We have three active research projects:
The overall goal of our translational research program is to develop novel therapeutics and pharmacologically-driven strategies for improving the treatment of cancer patients. There are three major project areas.
We have created a series of fusion proteins each of which contains a moiety that binds selectively to ovarian cancer cells, and a toxin capable of killing cells when even a few molecules are delivered intracellularly. One example is a protein containing a peptide that targets claudins that are over-expressed ovarian cancer cells linked to TNF. Another is granzyme B coupled to a protein that binds to the luteinizing hormone receptor found on ovarian, prostate and breast cancers. We are using cell biological, molecular engineering and genetic techniques to identify and validate other cell surface targets on ovarian cancers that can be used to further enhance the selectivity of such tumor-targeting toxins.
Resistance to cisplatin, carboplatin and oxaliplatin develops rapidly during chemotherapy and is a major obstacle to the cure of even initially responsible tumors. We have previously shown that these drugs enter tumor cells, are distributed to targets within cells and are exported from cells by transporters and chaperones that regulate copper homeostasis. We are studying how the major copper influx transporters, CTR1 and CTR2, mediate the influx of these platinum-containing drugs, and how the copper efflux transporters ATP7A and ATP7B export them. Guided by molecular modeling, we are identifying the structural components essential to Pt-drug transport by expressing mutant forms of these transporters in mammalian cells and determining how they alter the cellular pharmacology and efficacy of cisplatin, carboplatin and oxaliplatin. Insights from these studies are utilized to develop new strategies for the clinical use of these drugs.
This laboratory has launched a number of novel drug delivery systems into the clinic including the lipid foam particles that are the basis for the drug DepoCyt, and cisplatin and oxaliplatin-loaded polymers that enhance the amount of drug reaching many types of tumors that are currently in clinical trial. We have recently produced a paclitaxel-loaded polymer that out-performs Abraxane in animal models and is completing pre-IND studies. We collaborate with other members of the Center for Cancer Nanotumor Excellence at UCSD to use nanoparticles targeted to tumors with specific ligands as drug delivery vehicles. In addition to design and production, we carry out preclinical efficacy, toxicology and pharmacology studies of these novel drug delivery systems.