A First-in-Human, Phase I Clinical Trial of Mitochondrial-Targeted Hsp90 Inhibitor, Gamitrinib, in Advanced and Metastatic Prostate Cancer
Abstract
Men with localized prostate cancer have a broad range of therapeutic options and almost invariably good outcome, but the prognosis changes dramatically once the disease spreads beyond the prostate. In these settings, the tumor is resistant to hormonal and non-hormonal therapy; is largely insensitive to new treatments, such as Immunotherapy; and quickly disseminates to distant organs, especially the bone, causing major morbidity and mortality. With a 5-year survival rate of less than 28% and a median survival of only 15 to 36 months, advanced and metastatic prostate cancer remains an urgent, unmet medical need. Clearly, fresh thinking and new approaches are needed if we are to meaningfully prolong the survival of these patients. One potential and as yet unexplored therapeutic opportunity is the change in metabolism that occurs during prostate cancer progression. In this context, our work of the past decade, independently confirmed by others, has identified reprogramming of mitochondrial functions, the organelles that act as the cell’s powerhouse, as critically required to sustain resistance to therapy and metastatic dissemination in advanced prostate cancer. As there are currently no anticancer agents that target mitochondria, we synthesized Gamitrinib (GA mitochondrial matrix inhibitor), the first, mitochondrial-targeted drug. Using a new chemical structure, Gamitrinib selectively accumulates in mitochondria of tumor cells, disrupts their function in energy production and cell survival, and delivers potent anticancer activity, alone or in combination in models of advanced and disseminated prostate cancer. Solely supported by public funding from the Department of Defense (DoD), preclinical development of Gamitrinib is now complete, showing good drug-like properties and promising safety in two animal species and an easily accessible biomarker as evidence of target modulation in vivo. With this new DoD application, we propose to bring Gamitrinib to the clinic as the first-ever, mitochondriotoxic therapy in advanced prostate cancer patients. The first specific aim will support a phase I feasibility and safety clinical trial of once weekly intravenous administration of Gamitrinib in 20 patients with advanced prostate cancer. The trial will (1) identify the maximum tolerated dose (MTD) of this new therapy; (2) determine its dose-limiting toxicities (DLTs); and (3) characterize the pharmacokinetics in treated patients. Continuing the successful model used in preclinical studies, the Gamitrinib trial will be carried out as a conflict of interest-free, fee-for-service contract at South Texas Accelerated Research Therapeutics (START), the world’s largest oncology phase I contract research organization, under the leadership of Anthony W. Tolcher, M.D., founder and medical director of START. The second specific aim will characterize a signature of “cellular starvation” as a novel biomarker of Gamitrinib anticancer activity in prostate cancer patients. For these studies, we will examine pre- and post-treatment prostate cancer biopsies and peripheral blood mononuclear cells harvested from six patients in the Gamitrinib expansion cohort for changes in metabolic markers, modulation of bioenergetics, and inhibition of tumorigenic signaling. Altogether, the application is an ideal match to the Overarching Challenge of the DoD Prostate Cancer Research Program (PCRP) to “develop effective treatments and address mechanisms of resistance for men with high-risk or metastatic prostate cancer.” Overall, the proposed studies have the potential to revolutionize the therapeutic options for men with high-risk prostate cancer. For these patients, Gamitrinib could become a novel, potentially transformative therapeutic option, adding a new approach of disabling tumor metabolism to the current armamentarium of hormonal and non-hormonal therapies. For the broader field of oncology drug discovery, a successful Gamitrinib trial
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810334
Entities
People
- Dario C Altieri
Organizations
- United States Army
- Wistar Institute