic mutations commonly found in human CRPC contribute to immune suppression and immunotherapy resistance, and whether targeting these genetic mechanisms of immune evasion can lead to therapeutic benefit for CRPC patients. We have recently engineered a new approach to model genetic mutations found in human CRPC in mice. Using this mouse modeling platform, we can produce prostate cancers harboring different genetic mutations in mice that will allow us to understand how these specific mutations impact immune activity and response to immunotherapy. Our first aim will be to identify particular mutations associated with immune suppression. Once identified we will use sequencing approaches to understand the mechanisms by which these genetic alterations suppress immunity. We will then use genetic and pharmacological strategies to target candidate immune suppressive factors that these tumors produce to assess whether we can reverse immune suppression and get tumors to respond to checkpoint blockade immunotherapy. Those genetic mutations and tumor-produced factors associated with immune suppression in our mouse models will be validated in human CRPC samples containing similar genetic mutations from patients treated here at UMass Memorial Hospital. Our second aim is to use a screening approach we have developed to identify new molecularly targeted therapies that can block the oncogenic signaling pathways driven by genetic mutations that occur in CRPC. We and others have evidence suggesting that tumor targeted therapies can also provoke anti-tumor immune responses in certain contexts that can lead to immune-mediated tumor destruction. Indeed, we have recently shown that induction of a tumor suppressive pathway known as cellular senescence following treatment with cancer targeted therapies can stimulate immunity and synergize with immunotherapy, leading to long-lasting tumor control in other aggressive cancer types. Here we will perform drug screens using prostate cancer cell lines derived from our mouse models and human cell lines harboring different genetic mutations to (a) identify specific molecularly targeted therapies for each genetic mutation that can induce senescence, (b) characterize their impact on prostate cancer immunity, and (c) assess their efficacy in our preclinical mouse models in combination with immune checkpoint blockade. By understanding the genetic determinants of immune and immunotherapy responses, this project will establish genetic biomarkers predictive of CRPC patient tumors likely to respond to immunotherapy, as well as unveil new therapeutic targets to overcome immune suppression in CRPC patients unresponsive to such therapies. In addition, our screening pipeline will allow for the rapid iden
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210505
Entities
People
- Marcus Ruscetti
Organizations
- United States Army
- University of Massachusetts Medical School