Development of mutant GTPase-specific degraders for peripheral T cell lymphoma treatment
Yubin Zhou
PhD, MBBSTexas A&M Institute of Biosciences and Technology
Project Term: July 1, 2023 - June 30, 2026
This project aims to develop targeted therapies against peripheral T cell lymphoma (PTCL), a diverse group of aggressive blood cancers with poor clinical outcomes. This project is tightly relevant to cancer control and treatment, promising to advance our understanding on how blood cancers initiate and progress, and lead to new therapeutics for the treatment of peripheral T cell lymphoma (PTCL). We will develop targeted therapeutics to engage an oncogenic RHOA GTPase mutant to treat PTCL and other types of tumors with similar genetic backgrounds.
This project aims to develop targeted therapies against peripheral T cell lymphoma (PTCL), a diverse group of aggressive blood cancers with poor clinical outcomes. The current therapeutic options for PTCL are very limited and ineffective, owing to the lack of targeted therapeutics and incomplete understanding of the molecular basis for this dismissal disease. Recent high throughput sequencing studies in PTCL patient have unveiled concurrent TET2 and RHOA mutations as the major culprit for a subgroup of PTCL. The therapeutic potential to target TET2/RHOA defects is yet to be explored.
To address this key clinically-relevant knowledge gap, we will combine integrative epigenomics, innovative chemical biology and pharmacological approaches to explore the therapeutic potential of degrading the upstream RhoA-G17V mutant or repurposing FDA-approved drugs to modulate the downstream NFAT/AP1 transcriptional network to kill lymphoma cells. We have generated a unique mouse model of PTCL and novel molecular tools to accelerate our proposed studies. Key findings made in animal models will be further validated in clinically-relevant cells and patient samples via collaborations with clinicians.
This project is tightly relevant to cancer control and treatment, promising to advance our understanding on how blood cancers initiate and progress, and lead to new therapeutics for the treatment of lymphoma and other types of tumors sharing the similar genetic background. We will establish the preclinical rationale for targeting defective RHOA/TET2 to treat lymphoma and other types of tumors with similar genetic backgrounds.