Document text
Principal Investigator: Sydney X Lu
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $241,634
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Research: RNA binding proteins (RBPs) regulate diverse cellular processes including transcription,
translation, and regulation of gene expression, and are frequently dysregulated in cancers. Through an
unbiased genetic screen aimed at identifying cancer-specific RBP dependencies, we recently identified
a specific requirement for RBM39 in malignant myeloid cancers and that cancers bearing RNA splicing
factor mutations as being particularly sensitive to the anti-cancer sulfonamides. RBM39 is an RBP that
functions in RNA splicing and recently, a class of clinical-grade “anti-cancer sulfonamide” compounds
were demonstrated to degrade RBM39 protein by co-opting the Ddb1/CUL4 ubiquitin-ligase complex as
their mechanism of action. Thus, the primary goal of this project is to assess differential and
tissue-specific requirements for RBM39 in normal hematopoiesis versus myeloid malignancies,
and to assess requirements for RBM39 for leukemia initiation and maintenance. This proposal will
utilize a novel conditional knockout (cKO) mouse for Rbm39 and several associated newly developed in
vitro and in vivo murine models to pursue this goal. We expect these investigations to further our
understanding of the role of RBM39 in normal physiology and cancer as well as provide new
therapeutic insights into the on- and off-target toxicities of the anti-cancer sulfonamides. These goals
are particularly timely given that several of these molecules have already proven excellent safety in
multiple phase I/II trials and are now ripe for therapeutic testing in a patient population most likely to
benefit from RBM39 degradation. Candidate: Dr. Sydney X. Lu is a graduating hematology & medical
oncology fellow in the Department of Medicine at MSKCC. He aims to become an independent, tenure-
track physician-scientist investigating the molecular pathogenesis of hematological malignancies through
a combination of genetics, functional genomics, and murine modeling. Dr.Lu has outlined a five-year period
of mentored training to strengthen his skills in functional genomics and disease modeling. This training
period will be carried out under the mentorship of Dr. Omar Abdel-Wahab, a leader in the functional
genomics of hematopoietic malignancies. Dr. Lu has also assembled an advisory committee composed of
Drs. Ross Levine, Martin Tallman, Michael Kharas, and Christine Mayr who will help guide his training
and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting
more than 130 years to exceptional patient care, innovative research, and outstanding educational
programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a
strong commitment and track record of successfully supporting junior faculty who are seeking careers
as independent physician-scientists.
Terms: <AML - Acute Myeloid Leukemia><APF-1><ATP-Dependent Proteolysis Factor 1><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Advisory Committees><Assay><Bioassay><Biological Assay><Blood><Blood Precursor Cell><Blood Reticuloendothelial System><Body Tissues><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancer Center><Cancers><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Complex><Custom><Data><Dependence><Development><Drugs><Education><Educational aspects><Environment><Evaluation><Faculty><Gene Action Regulation><Gene Alteration><Gene Expression><Gene Expression Regulation><Gene Mutation><Gene Regulation><Gene Regulation Process><Gene Transcription><Genetic><Genetic Alteration><Genetic Change><Genetic Screening><Genetic Transcription><Genetic defect><Goals><HMG-20><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematology><Hematopoiesis><Hematopoietic><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Cellular Control Mechanisms><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Progenitor Cells><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hematopoietic stem cells><High Mobility Protein 20><Human><Immunology><In Vitro><Individual><Institution><Investigation><KO mice><Knock-out Mice><Knockout Mice><MSKCC><Maintenance><Malignant><Malignant - descriptor><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Malignant Neoplasms><Malignant Tumor><Mediating><Medical Oncology><Medication><Medicine><Memorial Sloan-Kettering Cancer Center><Mentors><Mentorship><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><Myelogenous><Myeloid><Myeloid Disease><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Null Mouse><PDX model><Pathogenesis><Patient Care><Patient Care Delivery><Patient derived xenograft><Pharmaceutical Preparations><Phase 1/2 trial><Phase I/II Trial><Physicians><Physiology><Play><Privatization><Production><Proteins><Putative RNA-Binding Region><RNA Binding><RNA Binding Domain><RNA Expression><RNA Processing><RNA Recognition Motif><RNA Splicing><RNA bound><RNA-Binding Proteins><RNP Domain><RNP Motif><RNP-1 Signature><Research><Role><Safety><Scientist><Somatic Mutation><Splicing><Subcellular Process><Sulfonamides><Task Forces><Therapeutic><Therapeutic Index><Tissues><Toxic effect><Toxicities><Training><Transcription><Translations><Ubiquitin><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Work><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><advisory team><anti-cancer><blood cancer><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cancer cell><cancer of blood><cancer of the blood><cancer type><care for patients><care of patients><career><caring for patients><cell type><clustered regularly interspaced short palindromic repeats screen><conditional knock-out><conditional knockout><customs><developmental><disease model><disorder model><drug/agent><experience><experiment><experimental research><experimental study><experiments><functional genomics><genome mutation><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><in vivo><innovate><innovation><innovative><insight><leukemia><leukemia initiating cell><malignancy><member><mouse model><murine model><myeloproliferative neoplasm><neoplasm/cancer><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><patient derived xenograft model><patient population><pharmacologic><progenitor><programs><protein function><side effect><skills><social role><somatic variant><tenure process><tenure track><therapeutic evaluation><therapeutic testing><translation><ubiquitin ligase>