Targeting the Proteasome

Researchers at University Hospital are focused on understanding regulation of the proteasome, the most complex, important, and intricately regulated protease in nature. The proteasome exerts regulatory effects over many aspects of cell biology under physiologic conditions and is deregulated in pathologies such as cancer, autoimmunity, proteinopathies, and neurodegenerative diseases. Our long-term goal is to translate advancements in our understanding of proteasomal biology with clinical research and to advance those findings from bench-to-bedside.

Personalized cancer care requires treatment that specifically targets biomolecules defining a given tumor, based on knowledge of the tumor’s molecular features. Our recent advances in genomics and proteomics in multiple myeloma have increased our understanding of disease pathogenesis, helped to identify novel therapeutic targets, and provided the scientific rationale for combining targeted therapies to increase tumor-cell cytotoxicity and abrogate drug resistance.

Research Aims to Understand the Regulation of Proteasomes

James J. Driscoll, MD, PhD, Assistant Director of the Hematologic Malignancies Translational Program at University Hospitals Cleveland Medical Center, and a member of the Division of Hematology & Oncology at UH as well as the Case Western Reserve University School of Medicine and Seidman Cancer Center, leads a robust portfolio of proteasome research. His NIH-funded research focuses on understanding the regulation of proteasomes, which control cell biology, a key in advancing cancer treatment.

Researchers Study the Blocking Function of TGFβ  Signaling Pathway to Slow Cancer Growth

James J. Driscoll, MD, Ph.D and James Ignatz-Hoover, MD, PhD were among the team of researchers at the University Hospitals Seidman Cancer Center to conduct a single-arm, phase 1b study examining if blocking the function of transforming growth factor-beta (TGFβ) signaling pathway slows cancer cell growth and improves the efficacy of cytotoxic and immunotherapies. They studied the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/orrefractory multiple myeloma patients who had received at least two lines of chemoimmunotherapy. Secondary endpoints showed sustained clinical responses, favorable pharmacokinetic parameters and a six-month progression-free survival of 82%. Researchers found that vactosertib combined with pomalidomide was well tolerated at all dose levels and displayed a manageable adverse event profile. Investigative analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of multiple myeloma cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. The findings demonstrated that Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Researchers indicated that Vactosertib shows promise in improving immunotherapeutic responses in heavily pretreated multiple myeloma patients who do not respond well to conventional agents. The findings were published in the August 27, 2024, issue of Nature Communications.