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Integrated genetic and pharmacologic interrogation of rare cancers.

ABSTRACT: Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.

SUBMITTER: Hong AL

PROVIDER: S-EPMC4917959 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Integrated genetic and pharmacologic interrogation of rare cancers.

Hong Andrew L AL Tseng Yuen-Yi YY Cowley Glenn S GS Jonas Oliver O Cheah Jaime H JH Kynnap Bryan D BD Doshi Mihir B MB Oh Coyin C Meyer Stephanie C SC Church Alanna J AJ Gill Shubhroz S Bielski Craig M CM Keskula Paula P Imamovic Alma A Howell Sara S Kryukov Gregory V GV Clemons Paul A PA Tsherniak Aviad A Vazquez Francisca F Crompton Brian D BD Shamji Alykhan F AF Rodriguez-Galindo Carlos C Janeway Katherine A KA Roberts Charles W M CW Stegmaier Kimberly K van Hummelen Paul P Cima Michael J MJ Langer Robert S RS Garraway Levi A LA Schreiber Stuart L SL Root David E DE Hahn William C WC Boehm Jesse S JS

Nature communications 20160622

Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRI ...[more]

PMID: 27329820

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Project description:ContextClinical applications of genomic assessment of thyroid cancers are rapidly evolving.Objectives, design, and settingWe studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable.Patient contextProgressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites.InterventionThe intervention was Foundation One tumor interrogation.Main outcome measuresMain outcome measures included genomic alterations, patient characteristics, and overall survival.ResultsSamples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine-refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)-but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC.ConclusionsWhereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

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Integrated genetic and pharmacologic interrogation of rare cancers.

Publications

Integrated genetic and pharmacologic interrogation of rare cancers.

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