Mitochondrial Targeted TRAP1 Inhibitors: Novel Antitumor Agents
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Unmet Need
Prostate cancer and glioblastoma represent two of the most devastating forms of cancer. Prostate cancer is the third most common cancer in the U.S. with 220,800 new cases and approximately 28,000 deaths per year (1). Unfortunately, current therapies are only partially effective and the five-year survival rate for men diagnosed with metastatic prostate cancer is only 28 percent. Glioblastomas are a group of heterogeneous and highly malignant primary brain tumors for which there is no cure. Survival rarely exceeds 12 to 15 months after diagnosis despite surgical resection and therapy (2). One-third of patients diagnosed with glioblastomas survive for one year and less than five percent live beyond five years (3).
Opportunity
The molecular chaperone heat-shock protein-90 (HSP90) has previously been pursued as a drug target, due to its role as a cancer “nodal” protein. Although several large pharmaceutical companies have developed HSP90 inhibitors, these compounds target the ATPase domain, which is highly conserved among HSP family members, and therefore these programs have proven disappointing in the clinics due to off target effects.
Stage of Development
Wistar scientists have leveraged a breakthrough in HSP90 biology to overcome the barriers that have hampered the potential of HSP90 inhibitors. They have discovered a subcellular pool of HSP90 compartmentalized in the mitochondria of tumor cells, which is absent in most normal tissues. Mitochondrial HSP90 blocks cyclophilin D-dependent initiation of mitochondrial permeability transition and preserves organelle integrity against cell death stimuli. To target this pool of HSP90, the researchers have developed Gamitrinibs (GA mitochondrial matrix inhibitors), HSP90 ATPase antagonists derived from geldanamycin (GA) conjugated to a mitochondrial targeting moiety (4). This moiety drives the compounds into the mitochondria, thereby targeting the correct subcellular pool of HSP90 and diminishing off-target effects. Gamitrinibs selectively (in tumor cells) cause a sudden and irreversible collapse of mitochondrial integrity, mediated by cyclophilin D-dependent opening of a permeability transition pore, ultimately leading to the release of pro-apoptotic cytochrome C into the cytosol and initiation of caspase-dependent apoptosis (5).
Preclinical studies:
Gamitrinibs are useful for treating highly recalcitrant cancers such as prostate cancer and glioblastomas. Gamitrinibs are effective as monotherapies and in combination therapies with both TRAIL inhibitors and PI3K inhibitors (6,7). Gamitrinibs alone were found to be efficacious against all cancer types in a screen of 60 different cancer cell lines, regardless of genetic makeup, loss of tumor suppressors, or expression of survival pathways responsible for resistance to other classes of therapeutics, with each line showing at least a 50 percent reduction in cell growth (8).
Prostate cancer: Micromolar concentrations of Gamitrinibs effectively kill hormone-refractory, drug-resistant, localized, and bone metastatic prostate cancer cells in vitro leaving no viable cells (6). In a genetic model of prostate cancer, Gamitrinibs inhibited localized and metastatic prostate cancer growth. Importantly, systemic administration of Gamitrinibs is well-tolerated by mice and inhibits bone loss in 100 percent of subjects in an orthotopic model of bone metastatic prostate cancer, CB17 SCID/beige mice injected in the tibiae with PC3 cells (8).
Glioblastoma: Gamitrinibs are effective at killing glioblastoma cells in vitro, showing between a five- and tenfold improvement over an HSP90 inhibitor (17-AAG) that has been used in clinical trials (6). In nude mice carrying intracranial U87-Luc glioblastomas, Gamitrinibs used in combination with a TRAIL inhibitor were shown to dramatically suppress the growth of established tumors up to ten times better than vehicle and five times better than Gamitrinibs or TRAIL inhibitors alone (6).
IND enabling studies:
Based on significant amounts of preclinical data demonstrating the efficacy of Gamitrinib, The Wistar Institute has initiated IND enabling studies of its lead Gamitrinib compound.
Intellectual Property
We have developed a robust patent portfolio including issued and pending U.S. and foreign patents (US8466140; 15/070657; 15/192,516; 14/378691; CN101854955; CA2699794; EP2200653; PCT/US2015/028850 [U.S., EPO, Mexico, Canada]; PCT/US2016/045721).
Collaboration Opportunity
We are completing the assembly of an IND package and are actively seeking a clinical development collaborator.
References
- https://seer.cancer.gov/statfacts/html/prost.html
- Siegelin et al. Mol Cancer Ther. 2010 Jun;9(6):1638-1646. PMID: 20501802
- Xu et al. Cancer Biol Med. 2015 Sep;12(3):223-237. PMID: 26487967
- Kang et al. J Clin Invest. 2009 Mar;119(3):454-464. PMID: 19229106
- Atay et al. J Clin Invest. 2009 Mar;119(3):445-448. PMID: 19306500
- Siegelin et al. J Clin Invest. 2011 Apr;121(4):1349-1360. PMID: 21364280
- Ghosh et al. J Natl Cancer Inst. 2015 Feb 3;107(3). PMID: 25650317
- Kang et al. Clin Cancer Res. 2010 Oct 1;16(19):4779-4788. PMID: 20876793