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Carpizo Lab - Research Overview

Carpizo Lab TeamGastrointestinal cancers such as pancreatic, bile duct and liver cancers are plagued by ineffective systemic therapies underscoring the tremendous unmet need for novel therapies. The Carpizo Laboratory studies cancer biology with an emphasis on developmental therapeutics. Our studies range from basic biology to provide clues for novel therapies, to translational research projects to move forward exciting new technologies for cancer treatment.

TP53 is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists. One area of focus is on developing zinc metallochaperones as effective mutant p53 targeted anti-cancer drugs. Our laboratory discovered ZMC1 (zinc metallochaperone-1), which is a small molecule drug that reactivates mutant p53 (PMID: 22624712). The paper was featured in Nature, Nature Reviews Drug Discovery and Cancer Discovery for its significance. ZMC1 and other zinc metallochaperones function to reactivate mutant p53 using a mechanism which involves the molecule binding zinc in the extracellular environment and moving intracellularly to increase zinc concentrations sufficiently to allow mutant p53 to undergo a conformation change to wild type. The pharmacologic delivery of a metal ion to restore wildtype structure of a mutant protein is unprecedented in the field of drug discovery and we have named this new class of anti-cancer drugs, “Zinc Metallochaperones.” (PMID: 25294809), Figure 1. We are currently are funded by the National Cancer Institute and multiple foundations (Breast Cancer Research Foundation, Pancreatic Cancer Action Network) as well as the biotechnology industry (BioMotiv) to continue this research.

Another focus of the lab is the study of the biology of cancer recurrence or othwerwise known as metastatic dormancy. One of the most significant clinical problems in oncology is the recurrence of cancer following an attempt at curative surgery where the patient is disease free for some period of time (sometimes many years) before suffering a recurrence of their cancer due to the activation of “dormant” metastatic cells. This is best exemplified by pancreatic cancer where recurrence is over 75%. Therapies for recurrence are often ineffective indicating a tremendous need for research. Unfortunately this field of cancer research is only in its infancy due to a lack of mouse models that recapitulate recurrence. We have established several mouse models of dormancy in pancreatic cancer using both orthtopic cell injection and spontaneous genetically engineered models.  We are engaged in studies to characterize these cells from a cell and molecular standpoint and to understand the mechanisms of tumor cell dormancy.  

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