Browsing by Author "Orillion, Ashley"

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    EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming
    (Cancer Research, 2017-12-01) Adelaiye-Ogala, Remi; Budka, Justin; Damayanti, Nur P.; Arrington, Justine; Ferris, Mary; Hsu, Chuan-Chih; Chintala, Sreenivasulu; Orillion, Ashley; Miles, Kiersten Marie; Shen, Li; Elbanna, May; Ciamporcero, Eric; Arisa, Sreevani; Pettazzoni, Piergiorgio; Draetta, Giulio F.; Seshadri, Mukund; Hancock, Bradley; Radovich, Milan; Kota, Janaiah; Buck, Michael; Keilhack, Heike; McCarthy, Brian P.; Persohn, Scott A.; Territo, Paul R.; Zang, Yong; Irudayaraj, Joseph; Tao, W. Andy; Hollenhorst, Peter; Pili, Roberto
    Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro- apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.
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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.