Vanquish’s most advanced development efforts are focused on our novel Procaspase 3 Activation (P3A) Program. This Program has identified a series of tractable small molecules that induce apoptosis by specifically “turning on” procaspase-3 (PC3). Procaspase-3 serves as a central trigger point in the apoptotic pathway, is aberrantly elevated in many cancer types and when activated induces cancer cell death. The “turning on” process is the proteolytic conversion of inactive procaspase-3 to what is known as the executioner caspase, caspase-3; akin to opening up the throttle of the cellular apoptotic engine.
A) Apoptosis in normal cells, showing the intrinsic and extrinsic pathways. B) Cancer cells have key aberrations in the apoptotic pathways enabling them to resist both intrinsic (through restriction of p53) and extrinsic (through decrease procaspase-8 expression) apoptotic triggers. C) PAC-1 directly activates procaspase-3 to caspase-3, thus inducing apoptosis even in cancer cells with damaged apoptotic circuitry. As procaspase-3 levels are elevated in many cancers relative to normal cells, PAC-1 is highly selective for cancer.
Target Dependent Action
Elevated levels of procaspase-3 are observed in many types of cancer. Vanquish has data from multiple pairs of normal/tumor colon tissue and from cell lines covering lung, breast, melanoma, adrenal, renal, lymphoma, leukemia and neuroblastoma cancers that demonstrates a clear correlation between cellular procaspase-3 levels and selective apoptosis induction and cell death by P3A compounds. Vanquish is expanding on this data set to include additional tumor types and animal models.
Safety & Efficacy
Vanquish has substantial pre-clinical efficacy, DMPK and toxicity data on several compounds from its P3A Program, the most advanced of which is PAC-1 (aka VO-100). PAC-1 has demonstrated significant efficacy in many in vitro and in vivo experiments including the mouse xenograft studies. PAC-1 has a high blood brain barrier (“BBB”) penetration which can be a clear benefit for treating CNS cancers as well as systemic cancers that have or are likely to metastasize to the brain. PAC-1 has been shown to be tolerated in rodents and canines by a variety of administration routes (e.g. MTD of 200 mg/kg IP rodent). Current efforts are focusing on PAC-1 oral administration and combination treatments which promise significant gains in therapeutic index. PAC-1 has shown efficacy in several animal models including:
- PAC-1, administered via oral gavage, dramatically retards the growth of lung cancer cells (NCI-H226) in a subcutaneous murine xenograft model.
- PAC-1, administered via oral gavage, dramatically reduces tumor burden in an experimental metastases murine lung cancer model (NCI-H226 cells).
- PAC-1, administered as an implanted cholesterol pellet, dramatically reduces the growth of renal cancer cells (ACHN cells) in a subcutaneous murine xenograft model.
PAC-1 activity in Brain Tumors
A large unsolved problem in anticancer therapy is the treatment of primary CNS cancers and metastases to the brain. Treatment of such cancers is problematic as many frontline anticancer drugs (doxorubicin, cisplatin, etoposide, vincristine, etc) do not penetrate the blood-brain barrier (BBB) to any significant extent. Thus, a therapeutic agent that is predicted to be effective against many cancers and concurrently BBB penetrant could offer unique advantages for the management of certain primary CNS tumors and metastatic disease. As recently published, PAC-1 is BBB penetrant.
Vanquish is currently conducting pre-clinical, IND enabling CMC and Pharm/tox activities for PAC-1. A phase I clinical trial in human cancer patients began in 2015.