The Gene and Linda Voiland School of Chemical Engineering and Bioengineering is hosting a seminar presented by Dr. Rock Mancini, Assistant Professor, Department of Chemistry, Washington State University, Feb. 5, at 4:10 p.m. in ADBF 1002/FLOYD 256 (Tri-Cities).
Rock received his B.S. degree in Chemistry from the University of Pittsburgh where he performed research with Toby Chapman on lysine dendrimers as vectors for gene delivery. From there, he ventured to Los Angeles, California where he received his Ph.D. in Organic Chemistry researching as a NSF-IGERT fellow in the lab of Heather Maynard at UCLA. After receiving his Ph.D., Rock performed a short postdoctoral position at the University of California, Irvine with Aaron Esser-Kahn where he was introduced to the field of synthetic immunology, his current field of research. Following this, Rock joined the Washington State University faculty in 2015 where he is presently an Assistant Professor in the Department of Chemistry.
Drugging Drug Resistance with Enzyme-Directed Imidazoquinolines
Acquired drug resistance in cancer is a long-standing challenge that reduces the efficacy of all chemotherapeutic drugs. In contrast, the efficacies of modern cancer immunotherapies are not typically affected by the prevalence of chemo-resistant phenotypes. Here, we improve upon this paradigm by targeting the action of immunotherapeutics to two general mechanisms of acquired drug resistance: irregular metabolism and drug efflux mediated by the ABC superfamily of transport proteins. In chemo-resistant cancer cells, we demonstrate that these two mechanisms act in concert to selectively convert our newly developed class of enzyme-directed imidazoquinoline prodrug to the immunotherapeutic Imiquimod. Following metabolism, the liberated Imiquimod metabolite undergoes drug efflux to the extracellular space, where it activates bystander immune cells in local proximity. In-vitro, we characterize this process of Bystander-Assisted ImmunoTherapy (BAIT) in an AT3B-1 chemo-resistant prostate cancer model with RAW-Blue and JAWSII reporter immune cell lines. Co-culture of AT3B-1 cancer cells with reporter immune cells and our prodrug results in immunogenicity mediated selectively by chemo-resistant cancer cells. This is observed by enhanced NF-κB transcription, as well as expression of cell surface markers and secreted cytokines, indicative of a cell-mediated immune response. Our prodrug is non-immunogenic with healthy cells alone and the enzyme-directing groups are stable for several days in serum. Taken together, these results demonstrate that BAIT co-opts common mechanisms of drug resistance to elicit immunogenicity mediated by cancer cells themselves. We anticipate that BAIT will find use as a new mechanism of action that exploits drug resistance to generate an anti-cancer immune response.
