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Principal Investigator: Yubin Zhou
Organization: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
Fiscal Year: 2024
Award: $168,026
Funding agency: National Cancer Institute
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 approaches and drug
candidates that we develop can be applied to encompass the study of other cancers.
Terms: <3-D structure><3-dimensional structure><3D structure><AILD><AILT><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><ARH12><Acceleration><Activator Protein-1><Address><Affect><Angioimmunoblastic Lymphadenopathy><Angioimmunoblastic Lymphadenopathy Type T-Cell Lymphoma><Angioimmunoblastic Lymphadenopathy with Dysproteinemia><Angioimmunoblastic T-Cell Lymphoma><Animal Model><Animal Models and Related Studies><B lymphoma><B-Cell Lymphomas><Basal Transcription Factor><Basal transcription factor genes><Bio-Informatics><Bioinformatics><Biology><Biometrics><Biometry><Biostatistics><Blood Cells><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Calcineurin><Calcineurin antagonist><Calcineurin inhibitor><Cancers><Caring><Causality><Cell Communication and Signaling><Cell Signaling><Clinical><Clinical Management><Clinical Trials><Combined Modality Therapy><Cytotoxic cell><DNA Methylation><Diagnosis><Disease><Disorder><Drug usage><Drugs><Enhancer-Binding Protein AP1><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><FDA approved><FK 506><FK506><Family member><GTP Phosphohydrolases><GTPases><Gene Modified><GeneHomolog><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Genotype><Germinoblastic Sarcoma><Germinoblastoma><Goals><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Hand><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Homolog><Homologous Gene><Homologue><Hot Spot><Human><Immunoblastic Lymphadenopathy><Intervention><Intervention Strategies><Intracellular Communication and Signaling><K lymphocyte><Lead><Lesion><Lymphoma><Lymphomagenesis><Malignant><Malignant - descriptor><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Malignant Lymphoma><Malignant Neoplasms><Malignant Tumor><Mature T-Cell><Mature T-Lymphocyte><Medication><Medicinal Chemistry><Mice><Mice Mammals><Modern Man><Modification><Molecular><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><NF-AT><NF-AT proteins><NFAT proteins><NFAT-1><NFATC proteins><NK Cells><Natural Killer Cells><Oncogenic><PP2B><Pathogenicity><Pathway interactions><Patients><Pb element><Penetrance><Peripheral><Peripheral Blood Cell><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pilot Projects><Play><Position><Positioning Attribute><Preclinical Testing><Progression-Free Survivals><Property><Protac><Protein Phosphatase-2B><Proteolysis targeting chimeric><RHOA><RHOA gene><RHOH12><Records><Reticulolymphosarcoma><Rho12><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Somatic Mutation><Structure><Subgroup><System><T-Cell Lymphoma><T-Cell Non-Hodgkin's Lymphoma><T-Cell NonHodgkins Lymphoma><T-Cell Transformation><T-Cell and NK-Cell Non-Hodgkin's Lymphoma><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Tacrolimus><Technology><Test Result><Testing><Therapeutic><Transcription Factor AP-1><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Tumor Burden><Tumor Load><United States><anti-tumor effect><antitumor effect><biological signal transduction><blood cancer><cancer cell><cancer of blood><cancer of the blood><causation><clinical relevance><clinically relevant><combination therapy><combined modality treatment><combined treatment><cytoplasmic nuclear factor of activated T-cells><design><designing><determine efficacy><disease causation><drug candidate><drug use><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epigenetically><evaluate efficacy><examine efficacy><gene modification><genetically modified><genome mutation><guanosinetriphosphatase><hands><heavy metal Pb><heavy metal lead><improved><in vivo><intervention design><interventional strategy><malignancy><model of animal><mouse model><multi-modal therapy><multi-modal treatment><murine model><mutant><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nuclear factors of activated T-cells><pathway><pilot study><pre-clinical><pre-clinical testing><preclinical><proteolysis targeting chimera><public health relevance><rho><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><screening><screenings><small molecule><somatic variant><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapy design><three dimensional structure><thymus derived lymphocyte><tool><transcription factor><transcription factor NF-AT><translational study><treatment design><tumor><tumor growth>