# Therapeutic targeting of RNA splicing catalysis through inhibition of Protein Arginine Methylation

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $663,748

## Abstract

SUMMARY
Mutations in splicing factors (SF) are highly enriched in a variety of cancer types, particularly myelodysplastic
syndromes (MDS), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL), in addition to solid
tumors such as uveal melanoma. Our group has identified that cells bearing SF mutations cannot tolerate
further perturbations to splicing catalysis and, consistent with this, we have identified that spliceosomal mutant
cancer cells are preferentially sensitive to small molecules that disrupt pre-mRNA splicing.
While the above effort has resulted in an ongoing phase I clinical trial of a spliceosome modulatory compound
for patients with refractory myeloid leukemias, we do not currently know the safety or efficacy of pharmacologic
modulation of core spliceosome function. To this end, our group has also recently identified that inhibiting
spliceosomal assembly through inhibition of arginine methylation of Sm proteins provides an alternate means
of therapeutic splicing inhibition. We have identified that inhibiting either symmetric arginine methylation
(mediated by the protein arginine methyltransferase 5 (PRMT5)) or asymmetric dimethyl arginine methylation
(mediated by type I PRMTs (PRMT1, 4, and 6)) reduces splicing fidelity resulting in strong preferential killing of
SF-mutant leukemias over their wildtype counterparts.
Here we aim to determine if in leukemia, SF-mutations portend greater vulnerability to a “second hit” targeting
splicing through inhibition of type I (PRMT1/4/6) and/or type II (PRMT5) PRMTs. In Aim 1 we will define the
therapeutic potential of inhibiting PRMT5, type I PRMTs, and core spliceosome function, alone or together in
leukemia models with or without a SF mutation. In addition, we will understand the consequences of combined
PRMT inhibition on RNA splicing and gene expression relative to inhibiting PRMT5 or Type I PRMTs alone.
In parallel to the above studies, in Aim 2, we will define the molecular basis for the cooperation between PRMT
inhibition and SF mutations, by first determining the methylation substrates of PRMT5 or Type I PRMTs, and
secondly by determining if individual spliceosomal changes mediated by inhibiting PRMTs or core spliceosome
function can be mimicked by anti-sense oligonucleotides, thereby providing an orthogonal novel therapeutic
approach to eliminate SF-mutant cancer cells.
The significance of these studies is that inhibitors of PRMTs are now entering phase I clinical trials in patients
with a variety of cancer types and defining the mechanistic effects and therapeutic utility of PRMT inhibitors for
specific genetic subsets of cancers may have incredible therapeutic importance. The health relatedness is
that our studies may identify new therapeutic opportunities for a variety of cancer types that have no curative
therapies for the majority of patients with these diseases currently.

## Key facts

- **NIH application ID:** 10165673
- **Project number:** 5R01CA249204-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ernesto Guccione
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $663,748
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165673

## Citation

> US National Institutes of Health, RePORTER application 10165673, Therapeutic targeting of RNA splicing catalysis through inhibition of Protein Arginine Methylation (5R01CA249204-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165673. Licensed CC0.

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