An engineered prodrug for inhibition of cancer growth and metastasis - Treatments for metastatic and recurrent solid tumors, including ovarian, lung and colon cancers, remain a challenge due to lack of potent, selective and effective therapeutics. Clinically approved chemotherapies aim to slow or stop tumor growth; however, cancer cells continue to evolve between chemotherapy cycles, acquiring properties that allow cell survival and successful dissemination, subsequently developing into life-threatening metastatic tumors. There is an urgent need to develop more effective therapeutic strategies based on the biology of metastatic tumors to achieve long-term remission. We are developing the basis for a transformative anti- cancer strategy based on drug delivery by anthrax toxin (AT) proteins engineered to be selectively activated by the catalytic power of dysregulated zymogen-activating proteases on the surface of malignant tumor cells. Specifically, we are leveraging tumor-associated hyperactive membrane-anchored serine proteases (MASPs) to selectively deliver potent cytotoxins that inactivate signaling pathways used by tumors for survival and chemotherapy resistance. We are applying this novel anti-tumor strategy to serous ovarian cancer (OC), a deadly disease which presents in many different molecular and pathological subtypes that complicate rational drug treatment and design. Current clinical management is primarily based on maximal cytoreductive surgery and combination carboplatin-paclitaxel (CPTX) chemotherapy. While targeted therapies have shown some improvements, they have failed to increase the overall survival rate. A high rate of recurrence following the initial treatment has been observed with patients presenting with metastatic tumors that respond poorly to chemotherapy. We have developed a prototype AT prodrug (PAS) that has been re-engineered to be specifically activated by deregulated MASPs on tumor cells, and which, in combination with the cargo lethal factor (LF), delivers potent and selective anti-tumor cytotoxicity. Preliminary data demonstrate that the engineered PAS:LF is a tumor-selective and potent cytotoxic agent that is without side effects at effective therapeutic doses. Notably, we find that exposure of OC cells to CPTX chemotherapy increases tumor-associated MASP cell surface activity and stimulates MAPK prosurvival pathways, which together inadvertently increases metastatic potential, but serendipitously also serves to enhance the efficacy of PAS:LF for tumors exposed to CPTX. The hypothesis to be tested in this proposal is that leveraging hyperactive MASPs on the tumor cell surface to deliver potent cytotoxins selectively into cancer cells using PAS:LF is an effective strategy to target tumor cells and enhance sensitivity to CPTX. The experimental plan proposes to 1) define mechanisms of PAS:LF and other ZMT:LFn drug actions in the absence and presence of CPTX, and 2) determine the efficacy, pharmacokinetic and pharmacodynamic properties of combination of standard-of care CPTX plus PAS:LF for treating high grade OC in preclinical models. This new class of drugs are strong candidates for therapeutic development to improve the prognosis for women with OC, and other solid tumors.
