Receptor Triage as a Novel Anticancer Therapeutic Strategy
Faculty Information
Name:
Dr. Brian Law Ph.D.
Email
bklaw@ufl.edu
Phone
(352) 273-9423
Faculty Department/Division
Pharmacology & Therapeutics
This project is primarily:
Translational
Research Project Description:
Background: Breast cancer remains a major cause of mortality. This is because while early cancers can be effectively treated, advanced cancers that have acquired resistance to therapeutics and the capacity to spread are almost uniformly lethal. Solving these problems requires the dual strategy that employs relevant models of breast cancer metastasis and drug resistance, and new therapeutic agents that are effective against cancer that has already disseminated. We have developed a breast cancer model that forms liver metastasis in parallel with formation of the primary breast tumor. This permits evaluation of the efficacy of treatment regimens against both primary tumors and metastases. Further, we are optimizing a new chemical class of anticancer agents that inhibits four of the > 20 human protein disulfide isomerase (PDI) enzymes. This subset of PDIs, including PDIA1, ERp44, AGR2, and AGR3 are promising anticancer targets based on PDIA1 as an established therapeutic cancer target and recent genetic profiling that identifies ERp44, AGR2, and AGR2 as cancer dependencies. These PDI inhibitors, termed Disulfide bond Disrupting Agents (DDAs) appear to trigger a “receptor triage” process in which pro-cancer receptors are downregulated, while cancer cytotoxic receptors are upregulated and activated. Specifically, the DDAs block the production of multiple receptor tyrosine kinases that promote drug resistance and cancer metastasis, including EGFR, HER2, HER3 and MET. The Wnt signaling pathway plays an important role in drug resistance, metastasis, and cancer stem cell-like activity and DDAs downregulate the essential Wnt coreceptors LRP5 and LRP6. In contrast DDAs upregulate and activate pro-apoptotic Death Receptor 5 (DR5) selectively in cancer cells and oncogene-transformed cells. Based on these observations and our preliminary results, we hypothesize that DDAs optimized for potency, PDI selectivity, safety, and metabolic stability will induce regression of established metastatic breast cancer. This hypothesis will be tested in the following specific aims:
Aim 1: Elucidate the roles of individual Protein Disulfide Isomerases (PDIs) for breast cancer formation and metastasis
1a. Examine the requirement for ERp44 and AGR2 in formation of primary and metastatic cancer lesions
1b. Define the PDI client receptors and secreted proteins essential for cancer metastasis
Aim 2: Optimization of the potency, selectivity, and delivery of isoform-selective PDI inhibitors
2a. Profile the PDI selectivity of a new generation of PDI inhibitors
2b. Select the most favorable cyclodextrin excipient for maximizing oral delivery of PDI candidates
2c. Define structural features of PDI inhibitors associated with maximal metabolic stability and minimal toxicity
Aim 3: Evaluate the efficacy of mono- and combination therapies of novel PDI inhibitors against established metastatic breast cancer
3a. Identify the PDI inhibitor with maximal anticancer efficacy in animal models
3b. Assess the activity of PDI inhibitor-based combination therapies against primary and disseminated cancer
3c. Determine the molecular mechanisms of anticancer activity of PDI inhibitor-based combination regimens
Does this project have an international component or travel?
No
If your project has an international component please give details (where, when, data collection involved, etc.):
NA