Research / Clinical Summary

Stephen Howell, MD Professor, Medicine Tumor Growth, Invasion & Metastasis Program Contact by Email Visit the Website

Other Leadership Roles:
Associate Director for Clinical Research
Co-Leader, Tumor Growth, Invasion and Metastasis Research Program
Director, Pharmacology and Toxicology Core Lab, Center for Cancer Nanoparticle Excellence

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. The first is directed at elucidating the mechanisms by which tumors become resistant to the platinum-containing drugs with the goal of developing strategies for preventing or overcoming resistance. The second is focused on the construction, production and testing of proteins that contain two moieties, one that targets the molecule to tumors and another that is a potent toxin capable of selectively killing tumor cells or their supporting vessels or stroma. The third involves the use of nanoparticles and polymers to produce novel drug delivery systems that increase chemotherapeutic efficacy.

Resistance to cisplatin, carboplatin and oxaliplatin develops rapidly during chemotherapy and is a major obstacle to the cure of even initially responsible tumors. Our team documented that these drugs enter tumor cells, are distributed to targets within cells and are exported from cell 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 Pt-containing drugs, and we are using knockout and RNAi technology to elucidate the role of the other proteins known to influence copper homeostasis on the cellular pharmacology of these drugs. This includes expression profiling of isogenic drug-sensitive and resistant pairs of human ovarian carcinoma cells and examination of how their microRNA levels differ. Insights from these cell and molecular biologic studies are utilized to develop new strategies for the clinical use of these drugs. One such strategy involves controlling the level of the CTR1 influx transporter through inhibition of its degradation by the proteosome inhibitor bortezomib.

Protein therapeutics have become important drugs. We are developing a novel class of tumor-targeting toxins that builds on major advances in the ability to combine functional domains from different kinds of proteins to create molecules that both accumulate in specific types of tumors and carry a payload capable of killing the tumor cells when either concentrated on the cell surface or after internalization via endocytosis. In one case we are on targeting the human luteinizing hormone receptor (hLHR) which is expressed at high levels on ovarian, breast and prostate cancers. We have constructed a molecule consisting of both the alpha and beta chains of human chorionic gonadotropin fused together via a flexible linker; this is subsequently fused to one of several toxins capable of triggering apoptosis including granzyme B, TNF or the plant toxin gelonin. Other parts of this project involve the development of a human single chain antibody capable of binding to the hLHR, and the use of phage and bacterial display strategies to identify short peptides that bind to the hLHR or other receptors on tumor cells for use in directing drug-loaded nanoparticles to tumor cells.

Nanoparticles hold great promise as drug delivery systems. We are testing nanoparticles payloaded with both standard and novel drugs and coated with ligands that direct the particles to the tumor when delivered either intravenously or, in the case of ovarian cancer, intraperitoneally. Similar studies are utilizing novel types of polymers that spontaneously form micelles as drug delivery vehicles. The work encompasses both early stage development and the execution of IND-enabling studies.