Clin Cancer Res
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The multikinase inhibitor sorafenib displays antitumor activity in preclinical models of osteosarcoma. However, in sorafenib-treated patients with metastatic-relapsed osteosarcoma, disease stabilization and tumor shrinkage were short-lived and drug resistance occurred. We explored the sorafenib treatment escape mechanisms to overcome their drawbacks. ⋯ mTORC2 activation is an escape mechanism from sorafenib treatment. When sorafenib is combined with everolimus, its antitumor activity is increased by complete inhibition of the mTOR pathway in the preclinical setting.
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Multiple myeloma is a usually incurable malignancy of plasma cells. New therapies are urgently needed for multiple myeloma. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies, but an ideal target antigen for CAR-expressing T-cell therapies for multiple myeloma has not been identified. B-cell maturation antigen (BCMA) is a protein that has been reported to be selectively expressed by B-lineage cells including multiple myeloma cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells. ⋯ BCMA is a suitable target for CAR-expressing T cells, and adoptive transfer of anti-BCMA-CAR-expressing T cells is a promising new strategy for treating multiple myeloma.
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Randomized Controlled Trial
Enzalutamide: a novel antiandrogen for patients with castrate-resistant prostate cancer.
Enzalutamide (MDV3100, Xtandi, Medivation\Astellas) is an oral inhibitor of androgen receptor signaling that blocks androgen receptor interaction, inhibits translocation of the androgen receptor to the nucleus, impairs androgen receptor binding to DNA, and inhibits coactivator recruitment and receptor-mediated DNA transcription. In a phase III randomized study comparing enzalutamide with placebo in men with progressive castration-resistant prostate cancer (CRPC) who were previously treated with docetaxel, enzalutamide showed an improvement in overall survival (18.4 vs. 13.6 months, HR, 0.63; P < 0.001). In addition, all secondary endpoints including proportion of patients with prostate-specific antigen (PSA) decline, soft-tissue response, quality-of-life response, time to PSA progression, radiographic progression-free survival, and the time to the first radiographic skeletal event all significantly favored patients treated with enzalutamide. ⋯ The preclinical studies along with the pivotal trials that led to its approval by the U. S. Food and Drug Administration (FDA) in September 2012 will be reviewed.
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The European Pediatric Medicine Regulation was launched in 2007 to provide better medicines for children. Five years later, the number of new anticancer drugs in early development in the pediatric population remains low, and most children with cancer are still largely denied access to innovative drugs in Europe, as compared with the United States. We analyzed individual pediatric investigation plan (PIP) and waiver decisions for oncology drugs and all oncology drugs that have been approved for marketing authorization since 2007 in Europe. ⋯ The most striking example is crizotinib. Implementation of the pediatric regulation should no longer be driven by the adult indication but should be guided instead by the biology of pediatric tumors and the mechanism of action of a drug. This change will be achievable through voluntary PIPs submitted by Pharma or revocation of the oncology class waiver list.
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Multicenter Study
Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma.
Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial. ⋯ Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.