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US-20260125760-A1 - METHODS OF TREATMENT AND DIAGNOSIS

US20260125760A1US 20260125760 A1US20260125760 A1US 20260125760A1US-20260125760-A1

Abstract

This disclosure relates generally to methods of treating cancers and methods of stratifying subjects having a cancer to a treatment regimen/predicting sensitivity to a treatment regimen, in particular wherein the cancer is detected in a pediatric subject or an adolescent subject.

Inventors

  • Ron Firestein
  • Ihara Shazia Adjumain
  • Paul Daniel

Assignees

  • Hudson Institute of Medical Research

Dates

Publication Date
20260507
Application Date
20241107

Claims (20)

  1. 1 . A method of treating a cancer in a subject in whom the cancer is detected at a paediatric or adolescent stage, the method comprising administering to the subject an agent that inhibits MCL1 activity, wherein the cancer detected in the subject at a paediatric or adolescent stage comprises a cell that exhibits DNA hypermethylation at the BCL2L1 gene locus in comparison to the level of DNA methylation at a BCL2L1 gene locus in a non-cancerous cell.
  2. 2 . A method of treating a cancer in a subject, the method comprising a) measuring the level of DNA methylation at the BCL2L1 gene locus of a cancer cell obtained from the subject at a paediatric or adolescent stage; (b) identifying whether the cancer cell exhibits DNA hypermethylation at the BCL2L1 gene locus in comparison to the level of DNA methylation at the BCL2L1 gene locus of a non-cancerous cell; and (c) where the subject is identified in step (b) as exhibiting DNA hypermethylation at the BCL2L1 gene locus, administering to the subject a therapeutically effective amount of an agent that inhibits MCL1 activity.
  3. 3 . A method of stratifying a subject having a cancer to a treatment regimen comprising an agent that inhibits MCL1 activity, the method comprising: (a) measuring the level of DNA methylation at the BCL2L1 gene locus of a cancer cell obtained from the subject at a paediatric or adolescent stage; (b) identifying whether the cancer cell exhibits DNA hypermethylation at the BCL2L1 gene locus in comparison to the level of DNA methylation level at the BCL2L1 gene locus of a non-cancerous cell; and (c) where the subject is identified in step (b) as exhibiting DNA hypermethylation at the BCL2L1 gene locus is stratified to a treatment regimen comprising an agent that inhibits MCL1 activity.
  4. 4 . (canceled)
  5. 5 . The method of claim 1 , wherein the BCL2L1 gene locus corresponds to the region spanning chr20:31,664,458 to chr20:31,724,161.
  6. 6 . The method of claim 1 , wherein the BCL2L1 gene locus corresponds to the region spanning chr20:31,664,777 to chr20:31,724,161.
  7. 7 . The method of claim 1 , wherein the DNA hypermethylation at the BCL2L1 gene locus is at one or more CpG sites selected from the group consisting of cg06892281, cg25812375, cg17997762, cg17168956, cg15401244, cg14517873, cg21948170, cg00782854, cg12896779, cg07379251, cg21306641, cg03816593, cg11551419, cg23752198, cg11809604, cg07602173, cg09190106, cg04897370, cg14002228, cg00300298, cg08257293, cg02538009, cg00058652, cg11265696, cg18787420, cg12873919 and/or cg13989999.
  8. 8 . The method of claim 1 , wherein the DNA hypermethylation at the BCL2L1 gene locus is at one or more CpG sites within the exon 2 and/or intron 2 junction of BCL2L1 gene.
  9. 9 . The method of claim 1 , wherein the DNA hypermethylation at the BCL2L1 gene locus is at one or more CpG sites within chr20:31,704,843-chr20:31,721,915.
  10. 10 . The method of claim 1 , wherein the DNA hypermethylation at the BCL2L1 gene locus is at one or more CpG sites selected from the group comprising cg13989999, cg12873919, cg18787420, cg00300298, cg08257293, cg00058652, cgl1265696, cg04897370, cg14002228 and cg02538009.
  11. 11 . The method of claim 1 , wherein the DNA hypermethylation at the BCL2L1 gene locus is at one or more CpG sites selected from the group comprising cg00300298, cg08257293, cg12873919, cg13989999 and cg18787420.
  12. 12 . The method of claim 1 , wherein the DNA hypermethylation at the BCL2L1 gene locus is at cg12873919 and/or cg13989999.
  13. 13 . The method of claim 1 , wherein the BCL2L1 gene locus is at cg00300298.
  14. 14 . The method of claim 1 , wherein the cancer is a glioma, an Atypical Teratoid Rhabdoid Tumors (ATRT), an ependymoma (EPD), an Ewing sarcoma (ES), an Embryonal Tumor with Multilayered Rosettes (ETMR), a High-Grade Neuroepithelial Tumor (HGNET) or an osteosarcoma (OS).
  15. 15 . The method of claim 14 , wherein the cancer is a glioma.
  16. 16 . The method of claim 15 , wherein the cancer is a high-grade glioma.
  17. 17 . The method of claim 1 , wherein the non-cancerous cell is a non-cancerous cell from the same subject.
  18. 18 . The method of claim 1 , wherein the agent that inhibits MCL1 activity is an MCL1-siRNA, an MCL-1 antisense oligonucleotide, S64315, S63845, AZD5991, AMG-176, AMG-397, ABBV-475, ANJ810, TTX-180, ABBV-467 and/or PRT1419.
  19. 19 . The method of claim 1 , wherein the agent that inhibits MCL1 activity is AZD5991.
  20. 20 . The method of claim 1 , wherein the cancer is detected in the subject aged between 0-21 years old.

Description

REFERENCE TO A SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in xml format and is hereby incorporated by reference in its entirety. Said xml copy, created on Nov. 6, 2024, is named 35624017-SQL.xml and is 6,955 bytes in size. FIELD OF THE ART This disclosure relates generally to methods of treating cancers and methods of stratifying subjects having a cancer to a treatment regimen/predicting sensitivity to a treatment regimen, in particular wherein the cancer is detected in a paediatric subject or an adolescent subject. BACKGROUND Cancer is a leading cause of death for children and adolescents. Each year, an estimated 400,000 children and adolescents develop cancer. While a good proportion of these cancers can be cured or clinically managed; difficulty of diagnosis, misdiagnosis or delayed diagnosis, incorrect treatment and/or drug toxicity can complicate outcomes. As it is generally not possible to prevent cancer in children and adolescents, the most effective strategy to reduce the burden of cancer in this unique patient population and improve outcomes is to focus on a prompt, correct diagnosis followed by effective, evidence-based therapy with tailored supportive care. Recent advances in molecular, genetic, and epigenetic profiling have highlighted significant differences in the underlying biology of adult and paediatric cancers, even when they occur in similar tissue types. For example, high-grade gliomas (HGGs), which are malignant central nervous system (CNS) neoplasms can occur in both adult and paediatric populations; however recent studies revealed distinct differences in the epigenetic dysregulation driving oncogenesis in paediatric HGGs (pHGGs) by showing recurrent alterations in histone coding genes H3F3A and HIST1H3B/C genes that are essential for tumorigenesis. In contrast, adult HGGs (aHGGs) preferentially harbor mutations in components of receptor tyrosine kinase (RTK) signaling pathways, such as EGFR and PTEN. Despite apparent similarities, that adult and childhood gliomas have different underlying biologies may necessitate different treatment strategies. For instance, paediatric high-grade gliomas (pHGGs) are well-known to be divergent from adult brain cancers in terms of their genetic complexity, driver mutations, underlying mutational processes, and response to therapy. Therefore, there remains an urgent need to identify potential biomarkers and drug targets for improved therapies, including for paediatric- and adolescent-onset cancers. SUMMARY In one aspect, there is provided a method of treating a cancer in a subject in whom the cancer is detected at a paediatric or adolescent stage, the method comprising administering to the subject an agent that inhibits MCL1 activity, wherein the cancer detected in the subject at a paediatric or adolescent stage comprises a cell that exhibits DNA hypermethylation at the BCL2L1 gene locus in comparison to the level of DNA methylation at a BCL2L1 gene locus in a non-cancerous cell. In another aspect, there is provided a method of treating a cancer in a subject, the method comprising: a) measuring the level of DNA methylation at the BCL2L1 gene locus of a cancer cell obtained from the subject at a paediatric or adolescent stage;b) identifying whether the cancer cell exhibits DNA hypermethylation at the BCL2L1 gene locus in comparison to the level of DNA methylation at the BCL2L1 gene locus of a non-cancerous cell; and where the subject is identified in step (b) as exhibiting DNA hypermethylation at the BCL2L1 gene locus, administering to the subject a therapeutically effective amount of an agent that inhibits MCL1 activity. In another aspect, there is provided a method of stratifying a subject having a cancer to a treatment regimen comprising an agent that inhibits MCL1 activity, the method comprising: a) measuring the level of DNA methylation at the BCL2L1 gene locus of a cancer cell obtained from the subject at a paediatric or adolescent stage;b) identifying whether the cancer cell exhibits DNA hypermethylation at the BCL2L1 gene locus in comparison to the level of DNA methylation level at the BCL2L1 gene locus of a non-cancerous cell; and where the subject is identified in step (b) as exhibiting DNA hypermethylation at the BCL2L1 gene locus is stratified to a treatment regimen comprising an agent that inhibits MCL1 activity. In another aspect, there is provided a method of predicting sensitivity to a treatment regimen comprising an agent that inhibits MCL1 activity in a subject with cancer, the method comprising: a) measuring the level of DNA methylation at the BCL2L1 gene locus of a cancer cell obtained from the subject at a paediatric or adolescent stage; andb) identifying whether the cancer cell exhibits DNA hypermethylation at the BCL2L1 gene locus in comparison to the level of DNA methylation level at the BCL2L1 gene locus of a non-cancerous cell; wherein hypermethylation at the BCL2L1 g