The Dolloff Lab

Research Overview:

The overall goal of the Dolloff Lab is to discover new molecular targeted cancer therapeutics and develop them into new drugs that will ultimately improve the lives of patients. We conduct research spanning nearly the entire continuum of preclinical drug development from high throughput drug screening (HTS) and lead optimization through early toxicology. Our approach to drug screening has a strong focus in combatting therapeutic resistance, with an emphasis on finding new chemical scaffolds and druggable targets that enhance existing cancer therapies. The major cancer of interest in recent years has been multiple myeloma (MM), a plasma cell malignancy that remains incurable for most patients. We are currently developing a new chemical class of protein disulfide isomerase (PDI) inhibitor for treatment refractory MM. PDI catalyzes disulfide bridge formation in newly synthesized proteins and therefore plays a critical role in oxidative protein folding, which is an Achilles’ heel of MM given the mass amounts of immunoglobulins proteins that MM plasma cells produce. An interesting property of our proprietary PDI inhibitors is that they overcome resistance and enhance the activity of proteasome inhibitors (e.g., bortezomib/Velcade) and epigenetic drugs (e.g., HDAC inhibitors). We are currently exploring the molecular basis for these synergistic combinations and designing a clinical development plan that exploits them in proof of concept studies in humans.

Current and future directions of the Dolloff Lab include exploring PDI inhibitor plus epigenetic therapy in solid tumors including glioblastoma and pancreatic cancer, two of the deadliest and most difficult to treat cancers. These projects are being conducted with collaborators at MUSC/Hollings Cancer Center and other leading institutions around the country. As a training environment, the lab provides students and postdocs with the opportunity to learn the drug discovery process, to explore the basic biology behind what makes cancer drugs work (or not work in the case of drug resistance), and to develop the skills required for a productive career in science. Entrepreneurship is also a cornerstone of the lab. The commercialization process is essential in the development of therapeutics, and we focus on capturing commercial value from our research wherever possible. In this way, trainees benefit from exposure to the business side of academic drug discovery and gain experience in intellectual property protection, patent applications, involvement in SBIR/STTR small business projects, along with having access to resources that have traditionally been available only to industry scientists, such as medicinal chemistry contracts, ADME-PK, safety pharmacology, and toxicology.

Highlighted Publications: Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells High-throughput drug screening identifies compounds and molecular strategies for targeting proteasome inhibitor-resistant multiple myeloma