Unit: Drug Discovery and Development
Harrison College of Pharmacy
357 Pharmacy Research Building
720 South Donahue Drive
Auburn, AL 36849
1992-94: Visiting Graduate Student, Max von Pettenkofer-Institute, Ludwig-Maximilian University, Munich, Germany
1995: Visiting Scientist, Max-Planck-Institute for Biochemistry, Martinsried, Germany
1995-2004: Postdoctoral Fellow, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
2004-17: Member, Molecular Therapeutics Program, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
2004-11: Assistant Professor of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
2011-16: Associate of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
2016-17: Biomedical Research Scientist, Veterans Affairs Medical Center, White River Junction, Vermont, and Associate Professor of Medicine (Hematology/Oncology), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
2016-present: Founder and Chief Scientific Officer, InhiProt LLC
2017-present: Associate Professor of Drug Discovery and Development, Auburn University Harrison College of Pharmacy
2020-present: Scientist, Experimental Therapeutics Program, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham
Proteasome inhibitor for the treatment of solid tumors
Funder: NCI R01 CA213223
Role: Principal Investigator
Total Cost: $1,805,000
Goal: The major goal of this project is to determine whether 2-specific proteasome inhibitors sensitize triple-negative breast cancer cells to FDA-approved proteasome inhibitors, and whether inhibition of the recovery of proteasome will also sensitize them to these agents.
Overview - My laboratory is focused on targeting the proteasome for the treatment of cancer. The proteasome is a multi-subunit, multiple active sites proteolytic complex that, through degradation of abnormal polypeptides, plays a key role in protein quality control in every mammalian cells. It also degrades many regulatory proteins and thus plays a major role in the regulation of many cellular functions (e.g., cell cycle, gene transcription). Rapidly proliferating tumor cells depend more on proteasome function than non-malignant cells, creating a therapeutic window for using proteasome inhibitors for the treatment of cancer. Three proteasome inhibitors, bortezomib, carfilzomib and ixazomib, are approved by the FDA for the treatment of multiple myeloma and mantle cell lymphoma.
Major Accomplishments - The major accomplishment of our laboratory is the development of specific inhibitors of b5, b1 and b2 active sites and using these inhibitors to define the roles of these sites as drug targets in cancer. We found that inhibition of b5 sites, which are the prime targets of the FDA-approved inhibitors, is not sufficient to cause apoptosis of tumor cells, and that specific inhibitors of b1 and b2 sites dramatically sensitize malignant cells to b5 inhibitors.
Current Projects - The major goal of our laboratory is to expand the use of proteasome inhibitors to the treatment of different cancers, using the knowledge about optimal active site profile of these agents that we generated using site-specific inhibitors. We are focusing on acute lymphoblastic leukemia (ALL) and triple-negative breast cancer (TNBC) because cell lines derived from these cancers are as sensitive to bortezomib as multipel myeloma cells. We are pursuing several projects.
Nanoparticle formulations of proteasome inhibitors to solid tumors. The major obstacle to expanding use of proteasome inhibitors to the treatment of solid tumors is their low metabolic stability, poor tumor penetration and on-target toxicities due to inhibition of proteasome in normal tissues (e.g., gastrointestinal, cardiac and renal toxicities). To overcome these problems, we are developing, in collaboration with Dr. Arnold in our department, liposomal nanoparticle formulations of proteasome inhibitors.
Immunoproteasome inhibitors for the treatment of hematologic malignancies. Hematologic malignancies are difficult to target with nanoparticles, and our approach to selective inhibition of proteasome in these tumors is to target lymphoid-tissue specific form of proteasome called the immunoproteasome. ALL cells express the highest ratio of immune to constitutive proteasomes among hematologic malignancies, and we found that ALL cells are very sensitive to immunoproteasome inhibitors. This projects is focused on a subtype of ALL that is driven by t(4;11) chromosomal translocation that results in the expression of MLL-AF4 fusion protein, confers poor prognosis, but makes cells highly sensitive to proteasome inhibitors. Most infant ALLs are driven by this translocation and an additional benefit of using immunoproteasome inhibitors instead of FDA-approved inhibitors is that it will reduce pediatric specific toxicities (e.g., inhibition of bone growth and testicular development) caused by inhibition of constitutive proteasome in non-lymphoid tissues.
Mechanism of recovery of proteasome activity after treatments with inhibitors. Another obstacle to clinical efficacy of proteasome inhibitors is the rapid recovery of proteasome activity after clinically relevant pulse-treatment. According to the published literature, the recovery is a transcriptional response mediated by the transcription factor Nrf1 (NFE2L1), which is activated by a novel aspartic protease DDI2. We have obtained strong evidence that there is a second pathway for the recovery of proteasome activity and are currently dissecting this pathway.
Mechanistic basis of sensitivity of non-myeloma cells to proteasome inhibitors. Despite an essential role of proteasome in the quality control of nascent polypeptides, proteasome inhibitors are effective in MM cells because these cells produce and secreted large amounts of immunoglobulins creating a very high load on proteasome. Together with other laboratories, we found that sensitivity of myeloma cells to proteasome inhibitors depends on the load of proteasomes in these cells. ALL and TNBC cells are as sensitive to proteasome inhibitors as MM in vitro but molecular basis of such sensitivity is not known. We are currently testing whether high load on proteasome in these cells is responsible for higher sensitivity and why the load on proteasomes in these cells is higher than in other tumors.
Novel proteasome inhibitors. 26S proteasome consists of 20S proteolytic core, which contains 1, 2, and 5 proteolytic sites, and 19S regulatory particle that recognizes and unfold substrates, and controls access to the 20S proteolytic core. Unfolding is carried out by 6 ATPase subunits of the 19S particles. There are no inhibitors of proteasome 19S ATPase activity. While investigating the mechanism of synergy between proteasome inhibitors and inhibitors of Bruton’s tyrosine kinase (BTK) kinase we found that some of them inhibit multiple proteolytic activities of the 20S core and ATPase activity of the 26S proteasome. This work demonstrates the feasibility of the development of inhibitors of the 26S proteasome ATPase activity.