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Principal Investigator: Omar Abdel-Wahab
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $683,443
Funding agency: National Cancer Institute
SUMMARY
Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors, resulting in
sequence-specific changes in RNA splicing that promote disease initiation and progression. These
“spliceosomal mutations” are the most common class of mutations in myelodysplastic syndromes (MDS) and
related hematologic disorders, which have few effective, FDA-approved treatments. Despite the high frequency
of spliceosomal mutations and corresponding need for new therapeutics, there currently exist no therapies that
specifically and selectively target these lesions.
Here, we propose to address this clinical need by creating new precision therapeutics that selectively
kill cells with spliceosomal mutations. Our interdisciplinary team consists of a physician-scientist with expertise
in cancer biology and patient care (Abdel-Wahab), a basic scientist with expertise in RNA splicing and
functional genomics (Bradley), and a bioengineer with expertise in drug delivery (Heller). In preliminary
experiments, we developed the “synthetic intron” technology to harness altered RNA splicing activity
caused by spliceosomal mutations to drive cancer-specific gene expression, showed that synthetic
introns permit highly selective expression of therapeutic payloads in cancer cells while leaving healthy
cells unharmed, and used this system to suppress the growth of diverse cancer types in vivo (North et
al, Nature Biotechnology, 2022). We additionally demonstrated that synthetic introns enable simultaneous and
selective delivery of multiple therapeutic payloads and allow for detailed mechanistic dissection of the cis- and
trans-acting sequence elements and splicing factors that govern pro-tumorigenic mis-splicing caused by
recurrent spliceosomal mutations.
We will now build on these preliminary studies to develop synthetic intron-based therapeutics for
myeloid neoplasms, including MDS, acute myeloid leukemia (AML), and chronic myelomonocytic leukemia
(CMML), and additionally utilize synthetic introns to understand the mechanistic basis for aberrant splicing in
these diseases as follows: Aim 1, Dissect and exploit the molecular mechanisms underlying common as well
as allele-specific splicing changes induced by different SF3B1 mutations; Aim 2, Develop synthetic introns that
enable selective therapeutic protein expression for each of the commonly mutated RNA splicing factors in
leukemia; Aim 3, Optimize in vivo delivery and rigorously test an immunostimulatory therapy for treating
SF3B1-mutant hematopoietic malignancies.
The significance of these studies is that they will develop a new
technology that enables mechanistic studies of cancer-associated spliceosomal mutations and also provides a
specific means for therapeutically targeting these mutations. The health relatedness is that the proposed work
will create specific therapeutic products for treating cancer types that currently have few effective, FDA-
approved treatments.
Terms: <3' Splice Site><AML - Acute Myeloid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Address><Affect><Alleles><Allelomorphs><Anatomic Sites><Anatomic structures><Anatomy><Biomedical Engineering><Biotech><Biotechnology><Blood Diseases><Body Tissues><Breast Cancer><Breast Cancer Cell><Cancer Biology><Cancer Patient><Cancers><Cell Body><Cells><Chronic Myelomonocytic Leukemia><Clinical><Deoxypyrimidine Kinase><Deoxythymidine Kinase><Disease><Disorder><Dissection><Drug Delivery><Drug Delivery Systems><Drugs><Dysmyelopoietic Syndromes><Elements><Engineering><Event><Exons><FDA approved><Frequencies><Ganciclovir><Gancyclovir><Gene Expression><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Granulocytic Leukemia><Growth><HSV><Health><Hematologic Cancer><Hematologic Diseases><Hematologic Malignancies><Hematologic Neoplasms><Hematological Disease><Hematological Disorder><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Herpes Simplex Virus><Herpes labialis Virus><Heterograft><Heterologous Transplantation><IL-15><IL15><IL15 Protein><In Vitro><Individual><Interleukin-15><Interleukin-15 Precursor><Intervening Sequences><Introns><Left><Lesion><Leukemic Cell><MGC9721><Malignant Breast Neoplasm><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Melanoma><Melanoma Cell><Messenger RNA><Methods><Molecular><Mutate><Mutation><Myelocytic Leukemia><Myelodysplastic Disease><Myelodysplastic Syndromes><Myelogenous Leukemia><Myeloid Disease><Myeloid Leukemia><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Nature><Non-Lymphoblastic Leukemia><Non-Lymphocytic Leukemia><Nonlymphoblastic Leukemia><Nonlymphocytic Leukemia><Nordeoxyguanosine><Patient Care><Patient Care Delivery><Patients><Pattern><Pharmaceutical Preparations><Physicians><Precision therapeutics><Production><Proteins><RNA Splicing><Recurrence><Recurrent><Refractory><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><SC35><SRSF2><SRSF2 gene><Safety><Scientist><Serine/Arginine-Rich Splicing Factor 2><Simplexvirus><Smoldering Leukemia><Solid Neoplasm><Solid Tumor><Splice Acceptor Sites><Spliceosomes><Splicing><System><Technology><Testing><Therapeutic><Thymidine Kinase><Tissue Growth><Tissues><Work><Xenograft><Xenograft procedure><Xenotransplantation><acute granulocytic leukemia><acute myeloid leukemia><bio-engineered><bio-engineers><bioengineering><biological engineering><blood cancer><blood disorder><breast tumor cell><cancer cell><cancer of blood><cancer of the blood><cancer type><care for patients><care of patients><caring for patients><cell killing><cell type><clinical phenotype><conventional therapy><conventional treatment><determine efficacy><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><functional genomics><genome mutation><hemopoietic><immunostimulatory therapy><immunostimulatory treatment><in vivo><insight><leukemia><lipid based nanoparticle><lipid nanoparticle><loss of function><mRNA><malignancy><malignant breast tumor><mutant><myelodysplasia><myeloid granulocytic leukemia><myeloproliferative neoplasm><myelosis><native protein drug><neoplasm relapse><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new technology><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel technologies><novel therapeutics><novel therapy><ontogeny><pharmaceutical protein><precision therapies><precision treatment><protein drug agent><protein expression><protein-based drug><selective expression><selectively expressed><side effect><suicide gene><therapeutic protein><therapeutic target><tumor><tumorigenic><xeno-transplant><xeno-transplantation>