G Mauri1, S Arena2, S Siena1, A Bardelli3, A Sartore-Bianchi4. 1. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy. 2. Candiolo Cancer Institute, FPO - IRCCS, Candiolo (TO), Torino, Italy; Department of Oncology, University of Torino, Candiolo (TO), Italy. Electronic address: sabrina.arena@unito.it. 3. Candiolo Cancer Institute, FPO - IRCCS, Candiolo (TO), Torino, Italy; Department of Oncology, University of Torino, Candiolo (TO), Italy. Electronic address: alberto.bardelli@unito.it. 4. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy. Electronic address: andrea.sartorebianchi@unimi.it.
Abstract
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 RESULTS: 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.
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 RESULTS: 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.
Authors: Alberto Puccini; Kelsey Poorman; Fabio Catalano; Andreas Seeber; Richard M Goldberg; Mohamed E Salem; Anthony F Shields; Martin D Berger; Francesca Battaglin; Ryuma Tokunaga; Madiha Naseem; Wu Zhang; Philip A Philip; John L Marshall; W Michael Korn; Heinz-Josef Lenz Journal: Oncogene Date: 2022-05-26 Impact factor: 8.756
Authors: Weili Duan; Xue Kong; Juan Li; Peilong Li; Yinghui Zhao; Tong Liu; Helen Barong Binang; Yunshan Wang; Lutao Du; Chuanxin Wang Journal: Front Cell Dev Biol Date: 2020-10-15