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Principal Investigator: Michael Method
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $638,605
Funding agency: National Cancer Institute
Project Summary
The 5-year overall survival from acute myeloid leukemia (AML) is less than 30%. While some patients are cured
with initial induction therapy, most patients relapse, and the expected outcomes in patients with relapsed and
refractory (R/R) AML are dismal. For this reason, developing methods to identify therapies likely to benefit R/R
AML patients is a top priority. This proposal aims to address critical unmet needs with a unique Academic-
Industry Partnership (AIP) between investigators at Vanderbilt University Medical Center, Karyopharm
Therapeutics, and Notable Labs. The BCL2 inhibitor, venetoclax (VEN), is transforming clinical practice for AML,
but activity in R/R AML is less pronounced, and resistance occurs in most patients. AIP investigators currenty
lead a multi-site investigator-sponsored study, testing VEN in combination with the selective inhibitor of nuclear
export (SINE) selinexor (SEL) in a Phase I trial for R/R AML (NCT03955783). This SEL/VEN trial grew from the
discovery that SEL synergizes with VEN and overcomes resistance mechanisms in some VEN-insensitive
patient samples. Given this, our AIP team has worked together to develop a precision medicine functional
platform for this novel combination in R/R AML. Notable Labs utilizes an automated high-throughput,
immunophenotype-based flow cytometry method to provide real time drug sensitivity data on multiple, specific
cell populations simultaneously within a given patient sample. Building from the only annotated cohort of patient
samples treated with SEL/VEN in the world, we propose to develop a precision medicine functional assay to
identify R/R AML patients most likely to benefit from SINE/VEN combination therapy. We will build, refine and
optimize the functional platform for SEL/VEN with samples from our current Phase I study and train the platform
on samples from the Phase 2 SEL/VEN clinical trial proposed by the AIP. Aim 1 will focus on determining assay
parameters specifically for SEL/VEN in R/R AML. Aim 2 will train the model with the phase II clinical trial of
SEL/VEN in R/R AML, and Aim 3 will contextualize the predictive analytic model on heterogenous genotypes
found in R/R AML. At the conclusion of this study, the functional medicine platform will be a companion
diagnostic ready for external validation which we will lead in a phase III efficacy trial of SEL/VEN in R/ R AML,
and serve as proof-of-principle for development of similar therapy-specifc precision medicine tools.
Terms: <AML - Acute Myeloid Leukemia><Abscission><Academic Medical Centers><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Address><Antioncogene Protein p53><Apoptotic><Assay><B cell lymphoma 2><B-Cell CLL/Lymphoma 2 Gene><B-cell lymphoma/leukemia-2><BCL2><BCL2 gene><Bcl-2><Bioassay><Biological Assay><Blood monocyte><CRM1 protein><Caring><Cell Body><Cell Line><Cell Nucleus><CellLine><Cells><Cellular Tumor Antigen P53><Clinical><Clinical Management><Clinical Trials><Combined Modality Therapy><Cytoplasm><Data><Data Set><Dependence><Development><Disease><Disease-Free Survival><Disorder><Dose><Effectiveness><Evaluation><Event-Free Survival><Excision><Exhibits><Exportins><Extirpation><FLK2><FLT3><FLT3 gene><FMS-like tyrosine kinase 3><Family><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fms-Related Tyrosine Kinase 3><Genetic Alteration><Genetic Anticipation><Genetic Change><Genetic Markers><Genetic defect><Genomics><Genotype><Immunologic Subtyping><Immunophenotyping><Induction Therapy><Industry><Investigation><Investigators><Kinases><Laboratories><Lead><Leukemic Cell><Link><MCL-1><MCL1><MCL1 gene><Marrow monocyte><Measurement><Medicine><Methods><Minority><Modeling><Multimodal Therapy><Multimodal Treatment><Mutate><Mutation><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Nuclear><Nuclear Export><Nucleus><Oncoprotein p53><Outcome><P53><Patients><Pattern><Pb element><Phase><Phase 2 Clinical Trials><Phase I Study><Phase II Clinical Trials><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Phosphotransferase Gene><Phosphotransferases><Population><Predictive Analytics><Protein TP53><Protein Trafficking><Proteins><RAS Family Gene><Refractory><Regimen><Relapse><Removal><Reproducibility><Research><Research Personnel><Researchers><Resistance><STK-1 kinase><STK1><Safety><Sampling><Selection for Treatments><Sensitivity and Specificity><Site><Specificity><Stem Cell Tyrosine Kinase 1><Strains Cell Lines><Surgical Removal><TP53><TP53 gene><TRP53><Testing><Therapeutic><Time><Training><Translations><Transphosphorylases><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressor Proteins><University Medical Centers><Validation><Work><XPO1 protein><acute granulocytic leukemia><acute granulocytic leukemia cell><acute myeloblastic leukemia cell><acute myelocytic leukemia cell><acute myelogenous leukemia cell><acute myeloid leukemia><acute myeloid leukemia cell><acute nonlymphocytic leukemia cell><alternative treatment><analytical tool><anti-tumor effect><antitumor effect><bcl-2 Genes><ced9 homolog><chromosome region maintenance 1 protein><clinical practice><cohort><combination therapy><combined modality treatment><combined treatment><companion diagnostics><cultured cell line><developmental><drug sensitivity><dynamic mutation><effective therapy><effective treatment><efficacy trial><elderly patient><exportin 1><exportin 1 protein><fetal liver kinase-2><fetal liver kinase-3><flow cytophotometry><gene biomarker><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><genetic resistance><genome mutation><heavy metal Pb><heavy metal lead><high risk><immunophenotype><improved><induction therapies><industrial partnership><industry partner><industry partnership><inhibitor><leukemia><leukemia initiating cell><monocyte><multi-modal therapy><multi-modal treatment><myeloid cell leukemia 1><myeloid cell leukemia sequence 1><myeloid leukemia cell differentiation protein><new combination therapies><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><older patient><p53 Antigen><p53 Genes><p53 Tumor Suppressor><phase 1 study><phase 1 trial><phase 2 study><phase 2 trial><phase I trial><phase II protocol><phase II study><phase II trial><pre-clinical efficacy><pre-clinical study><precision medicine><precision-based medicine><preclinical efficacy><preclinical study><predict responsiveness><predicting response><pressure><protein p53><protein transport><relapse patients><resection><resistance mechanism><resistant><resistant mechanism><responders and non-responders><responders from non-responders><responders or non-responders><responders versus non-responders><responders vs non-responders><responders/nonresponders><response><selection of treatment><single cell technology><standard of care><synergism><targeted drug therapy><targeted drug treatments><targeted sequencing><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy selection><tool><translation><translational study><treatment selection><tumor suppressor><validations>