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Degradation of RPN13 for Treatment of Multiple Myeloma

In vivo and in vitro studies show potent anti-MM activity and a more favorable therapeutic window compared to proteasome inhibitors.

Therapeutics

Project Overview

Standard treatment protocols for Multiple Myeloma (MM) include proteasome inhibitors. While initially highly effective at limiting cancer growth, resistance mechanisms lead to diminished efficacy, highlighting the need for alternative approaches to proteasomal disruption in MM.
Dana-Farber scientists have developed a technology for degrading a novel protein target, RPN13, found in excess in MM.
The degrader-based technology targeting the RPN13 protein is available for further development as part of a collaboration, research agreement, or through licensing.

Technology

Multiple Myeloma (MM) is a largely incurable malignancy of plasma cells that accounts for approximately 10% of all hematologic cancers. Standard MM treatment protocols include proteasome inhibitors, such bortezomib, that act by inhibiting the catalytic activity of the 20S component of the ubiquitin-proteasome system. While initially highly effective at limiting cancer growth, proteasome inhibitors are associated with diminished efficacy over time due to the development of resistance mechanisms by the cancer cells. Furthermore, high systemic concentrations of proteasome inhibitors are required for effective treatment, leading to adverse side effects. There remains a need for alternative approaches to proteasomal disruption in MM.

Researchers at Dana-Farber Cancer Institute have identified a proteasome-associated ubiquitin receptor, RPN13, upstream of the 20S protein that is overexpressed in MM cells and, therefore, serves as a promising alternative target for proteasome-based therapeutics. The technology described herein is a PROTAC degrader that targets the RPN13 protein. Whereas an inhibitor simply blocks a protein’s function, this degrader-based strategy induces destruction of the RPN13 protein, thereby preventing the development of resistance mechanisms that undermine the efficacy of proteasome inhibitors.

Treatment of MM cell lines and patient-derived MM cells with the RPN13 degrader resulted in reduced cancer viability. Importantly, anti-MM activity was sustained in further in vitro studies with bortezomib resistant MM cell lines and patient cells. In vivo studies of the RPN13 degrader in a human MM xenograft mouse model yielded inhibited cancer cell growth and prolonged host survival with half the dose required to elicit the same effect via proteasome inhibitors.

Benefits:

In vivo and in vitro studies show potent anti-MM activity
Shows anti-MM activity in bortezomib-resistant and p53-mutant cell lines
More favorable therapeutic window compared to proteosome inhibitors
No impact on the rest of the proteosome

Further Information:

Song, Y., Park, P.M.C., Wu, L. et al. Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma. Leukemia 33, 2685–2694 (2019).

Team Members: Jun Qi, PhD, Yan Song, PhD, Kenneth Anderson, MD, Dharminder Chauhan, JD, PhD, Lei Wu, PhD

Applications

Treatment of Multiple Myeloma, including proteasome inhibitor-resistant cases
Treatment of non-myeloma hematologic cancers (i.e., leukemias, lymphomas)

Opportunities

Dana-Farber is seeking strategic research agreements, collaboration, or licensing opportunities for this technology.

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