Metabolic Reprogramming of Prostate Cancer and Antitumor Immunity by Targeting LDH-A
Abstract
When prostate cancer metastasizes beyond the gland, it becomes a lethal disease. Although a majority of prostate cancers currently diagnosed by ultrasound guided biopsy are considered indolent and may never threaten a patient s life, an estimated 28,170 men will die of metastatic prostate cancer in the United States alone in 2014. Prostate cancer has a tremendous impact on the quality of health and daily life of millions of Americans, including the increasingly aging Veteran population. Therefore, development of new approaches for diagnosis, treatment, and monitoring of prostate cancer remains one of the overarching challenges of Prostate Cancer Research Program. There is growing evidence that the ability of tumor cells to invade adjacent normal tissues and locally grow and metastasize to distant sites is significantly impacted by changes in metabolism of cancer cells and the conditions of tumor environment. Increased activity of a metabolic mechanism termed glycolysis and generation of lactic acid, the product of the enzyme Lactate Dehydrogenase-A (LDH-A), plays a key role in facilitating growth and invasiveness of several types of tumors. Excretion of lactic acid, combined with poor blood supply, results in an acidic environment around tumors compared to normal tissues without tumors. This acidic environment is toxic to normal cells but promotes the ability of cancer cells to grow and spread because it induces several changes in the tissues surrounding the tumor. Among these changes, a reduced response of immune cells against the tumor has a key role. In our present study, we will combine an innovative molecular imaging method, named hyperpolarized 13C MRI, with a mouse model of prostate cancer to induce loss of LDH-A in order to determine whether reduced production of lactate reduces the aggressiveness and metastatic potential of prostate cancer. Hyperpolarized 13C MRI is a new molecular imaging method that uses a compound named hyperpolarized [1-13C]-pyruvate and allows rapid and noninvasive monitoring of dynamic metabolic and physiologic processes. This method detects responses to treatment at much earlier times than standard approaches that are currently in use in clinical practice. The safety and efficacy of using hyperpolarized [1-13C]-pyruvate has been recently demonstrated in prostate cancer patients. Ultimately, hyperpolarized 13C MRI may provide a highly personalized approach for prostate cancer therapy by stratifying patients into classes who would benefit most from therapies that inhibit tumor glycolysis, enable an early determination of hitting the therapeutic target (LDH-A inhibition) and better predict ultimate treatment response. Tumor immunotherapy is currently one of the most promising approaches to improve the outcome of cancer treatment. Although checkpoint blockade by targeting the CTLA-4 and PD-1 inhibitory receptors of T cells has provided promising outcomes, most responding patients eventually relapse and many patients do not develop anti-tumor responses. It is therefore necessary to develop new approaches to improve anti-tumor immunotherapy. The tissue environment of tumors contains not only cancer cells but also normal cells, including immune cells. An ideal approach to exploit therapeutic targeting of metabolism in prostate cancer would be to attack the tumor cells directly while simultaneously improving anti-tumor immune responses. Altering the metabolism of immune cells by targeting LDH-A will allow improved function of immune cell populations that recognize and attack tumors and will promote lysis of cancer cells. Thus, targeting LDH-A will have implications on prostate cancer but also on immune cells. Our studies will open new avenues in cancer research and translational medicine because will provide for the first time a novel approach to mediate simultaneous anti-tumor therapy and immunotherapy, while measuring response to treatment in real time with hyperpolarized 13C
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510687
Entities
People
- Vassiliki A Boussiotis
Organizations
- Beth Israel Deaconess Medical Center
- United States Army