期刊
ANNALS OF ONCOLOGY
卷 31, 期 9, 页码 1135-1147出版社
ELSEVIER
DOI: 10.1016/j.annonc.2020.05.027
关键词
DNA damage response; PARP inhibitors; PARPness; BRCA; ATM; colorectal cancer
类别
资金
- Fondazione AIRC under 5 per Mille 2018
- 21091 program
- Fondazione Regionale Ricerca Biomedica Regione Lombardia [CP 12/2018 IANG CRC]
- AIRC under MFAG 2017 [20236]
- FPRC 5xmille 2017 Ministero Salute PTCRC-Intra 2020 (REGENERATION-YIG 2020 project)
- TRANSCAN-2 JTC 2014 [TRS-2015-00000060]
- IMI [115749]
- AIRC IG [2018] [21923]
- AIRC IG [20685]
- Terapia Molecolare Tumori by Fondazione Oncologia Niguarda Onlus
- Genomic-Based Triage for Target Therapy in Colorectal Cancer Ministero della Salute [NET 02352137]
- AIRC-CRUK-FC AECC Accelerator Award [22795]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2014 e 2015 Ministero della Salute
- Ministero Salute, RC 2019
- [635342-2]
Background: Colorectal cancer (CRC) represents a major cause of cancer deaths worldwide. Although significant progress has been made by molecular and immune therapeutic approaches, prognosis of advanced stage disease is still dismal. Alterations in the DNA damage response (DDR) pathways are emerging as novel targets for treatment across different cancer types. However, even though preclinical studies have shown the potential exploitation of DDR alterations in CRC, systematic and comprehensive testing is lagging and clinical development is based on analogies with other solid tumors according to a tissue-agnostic paradigm. Recently, functional evidence from patient-derived xenografts and organoids have suggested that maintenance with PARP inhibitors might represent a therapeutic opportunity in CRC patients previously responsive to platinum-based treatment. Design and Result: In this review, we highlight the most promising preclinical data and systematically summarize published clinical trials in which DDR inhibitors have been used for CRC and provide evidence that disappointing results have been mainly due to a lack of clinical and molecular selection. Conclusions: Future preclinical and translational research will help in better understanding the role of DDR alterations in CRC and pave the way to novel strategies that might have a transformative impact on treatment by identifying new therapeutic options including tailored use of standard chemotherapy.
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