Summary
Development of an engineered anthrax toxin prodrug (PAS:LF) designed to selectively target and inhibit the growth and metastasis of solid tumors, particularly serous ovarian cancer, by leveraging tumor-associated proteases.
An engineered prodrug for inhibition of cancer growth and metastasis
US · IL
NIH
grant
awarded
#nih-5R01CA290796-02
What they want
The project aims to develop a transformative anti-cancer strategy based on drug delivery by anthrax toxin (AT) proteins engineered to be selectively activated by dysregulated zymogen-activating proteases on the surface of malignant tumor cells. Specifically, it leverages 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. This novel anti-tumor strategy is applied to serous ovarian cancer (OC). The hypothesis to be tested 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.
Deliverables
- Defined mechanisms of PAS:LF and other ZMT:LFn drug actions in the absence and presence of CPTX.
- Determined efficacy, pharmacokinetic and pharmacodynamic properties of combination of standard-of-care CPTX plus PAS:LF for treating high grade OC in preclinical models.
Technical requirements
- Engineered anthrax toxin (AT) proteins
- Zymogen-activating proteases
- Membrane-anchored serine proteases (MASPs)
- Prototype AT prodrug (PAS)
- Cargo lethal factor (LF)
- Carboplatin-paclitaxel (CPTX) chemotherapy
- MAPK prosurvival pathways
- Preclinical models
