Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer. Cancer treatment reviews

Filippo Pietrantonio, Giovanni Randon, Dario Romagnoli, Samantha Di Donato, Matteo Benelli, Filippo de Braud

Research output: Contribution to journalArticlepeer-review

Abstract

Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.
Original languageEnglish
JournalCancer Treatment Reviews
Volume82
DOIs
Publication statusPublished - 2020

Keywords

  • Humans
  • Antineoplastic Combined Chemotherapy Protocols
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Immune checkpoint inhibitors
  • *Colorectal Neoplasms/drug therapy/pathology
  • Antineoplastic Agents/pharmacology
  • DNA Mismatch Repair/drug effects
  • DNA Modification Methylases/genetics
  • DNA Repair Enzymes/genetics
  • Metastatic colorectal cancer
  • MGMT, Mismatch repair, Base excision repair
  • Temozolomide
  • Temozolomide/*pharmacology
  • Tumor Suppressor Proteins/genetics

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