Targeting Metabolic Adaptation Pathways to Inhibit Progression and Metastasis of Castration-Resistant Prostate Cancer
Abstract
Localized or organ-confined prostate cancer can be cured by surgery, or a combination of androgen deprivation therapy (ADT), radiotherapy, and/or chemotherapy. However, tumor recurrence occurs in some men due to the development of ADT-resistant clones, which greatly contributes to the lethality of prostate cancer. This aggressive lethal variant of the tumor, named as castration-resistant prostate cancer (CRPC), frequently metastasizes to distant organs such as bone. As a result, treatment becomes challenging and survival rate drops. Hence, there is an urgent need to develop new therapies to cure advanced prostate cancer. Development of aggressive CRPC tumors is favored by activation of several "escape pathways," among which androgen receptor (AR) coactivator (molecules that stimulate AR) such as steroid receptor coactivator-2 (SRC-2/NCOA2) plays a critical role promoting the growth and survival of metastatic prostate cancer. We recently demonstrated for the first time that oncogenic coactivator SRC-2 promotes a "metabolic switch" in advanced prostate tumors that predisposes them to be dependent on "glutamine" (an amino acid - building blocks of protein) to generate energy and macromolecules required for prostate cancer metastasis. Cutting off the energy generation pathways in metastatic tumors by targeting the atypical metabolic pathway remains an innovative therapeutic strategy to treat and cure this deadly disease. With this hypothesis and objective, here we propose to evaluate the therapeutic potential of targeting glutamine-metabolic pathway in metastatic prostate cancer and understand the molecular players that activate this axis in CRPC. For this, we have three major goals. First, we will evaluate the therapeutic potency of a glutamine-metabolic inhibitor, CB-839, to treat metastatic prostate cancer. CB-839 is currently being tested in clinical trials for treating other types of cancer and initial data are extremely promising. However, its effect on advanced prostate tumors has not been tested before. Since a majority of advanced prostate cancer metastasizes to the bone, we recently developed a metastatic prostate cancer mouse model to study bone metastasis. We propose to use this mouse model to investigative whether CB-839 treatment can selectively impair metastatic progression of prostate tumors to bone. Second, we also proposed to evaluate the mechanisms that promote aberrant usage of glutamine in metastatic prostate tumors. For this, we will evaluate the enzymatic activity of aconitase (an enzyme involved in energy oxidation pathway) in CRPC progression using frozen prostate tumors, either localized or metastatic compared to benign adjacent tissues. The National Cancer Institute-designated Dan L. Duncan Cancer Center at Baylor Tissue Bank will provide us the appropriate sample size required for this study. Finally, we will integrate the findings by understanding the glutamine-dependent signaling pathway that is prevalent in resistant tumors by evaluating the target genes that are turned on in metastatic tumors. Why this is important? If in vivo studies with glutamine-inhibitor show resistance in some animals, we can then combine current standards of care agents or use genetic inhibition of genes that are enriched in resistant tumors. To our knowledge, these studies have not been done before and our preliminary data support the proposed experiments. Our study will provide a strong rationale for a clinical trial with CB-839 in prostate cancer patients, and since the safety of the drug has already been validated, it could be rapidly translated into clinics for prostate cancer therapy, hopefully within 5 years. Our study focuses on deciphering the mechanisms that promote progression of therapy-resistant prostate tumors. Metabolism of prostate tumors is understudied, and our proposal will advance this field by understanding functions of novel metabolic enzymes. Our study will decipher dynami
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610297
Entities
People
- Subhamoy Dasgupta
Organizations
- Baylor College of Medicine
- United States Army