RIPK2 as a Therapeutic Target in Advanced Prostate Cancers
Abstract
Background: Prostate cancer is a leading cause of cancer death in men in the United States and many other developed countries, imposing significant social and economic burdens. Despite recent progress in prostate cancer therapeutics, men suffering from advanced prostate cancers only have a life expectancy of 2 to 3 years. Metastasis (tumor spreading to distant organs) and immune evasion (tumor evasion from surveillance by the immune system) are two major causes of prostate cancer progression to lethal disease and are intimately associated with drug resistance. However, therapies to effectively control prostate cancer metastasis and immune evasion remain elusive. Excitingly, we recently discovered that a protein kinase, named receptor-interacting protein kinase 2 (RIPK2), may play a critical role in fueling prostate cancer metastasis and suppressing desirable antitumor immune responses. Using multi-disciplinary approaches, we uncovered that RIPK2 protects c-Myc (a well-known driver of cancer metastasis and immune evasion) from being degraded and thus allows c-Myc to be accumulated to a pathogenic level in prostate cancer cells. Importantly, unlike c-Myc, which is generally considered undruggable, RIPK2 can be potently inhibited by a small-molecule drug approved by the Food and Drug Administration and several other preclinical small-molecule compounds. Of note, the RIPK2 inhibitors did not cause any discernable toxicity in mice, suggesting that they are safe compounds with low toxicity. Therefore, our findings have a great potential for being rapidly translated into the clinic to improve treatment outcomes. Hypotheses/Objectives: This proposal is designed to study whether RIPK2 promotes prostate cancer metastasis and immune evasion and whether treatment with RIPK2 inhibitors can control metastatic progression, increase immune cell-mediated tumor killing, and improve animal survival. To achieve the goal, I have assembled an outstanding team comprising experts in prostate cancer biology, urologic oncology, mouse models, tumor immunity, proteomics, imaging mass cytometry, bioimage analysis, biostatistics, and bioinformatics. We will utilize various preclinical models, clinical specimens, and leading technologies such as multiplexed quantitative proteomics, thermal proteome profiling, imaging mass cytometry, and circulating tumor cell-RNA assay. Specific Aims: Through Aim 1, we will determine the pro-metastatic and immune-evasive functions of RIPK2 by genetically manipulating RIPK2 expression levels in prostate cancer cell lines. Through Aim 2, we will determine the targets of RIPK2 inhibitors in living cells and evaluate the effects of RIPK2 inhibitors on reducing prostate cancer metastasis, improving tumor cell killing by immune cells, and extending animal survival. Through Aim 3, we will evaluate whether tumor cell RIPK2 protein levels correlate with worse patient survival and lower infiltration of cytotoxic immune cells into tumors, as well as identify a biomarker reflecting RIPK2 activity and examine the prognostic and predictive values of the biomarker in circulating tumor cells and extracellular vesicles. Ultimate Applicability: We envision that our research will directly lead to Phase 1/2 clinical trials of testing potent RIPK2 inhibitors, which can be taken orally, for precision treatment of advanced prostate cancers within the next 2 to 3 years. Patients to be enrolled will be selected using a non-invasive liquid biopsy biomarker, thereby avoiding unnecessary harm to those who will unlikely benefit from the anti-RIPK2 therapies. Because RIPK2 inhibition can dramatically slow down metastatic progression, patients with non-metastatic castration-resistant prostate cancer will experience substantially longer metastasis-free survival and thus fewer symptoms caused by metastases such as bone pain and fractures. In addition, patients with oligometastatic prostate cancer will benefit from RIPK2-targe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210131
Entities
People
- Wei Yang
Organizations
- Cedars-Sinai Medical Center
- United States Army