US 2026/0306672 A1 · TARGETING GPATCH8 FOR TREATING SF3B1-MUTANT CANCERS

Abstract

Embodiments of the present disclosure provide methods for treating a subject with cancer, wherein the cancer is characterized by a change-of-function or loss of-function mutation in a recurrently mutated RNA splicing factor gene. In some embodiments, the method can comprise administering to a subject a therapeutically effective amount of a composition that inhibits expression of a trans-acting splicing factor and/or inhibits expression of a cis-acting splicing factor, wherein a cancer-causing error triggered by the change-of-function or loss-of-function mutation in a recurrently mutated RNA splicing factor gene is partially or fully rescued by inhibiting expression of the trans-acting splicing factor and/or inhibiting expression of the cis-acting splicing factor.

Claims35

Dependent claims

A method of treating a subject with cancer, wherein the cancer is characterized by a change-of-function or loss-of-function mutation in a recurrently mutated RNA splicing factor gene, the method comprising:

administering to a subject a therapeutically effective amount of a composition that inhibits;
(i) a trans-acting splicing factor;
and/or
(ii) inhibits expression of a cis-acting splicing factor,
wherein a cancer-causing error triggered by the change-of-function or loss-of-function mutation in a recurrently mutated RNA splicing factor gene is partially or fully rescued by inhibiting expression of the trans-acting splicing factor and/or inhibiting expression of the cis-acting splicing factor.

2 more elements

An in vitro method to screen for a trans-acting splicing factor and/or a cis-acting splicing factor required for mis-splicing in a change-of-function or loss-of-function mutation in a recurrently mutated RNA splicing factor gene, the method comprising:

(a) generating an expression cassette comprising a coding sequence (CDS) interrupted by at least one artificial nucleic acid intron, a promoter operatively linked to the CDS, wherein upon splicing of the artificial nucleic acid intron the CDS encodes a detectable reporter protein in wild-type cells and wherein the CDS does not encode a detectable reporter protein in cells comprising the recurrently mutated RNA splicing factor gene;
(b) contacting the construct generated in (a) to a population of cells;
(c) performing a positive enrichment CRISPR screen to identify at least one gene whose knockout enhances expression of the detectable reporter protein in cells comprising the recurrently mutated RNA splicing factor gene;
and
(d) detecting expression of the detectable reporter protein, wherein expression of the detectable reporter protein in cells comprising the recurrently mutated RNA splicing factor gene is increased if the gene knockout is required for mis-splicing in recurrently mutated RNA splicing factor gene.

2 more elements

Dependencies are inferred from the claim text.

Targeting gpatch8 for treating sf3b1-mutant cancers

Life of this patent

Targeting gpatch8 for treating sf3b1-mutant cancers

Life of this patent

Abstract

Claims35