Therapeutic management of metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge. 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. Aggressive mCRPC 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 disease is favored by activation of several `escape pathways' among which AR- coactivators such as steroid receptor coactivator-2 (SRC-2/NCOA2) plays a critical role promoting the survival and rapid metastasis of CRPC. SRC-2 promotes a ?metabolic switch? in advanced tumors that predispose them to be dependent on `glutamine' to generate energy and macromolecules required for survival and metastatic growth. Ablation of SRC-2 suppresses prostate tumor survival and metastasis in vivo, indicating this may be a viable approach to treat advanced patients. So our objectives in this proposal are (1) to investigate the mechanisms that promote increased glutamine metabolism in tumors, (2) identify the upstream signaling events that stimulate SRC-2 transcriptional responses to regulate this metabolic reprogramming, and (3) examine the therapeutic benefits of targeting this `metabolic switch' to block cancer progression and metastasis. During the K22 award I expect to identify the molecular links between cellular metabolism and oncogenic events in mCRPC, and examine the potential benefits of targeting this pathway to selectively impair prostate cancer metastasis. The study will make novel insights depicting the altered metabolic pathways and underlying mechanisms promoting the emergence of CRPC, which may lead to the discovery of potential prognostic tools for early detection of clinically significant disease.
Despite advances in AR targeting agents, prostate cancer progression re-occurs in the form of metastatic castration-resistant prostate cancer (mCRPC), for which current treatment opportunities are limited. The goal of this project is to identify novel metabolic adaptations in mCRPC and to characterize the molecular players that activate this pathway. We will also therapeutically exploit the atypical metabolic pathways to selectively impair CRPC progression and metastasis in vivo.
|Dasgupta, Subhamoy; Rajapakshe, Kimal; Zhu, Bokai et al. (2018) Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature 556:249-254|