Mantle cell lymphoma (MCL), an aggressive and incurable subtype of B-cell lymphoma, shows a high possibility for disease progression and relapse even after complete remission with the current frontline therapies such as ibrutinib, venetoclax and more recently CAR T therapy approved by FDA with clinical trials led by Dr. Wang (co-PI in this proposal). Once relapsed, the patients will face more aggressive disease that requires immediate alternative therapies to overcome the resistance. Developing novel therapeutic approaches to overcome drug-resistance in MCL thus represents an unmet medical need. Inspired by our recent advances in translational and preclinical studies and the initiation of ph...

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Mantle cell lymphoma (MCL), an aggressive and incurable subtype of B-cell lymphoma, shows a high possibility for disease progression and relapse even after complete remission with the current frontline therapies such as ibrutinib, venetoclax and more recently CAR T therapy approved by FDA with clinical trials led by Dr. Wang (co-PI in this proposal). Once relapsed, the patients will face more aggressive disease that requires immediate alternative therapies to overcome the resistance. Developing novel therapeutic approaches to overcome drug-resistance in MCL thus represents an unmet medical need. Inspired by our recent advances in translational and preclinical studies and the initiation of phase I clinical trials using CDK9 inhibitors, CDK9 is a promising target for overcoming therapeutic resistance. Instead of developing conventional kinase inhibitors, here we apply a novel approach using proteolysis-targeting chimeras (PROTACs) to generate unique and patentable molecules with two functions acting as 1) CDK9 kinase inhibitors & 2) CDK9-specific degraders. Our hypothesis is that selective degradation of CDK9 protein represents a unique therapeutic approach for treatment of incurable MCL. Our pilot studies support the proof-of-concept that targeting CDK9 for degradation is a novel yet promising approach in overcoming therapeutic resistance in refractory/relapsed MCL. We will optimize our lead CDK9 PROTACs via chemical design and synthesis followed by in vitro cell-based assays and in vivo xenograft-based animal experiments to identify drug candidates for further clinical development. If successful, this project will have a major impact and a paradigm shift in developing a more efficient regimen for refractory/relapsed MCL patients who demand alternative efficacious therapies to overcome prior therapeutic resistance and in improving significant treatment outcomes, quality of life, and overall survival and prognosis.

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