Therapeutic treatment of microsatellite unstable cancers
The present disclosure relates to compositions and methods for the diagnosis and treatment or prevention of microsatellite unstable cancers. In particular, the instant disclosure provides for identification of a cancer as exhibiting microsatellite instability (MSI) and/or impaired mismatch repair (MMR), and selection and/or administration of an inhibitor of the WRN helicase as a therapeutic agent for such a cancer and/or subject having or at risk of developing such a cancer.
1. A method for treating a subject having or at risk of developing a cancer that exhibits microsatellite instability (MSI) and/or impaired mismatch repair (MMR), the method comprising:
(a) obtaining a sample from a subject having or at risk of developing a cancer that exhibits MSI and/or impaired MMR, wherein the subject has not responded to a previously administered programmed cell death 1 (PD-1) inhibitor immunotherapy;
(b) identifying the presence or absence in the sample of MSI and/or impaired MMR; (c)
(c) selecting a WRN inhibitor as a treatment for the subject if MSI and/or impaired MMR is identified in the sample, thereby selecting a treatment for the subject having or at risk of developing a cancer that exhibits MSI and/or impaired MMR; and
(d) administering the selected WRN inhibitor to the subject.
2. The method of claim 1 , wherein the cancer is selected from the group consisting of an endometrial cancer, a gastric cancer, a colorectal cancer and an ovarian cancer.
3. The method of claim 1 , wherein step (b) comprises performing a single multiplex PCR reaction that is analyzed by capillary electrophoresis.
4. The method of claim 1 , wherein step (b) comprises classifying the sample on the basis of the density of deletions in microsatellite regions and total deletions from whole genome or whole exome data, optionally as compared to available whole genome or whole exome cancer cell line encyclopedia (CCLE) data.
5. The method of claim 1 , wherein the WRN inhibitor is selected from the group consisting of:
distamycin A; netropsin; 3,6,9-trisubstituted acridine; NSC 617145; and NSC 19630; and an oligonucleotide inhibitor of WRN, optionally wherein the oligonucleotide inhibitor of WRN is selected from the group consisting of an antisense oligonucleotide, an siRNA and a sgRNA, optionally wherein the sgRNA is selected from the group consisting of sgWRN1 (GTAAATTGGAAAACCCACGG; SEQ ID NO: 1), sgWRN2 (ATCCTGTGGAACATACCATG; SEQ ID NO: 2), sgWRN3 (GTAGCAGTAAGTGCAACGAT; SEQ ID NO: 3), sgWRN-EIJ (AGCACGTACATAAGCATCAG; SEQ ID NO: 4), shWRN1-1 (CAGCACTGCCAATGGTTCCAA; SEQ ID NO: 5) and shWRN2-1 (GCCTTAACAGTCTGGTTAAAC; SEQ ID NO: 6).
6. The method of claim 1 , wherein the WRN inhibitor specifically inhibits the helicase activity of WRN.
7. The method of claim 1 , wherein the subject has further been previously administered a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor immunotherapy has not responded to said immunotherapy.
8. The method of claim 1 , wherein step (d) comprises administering a combination therapy comprising the selected WRN inhibitor and a second agent, optionally wherein:
the second agent is selected from the group consisting of a small molecule that induces DNA damage and/or modulates a DNA repair pathway and a chemotherapeutic agent, optionally wherein the small molecule that induces DNA damage and/or modulates a DNA repair pathway is calactin; and/or
the second agent is selected from the group consisting of a PARP inhibitor, a CHK 1/2 inhibitor and a DNA-PKCS inhibitor, optionally wherein the PARP inhibitor is palbociclib, the CHK1/2 inhibitor is prexasertib and/or the DNA-PKCS inhibitor is NU7441.
9. The method of claim 1 , wherein identifying step (b) comprises use of a kit of for identifying MSI and/or impaired MMR in a sample and selecting a subject for a WRN inhibitor therapy.
10. The method of claim 1 , wherein the subject is human.