The ability to match therapeutic compounds with cancer cells containing specific molecular aberrations can lead to profound and personalized anticancer activity. We have identified a class of compounds, exemplified by founding member PAC-1, which activate the enzyme procaspase-3, leading to apoptotic death even in cancer cells with common defects in their apoptotic cascade (e.g., p53 mutation, Bcl-2 overexpression, caspase-9 mutation). As many cancers overexpress procaspase-3, such procaspase-3 activating compounds have potential to be highly specific for cancer cells. As part of R01-CA120439, we elucidated the mode of action of PAC-1 in vitro and in cancer cells in culture, and explored its efficacy in advanced mammalian tumor models. Excitingly, in addition to its considerable single-agent efficacy, we have discovered that PAC-1 powerfully synergizes with standard-of-care drugs used in the treatment of two deadly cancers, glioblastoma multiforme (GBM) and metastatic osteosarcoma (OS), both of which express elevated levels of procaspase-3. In this renewal we will synthesize improved versions of PAC-1, assess them in sophisticated animal models of GBM and metastatic OS both alone and in conjunction with frontline therapies, and fully define the potential of PAC-1 to synergize with a variety of anticancer agents. Innovative aspects of this proposal include procaspase-3 activation as an anticancer target, the mechanistically-driven use of PAC-1 in synergy with conventional anticancer drugs, the exploitation of the blood-brain barrier penetrating property of PAC-1 for treatment of GBM, and the evaluation of PAC-1 in pet dogs with cancer, a highly relevant translational model and an opportunity to help these animals that might otherwise be euthanized. Our data suggest that PAC-1, both alone and operating in synergy with a wide variety of antitumor agents, has broad anticancer applications.
Glioblastoma multiforme (GBM) and metastatic osteosarcoma (OS) are two cancers for which no effective treatment options are available. Through the work proposed herein our multi- disciplinary team will develop procaspase-3 activating compounds for the treatment of these diseases. Optimized compounds will be identified through a defined tiered series of assays, and assessed in sophisticated animal models of GBM and metastatic OS.
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