Procaspase-3 is an executioner protein catalyzes the hydrolysis of more than 100 protein targets. These cleavage events ultimately lead to cell suicide, or apoptosis. Caspase-3 is triggered by the intrinsic and extrinsic apoptosis cascades.
Most tumors have disruptions in the protein signal cascades that produce active caspase-3. These disruptions thwart cell suicide and allow the cancer to grow unchecked. 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.
Vanquish has developed a small molecule, PAC-1 (Procaspase Activating Factor–1), that 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.PAC-1 likely acts by interfering with one of caspase-3’s safety features. The protein is normally in an inactive form called procaspase-3 until a domain of the protein is chopped off, thereby creating active caspase-3. A further three-amino-acid safety catch prevents procaspase-3 from activating itself by cleaving itself. PAC-1 is believed to work by interfering with this safety catch, thereby allowing procaspase-3 to activate itself and initiate cell death.
Unlike inhibitors that work stoichiometrically, PAC-1 is a catalytic activator, Hergenrother (University of Illinois, Urbana-Champaignsaid). “This is a benefit. One molecule of PAC-1 will activate procaspase-3 to produce caspase-3. Then PAC-1 is free to activate another one.”
“This is a novel strategy for a cancer therapy,” commented Michael F. Olson of the Beatson Institute for Cancer Research in Glasgow, Scotland. “Going straight to one of the key proteins that actually kills the cell and directly activating it could induce the death of cancer cells that are insensitive to many forms of standard chemotherapy.”
Initial research with patient tissue samples and mouse models shows that PAC-1’s ability to destroy cancer cells is related to the levels of procaspase-3 in a cell, Hergenrother said. “Since tumor procaspase-3 levels can be measured, one might be able to predict a priori what types of patients would respond to a procaspase-3 activator. This is a step toward personalized cancer therapy.”
A clinical trial was initiated last year – the Phase 1 dose escalation trial, which is still recruiting patients, is being evaluated in a number of cancers: Breast, gastrointestinal, genitourinary, gynecologic, head and neck, thoracic, as well as lymphomas, melanomas and solid tumors.