Novel Role and Therapeutic Targeting of LMO4 in Lethal Prostate Cancer
Abstract
Approximately 35,000 men are projected to die from prostate cancer (PC) in the United States in 2022, making it the second commonest cause of cancer death in men of all ages and the commonest cause of death from cancer in men over age 75. Hormone therapy, which prevents androgens such as testosterone from promoting PC’s biological effects, is the current dominant therapy. Though PC patients benefit from this type of therapy at first, PC inevitably progresses to castration resistance frequently associated with cancer spread to distant body sites (metastasis) and is then treated with more potent hormone therapies such as enzalutamide (Xtandi). However, PC can rapidly develop drug resistance to the newer hormone therapies and develop neuroendocrine features, a phenomenon that has been reported in up to 25% of therapy-resistant relapsed PC. Currently, the survival of patients who suffer from neuroendocrine disease is only ~7 months. These dismal facts underscore an urgent clinical need to develop new and effective targeted therapies against metastatic castration-resistant and neuroendocrine types of PC, which currently remain incurable. Recent studies, including ours, have discovered that PC cells can evolve or switch from a therapy-responsive luminal cell type to a therapy-resistant neuroendocrine cell type, a process referred to as tumor plasticity, under the selective pressure of newer hormone therapies like enzalutamide. Unraveling and targeting the molecular drivers of tumor plasticity will help us develop new molecularly targeted therapies for treating lethal PC by restoring their luminal cell identity and sensitivity to hormone therapies. We recently identified a transcription cofactor protein, LMO4, as a strong candidate driving factor promoting tumor plasticity and hormone therapy resistance. We found that LMO4 is overproduced in human prostate tumors associated with castration resistance, neuroendocrine features, higher incidence of metastasis and shorter overall survival times. Our preliminary studies also showed that silencing LMO4 effectively suppressed castration-resistant and neuroendocrine prostate tumor growth in experimental models. Based on these exciting findings, we propose to test the hypothesis that LMO4 plays an active role driving metastatic castration-resistant and neuroendocrine PC and that targeting LMO4 is a feasible strategy to treat these lethal forms of PC. We designed three specific aims to test our hypothesis. Aim 1 will characterize the role of LMO4 in driving metastatic castration-resistant and neuroendocrine PC. In Aim 2, we will elucidate the mechanisms by which LMO4, likely through partnering with other transcriptional regulatory proteins to produce coamplified effects and activate expression of many target neuroendocrine and pro-proliferative genes, induces lethal PC, as well as further establish the clinical relevance of the mechanistic findings in a large cohort of patient samples. In Aim 3, we will evaluate the safety and effectiveness of our newly identified first-in-field LMO4 inhibitors for treating lethal PC in a range of prostate tumor mouse models. Notably, one of the tumor mouse models we propose to use for efficacy testing is a patient-derived xenograft model where tumor tissue from patients is engrafted into mice, thus retaining the key features of human tumors to more faithfully reflect or predict clinical responses to LMO4 inhibitors. Our research addresses the FY22 PCRP Overarching Challenges of define the biology of prostate cancer progression to lethal prostate cancer to reduce death and develop treatments that improve outcomes for men with lethal prostate cancer. We can contribute to resolving one of the most important questions remaining to be answered in the PC research field – how castration-resistant and neuroendocrine PCs develop – by specifically investigating the previously unrecognized role of LMO4 in driving tumor plasticity and PC pro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310118
Entities
People
- Boyang Wu
Organizations
- United States Army
- Washington State University