Browsing by Author "Linehan, W. Marston"

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    Genetic Risk Assessment for Hereditary Renal Cell Carcinoma: Clinical Consensus Statement
    (Wiley, 2021) Bratslavsky, Gennady; Mendhiratta, Neil; Daneshvar, Michael; Brugarolas, James; Ball, Mark W.; Metwalli, Adam; Nathanson, Katherine L.; Pierorazio, Phillip M.; Boris, Ronald S.; Singer, Eric A.; Carlo, Maria I.; Daly, Mary B.; Henske, Elizabeth P.; Hyatt, Colette; Middleton, Lindsay; Morris, Gloria; Jeong, Anhyo; Narayan, Vivek; Rathmell, W. Kimryn; Vaishampayan, Ulka; Lee, Bruce H.; Battle, Dena; Hall, Michael J.; Hafez, Khaled; Jewett, Michael A.S.; Karamboulas, Christina; Pal, Sumanta K.; Hakimi, A. Ari; Kutikov, Alexander; Iliopoulos, Othon; Linehan, W. Marston; Jonasch, Eric; Srinivasan, Ramaprasad; Shuch, Brian; Urology, School of Medicine
    Background: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. Methods: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. Results: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC. Conclusions: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. Lay summary: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.
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    Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma
    (American Association for Cancer Research, 2018-12) Damayanti, Nur P.; Budka, Justin A.; Khella, Heba W. Z.; Ferris, Mary W.; Ku, Sheng Yu; Kauffman, Eric; Wood, Anthony C.; Ahmed, Khunsha; Chintala, Venkata Nithinsai; Adelaiye-Ogala, Remi; Elbanna, May; Orillion, Ashley; Chintala, Sreenivasulu; Kao, Chinghai; Linehan, W. Marston; Yousef, George M.; Hollenhorst, Peter C.; Pili, Roberto; Medicine, School of Medicine
    Purpose: Translocation renal cell carcinoma (tRCC) represents a rare subtype of kidney cancer associated with various TFE3, TFEB, or MITF gene fusions that are not responsive to standard treatments for RCC. Therefore, the identification of new therapeutic targets represents an unmet need for this disease. Experimental Design: We have established and characterized a tRCC patient-derived xenograft, RP-R07, as a novel preclinical model for drug development by using next-generation sequencing and bioinformatics analysis. We then assessed the therapeutic potential of inhibiting the identified pathway using in vitro and in vivo models. Results: The presence of a SFPQ-TFE3 fusion [t(X;1) (p11.2; p34)] with chromosomal break-points was identified by RNA-seq and validated by RT-PCR. TFE3 chromatin immunoprecipitation followed by deep sequencing analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway. Consistently, miRNA microarray analysis also identified PI3K/AKT/mTOR as a highly enriched pathway in RP-R07. Upregulation of PI3/AKT/mTOR pathway in additional TFE3–tRCC models was confirmed by significantly higher expression of phospho-S6 (P < 0.0001) and phospho-4EBP1 (P < 0.0001) in established tRCC cell lines compared with clear cell RCC cells. Simultaneous vertical targeting of both PI3K/AKT and mTOR axis provided a greater antiproliferative effect both in vitro (P < 0.0001) and in vivo (P < 0.01) compared with single-node inhibition. Knockdown of TFE3 in RP-R07 resulted in decreased expression of IRS-1 and inhibited cell proliferation. Conclusions: These results identify TFE3/IRS-1/PI3K/AKT/mTOR as a potential dysregulated pathway in TFE3–tRCC, and suggest a therapeutic potential of vertical inhibition of this axis by using a dual PI3K/mTOR inhibitor for patients with TFE3–tRCC.