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.

Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer / F. Pietrantonio, G. Randon, D. Romagnoli, S. Di Donato, M. Benelli, F. de Braud. - In: CANCER TREATMENT REVIEWS. - ISSN 0305-7372. - 82(2020 Jan).

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

Pietrantonio F.;Randon G.;de Braud F.
2020-01

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.
Immune checkpoint inhibitors; Metastatic colorectal cancer; MGMT, Mismatch repair, Base excision repair; Temozolomide; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; DNA Mismatch Repair; DNA Modification Methylases; DNA Repair Enzymes; Humans; Neoplasm Metastasis; Neoplasm Staging; Temozolomide; Tumor Suppressor Proteins; Colorectal Neoplasms
Settore MED/06 - Oncologia Medica
CANCER TREATMENT REVIEWS
Article (author)
File in questo prodotto:
File Dimensione Formato  
CancTreatReview_2020.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 2.66 MB
Formato Adobe PDF
2.66 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/702773
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 6
social impact