Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science advances	6	17	2020 04	eaaz3221	Sci Adv

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	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
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 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 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	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	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