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Browsing by Subject "Sunitinib"
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Item Anti-VEGF therapy as adjuvant therapy: clouds on the horizon?(BioMed Central, 2009-05-18) Schneider, Bryan P.; Sledge Jr, George W.; Medicine, School of MedicineAnti-angiogenic therapies have demonstrated their value in the setting of advanced cancer, and are being explored for use in micrometastatic disease. Recent preclinical studies suggest that adjuvant anti-vascular endothelial growth factor (VEGF) therapies may increase the risk of metastasis. How concerning are these preclinical studies, and should they affect our willingness to explore anti-VEGF therapy in the adjuvant setting?Item An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer(Elsevier, 2010-07-01) Kozloff, M.; Chuang, E.; Starr, A.; Huang, X.; Kern, K.A.; Miller, K.; Medicine, School of MedicineBackground Sunitinib has shown single-agent activity in patients with previously treated metastatic breast cancer (MBC). We investigated the safety of the combination of sunitinib and paclitaxel in an exploratory study of patients with locally advanced or MBC. Methods Patients received oral sunitinib 25 mg/day (with escalation to 37.5 mg/day as tolerated) on a continuous daily dosing schedule and paclitaxel 90 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Study endpoints included safety (primary endpoint), pharmacokinetics, and antitumor activity. Results Twenty-two patients were enrolled. The most frequent adverse events (AEs) were fatigue/asthenia (77%), dysgeusia (68%), and diarrhea (64%). Grade 3 AEs included neutropenia (43%), fatigue/asthenia (27%), neuropathy (18%), and diarrhea (14%). No drug–drug interaction was observed on the basis of pharmacokinetic analysis. Of 18 patients with measurable disease at baseline, 7 (38.9%) achieved objective responses (including 2 complete and 5 partial responses). Clinical responses were observed in three of nine patients with triple-negative receptor status (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor-2 negative). Conclusions These data indicate that sunitinib and paclitaxel in combination are well tolerated in patients with locally advanced or MBC. No drug–drug interaction was detected and there was preliminary evidence of antitumor activity.Item Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib(MDPI, 2022-11-08) Zhang, Dongyun; Yong, William H.; Movassaghi, Masoud; Rodriguez, Fausto J.; Yang, Issac; McKeever, Paul; Qian, Jiang; Li, Jian Yi; Mao, Qinwen; Newell, Kathy L.; Green, Richard M.; Welsh, Cynthia T.; Heaney, Anthony P.; Pathology and Laboratory Medicine, School of MedicineNeurocytomas are rare low-grade brain tumors predominantly affecting young adults, but their cellular origin and molecular pathogenesis is largely unknown. We previously reported a sellar neurocytoma that secreted excess arginine vasopressin causing syndrome of inappropriate anti-diuretic hormone (SIADH). Whole exome sequencing in 21 neurocytoma tumor tissues identified somatic mutations in the plant homeodomain finger protein 14 (PHF14) in 3/21 (14%) tumors. Of these mutations, two were missense mutations and 4 caused splicing site losses, resulting in PHF14 dysfunction. Employing shRNA-mediated knockdown and CRISPR/Cas9-based knockout approaches, we demonstrated that loss of PHF14 increased proliferation and colony formation in five different human, mouse and rat mesenchymal and differentiated cell lines. Additionally, we demonstrated that PHF14 depletion resulted in upregulation of platelet derived growth factor receptor-alpha (PDGFRα) mRNA and protein in neuroblastoma SHSY-5Y cells and led to increased sensitivity to treatment with the PDGFR inhibitor Sunitinib. Furthermore, in a neurocytoma primary culture harboring splicing loss PHF14 mutations, overexpression of wild-type PHF14 and sunitinib treatment inhibited cell proliferation. Nude mice, inoculated with PHF14 knockout SHSY-5Y cells developed earlier and larger tumors than control cell-inoculated mice and Sunitinib administration caused greater tumor suppression in mice harboring PHF-14 knockout than control SHSY-5Y cells. Altogether our studies identified mutations of PHF14 in 14% of neurocytomas, demonstrate it can serve as an alternative pathway for certain cancerous behavior, and suggest a potential role for Sunitinib treatment in some patients with residual/recurrent neurocytoma.