Targeting Histone Lysine Demethylase KDM4A in Neuroendocrine Prostate Cancer
Abstract
Our proposed studies will identify a novel therapy that targets a critical survival pathway in neuroendocrine prostate cancer (NEPC) to improve clinical outcomes. NEPC is a highly lethal subtype of prostate cancer that develops de novo or emerges in patients who initially respond to life-prolonging androgen pathway inhibitors (ARPI), such as XTANDI, but develop resistance later on. With the increasing use of ARPIs, the incidence of treatment-related NEPC (t-NEPC) is on the rise. Currently, therapy options for NEPC are limited. There is an urgent need to develop novel strategies to improve the clinical outcome for NEPC. Also, strategies to prevent or delay the emergence of NEPC could further improve the current standard of care for patients. A unique feature of NEPC is its high proliferation rate, observed both in human and mouse prostate cancer. This feature will enable its rapid progression, but will also create various types of cellular stress. One such type of stress in NEPC, known as endoplasmic reticulum (ER) stress, is caused by the increased amount of proteins that fail to properly fold into their functional states in the endoplasmic reticulum. ER stress will activate pathways to reduce the amount of misfolded protein in the cancer cells. If such stress persists, cancer cells will undergo apoptosis. Identifying the mechanisms by which NEPC copes with ER stress to avoid cell death will provide novel strategies to target this vulnerability and treat this lethal disease. Epigenetic regulators (transcription factors and histone modifiers) are key drivers in the development of t-NEPC, but therapeutically targeting them has proven difficult, and the available inhibitors lack robust efficacy. To this end, we have identified histone lysine demethylase KDM4A as a novel driver in NEPC progression that links epigenetic regulation to the regulation of ER stress in NEPC. These observations led us to consider testing the efficacy of targeting KDM4 with potent pan-KDM4 inhibitors and their combination with current therapies in NEPC. We hypothesize that KDM4A acts as a rheostat to control ER stress response to promote the survival of NEPC. Correspondingly, KDM4 inhibitors will induce cell death in NEPC. Also, combination therapies (e.g., KDM4 inhibitors + chemotherapy) will improve clinical outcomes for patients with NEPC. In this proposed study, we will perform well-designed experiments in complex and faithful preclinical models of NEPC to address the following questions: (1) Does KDM4A suppress the ER stress response pathway to promote cancer cell survival and tumor progression in NEPC? If so, can KDM4 inhibitors further potentiate the ER stress response that is active in NEPC to induce cell death and suppress tumor progression? (2) Can therapy outcomes be improved by combining KDM4 inhibitors with current therapies for NEPC? (3) How does KDM4A regulate ER stress response to promote the survival of NEPC? (4) Can KDM4A serve as a predictive marker for response to AR pathway inhibitors? Applicability of the research: The proposed study will identify a new therapeutic target and introduce a novel treatment strategy, i.e., KDM4 inhibitors, to NEPC treatment. This proposed study will contribute to two FY20 PCRP Overarching Challenges: “Define the biology of lethal prostate cancer to reduce death” and “Develop treatments that improve outcomes for men with lethal prostate cancer.” Types of Patients the Study Will Help: The new concept of targeting the survival pathways that cope with ER stress will be tested in patients who have de novo or treatment-related NEPC. If the concept is proven correct and the toxicity is acceptable, this may be applied in patients who are at risk of developing NEPC (patients who display an unfavorable response to ARPI) to prevent or delay the development of t-NEPC. Potential Clinical Applications, Benefits, and Risks: Although KDM4 inhibitors have not been teste
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110522
Entities
People
- Guocan Wang
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army