Project Summary / Abstract | The overarching goal of this project is to develop targeted therapies for peripheral T cell lymphoma (PTCL), a diverse group of aggressive lymphomas that develop from T cells or natural killer cells and lack standards of care. The current therapeutic options for PTCL are limited due to the lack of effective targeted therapeutics and incomplete understanding of the molecular etiology for this dismissal disease. In this application, the team aims to address this critical gap by developing novel Proteolysis Targeting Chimera (PROTAC) and repurposing existing drugs to treat PTCL with genetic defects in TET2 and RHOA (G17V as the hot spot mutation). The co-existence of TET2 and RHOA mutations is frequently detected in T cells of PTCL patients but not in other types of hematological neoplasms, making it an ideal target for targeted therapeutics development. We further discovered that an oncogenic synergy between TET2 and RHOA drives Vav1- calcineurin (CaN)-NFAT signaling axis to augment NFAT activation and promote malignant transformation of T cells. These novel findings led the team to hypothesize that targeting this oncogenic synergy can effectively reduce tumor burden. To accelerate the mechanistic and translational studies with clinically-relevant animal models, the team has generated genetically modified mouse models that recapitulate the PTCL-like genotype and the major disease hallmarks of PTCL. Capitalizing on the unique transgenic mouse models, the newly- determined 3D structure of the RHOA-G17V mutant, structure-aided screening of mutant RHOA-specific binders and degraders, as well as a suite of molecular tools to probe GTPase signaling, the team is uniquely suited to lead the proposed studies. In Specific Aim 1, the team will develop PROTAC degraders tailored for RHOA(G17V) and test their anti-tumor effects in cellular systems ex vivo. In Specific Aim 2, the team will test the anti-lymphoma efficacy of mutant RHOA degraders in vivo, as well as a combination therapy designed to suppress both upstream mutant RHOA and downstream CaN/NFAT activity with FDA-approved drugs (PROTAC + Tacrolimus). The team will also probe the mechanism of action to better inform the pathogenic mechanism underpinning PTCL. If successful, the proposed study will illuminate previously-underappreciated mechanisms underlying T-cell lymphoma, and establish the preclinical rationale for novel interventional approaches against PTCL. Preclinical testing results obtained from our study will form the basis for immediate follow-on clinical trials. Notably, the PROTAC strategy against RhoA(G17V) will provide one the first examples of targeting a specific GTPase for lymphoma treatment. The potential benefit will be significant considering that apporximately 50- 70% patients with angioimmunoblastic T-cell lymphoma (a subgroup of PTCL) harbor the RhoA(G17V) mutation but lack effective treatment options. Although we propose a study limited to PTCL, the a...