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Ref Type Journal Article
PMID (32494639)
Authors Wang Y, Wild AT, Turcan S, Wu WH, Sigel C, Klimstra DS, Ma X, Gong Y, Holland EC, Huse JT, Chan TA
Title Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas.
URL
Abstract Text Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132H high grade glioma sensitive Radiotherapy + Veliparib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with Veliparib (ABT-888) enhanced sensitivity to radiation therapy in immortalized astrocytes expressing IDH1 R132H in culture, resulting in greater decreased colony formation, and in a glioma cell line xenograft model, resulting in both increased tumor regression and survival compared to radiation therapy alone, with a median overall survival of 66 days vs 22 days, respectively (PMID: 32494639). 32494639
IDH1 mutant high grade glioma sensitive Radiotherapy + Veliparib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with Veliparib (ABT-888) enhanced the sensitivity of a glioma cell line xenograft model harboring an IDH1 mutation to radiation therapy, resulting in increased survival compared to radiation therapy alone, with a median overall survival of 21 days vs 14 days, respectively (PMID: 32494639). 32494639
IDH1 R132H high grade glioma sensitive Pamiparib + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with Pamiparib (BGB-290) enhanced the sensitivity of a glioma cell line expressing IDH1 R132H to radiation therapy, resulting in a reduction in tumor volume and increased survival compared to radiation therapy alone in a cell line xenograft model (PMID: 32494639). 32494639
IDH1 mutant high grade glioma sensitive Olaparib + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, treatment with Lynparza (olaparib) enhanced the sensitivity of a glioma cell line harboring an IDH1 mutation to radiation therapy in culture, resulting in decreased survival compared to radiation therapy alone (PMID: 32494639). 32494639
IDH1 R132C intrahepatic cholangiocarcinoma sensitive Olaparib + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, treatment with Lynparza (olaparib) enhanced the sensitivity of an intrahepatic cholangiocarcinoma cell line harboring IDH1 R132C to radiation therapy in culture, resulting in decreased survival compared to radiation therapy alone (PMID: 32494639). 32494639
IDH1 R132H high grade glioma sensitive Olaparib + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, treatment with Lynparza (olaparib) enhanced the sensitivity of immortalized astrocytes expressing IDH1 R132H to radiation therapy in culture, resulting in increased cell death and decreased colony formation compared to radiation therapy alone (PMID: 32494639). 32494639
IDH1 R132H intrahepatic cholangiocarcinoma sensitive Olaparib + Radiotherapy Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with Lynparza (olaparib) enhanced the sensitivity of an intrahepatic cholangiocarcinoma cell line expressing IDH1 R132H to radiation therapy, resulting in decreased survival in culture and delayed tumor growth and increased survival compared to radiation therapy alone in a cell line xenograft model, with a median overall survival of 60 days vs 47 days, respectively (PMID: 32494639). 32494639