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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA120439-06A1
Application #
8577782
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2005-12-01
Project End
2018-06-30
Budget Start
2013-07-02
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$451,618
Indirect Cost
$130,706
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Roth, Howard S; Hergenrother, Paul J (2016) Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities. Curr Med Chem 23:201-41
Peh, Jessie; Fan, Timothy M; Wycislo, Kathryn L et al. (2016) The Combination of Vemurafenib and Procaspase-3 Activation Is Synergistic in Mutant BRAF Melanomas. Mol Cancer Ther 15:1859-69
Roth, Howard S; Botham, Rachel C; Schmid, Steven C et al. (2015) Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics. J Med Chem 58:4046-65
Palchaudhuri, Rahul; Lambrecht, Michael J; Botham, Rachel C et al. (2015) A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed. Cell Rep 13:2027-36
Botham, Rachel C; Fan, Timothy M; Im, Isak et al. (2014) Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity. J Am Chem Soc 136:1312-9
Hsu, Danny C; Roth, Howard S; West, Diana C et al. (2012) Parallel synthesis and biological evaluation of 837 analogues of procaspase-activating compound 1 (PAC-1). ACS Comb Sci 14:44-50
West, Diana C; Qin, Yan; Peterson, Quinn P et al. (2012) Differential effects of procaspase-3 activating compounds in the induction of cancer cell death. Mol Pharm 9:1425-34
Palchaudhuri, Rahul; Hergenrother, Paul J (2011) Transcript profiling and RNA interference as tools to identify small molecule mechanisms and therapeutic potential. ACS Chem Biol 6:21-33
Lucas, Pamela W; Schmit, Joanna M; Peterson, Quinn P et al. (2011) Pharmacokinetics and derivation of an anticancer dosing regimen for PAC-1, a preferential small molecule activator of procaspase-3, in healthy dogs. Invest New Drugs 29:901-11

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