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Friedhelm Raue, Karin Frank-Raue
Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid cancer (DTC) with the two subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most frequent subtype of thyroid cancer; more rare subtypes are medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC). The incidence of DTC has increased rapidly in recent years due to the more frequent use of imaging methods such as ultrasound of the neck and fine-needle aspiration (FNA) of thyroid nodules...
October 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Steven A Lacy, Dale R Miles, Linh T Nguyen
Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq(®)) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC)...
October 12, 2016: Clinical Pharmacokinetics
Hongjuan Zhao, Rosalie Nolley, Andy M W Chan, Erinn B Rankin, Donna M Peehl
MET plays an important role in the development and progression of papillary renal cell carcinoma (pRCC). Evaluation of efficacy of MET inhibitors against pRCC has been hampered by limited preclinical models depicting MET abnormalities. We established a new patient-derived xenograft (PDX) model of pRCC carrying an activating mutation of MET and tested the ability of cabozantinib, an inhibitor of receptor tyrosine kinases including MET, to inhibit tumor growth and metastasis. Precision-cut, thin tissue slices from a pRCC specimen obtained by nephrectomy were implanted under the renal capsule of RAG2(-/-)γC(-/-) mice to establish first generation TSG-RCC-030...
August 11, 2016: Cancer Biology & Therapy
Sara M Tolaney, Hovav Nechushtan, Ilan-Gil Ron, Patrick Schöffski, Ahmad Awada, Chris A Yasenchak, A Douglas Laird, Bridget O'Keeffe, Geoffrey I Shapiro, Eric P Winer
PURPOSE: Cabozantinib (XL184), a multi-targeted oral tyrosine kinase inhibitor with activity against MET, VEGFR2, AXL, and other tyrosine kinases, was assessed in a cohort of metastatic breast cancer (MBC) patients in a phase II randomized discontinuation trial (RDT). METHODS: Patients received 100 mg cabozantinib daily during a 12-week lead-in stage. Those with stable disease per modified Response Evaluation Criteria in Solid Tumors version 1.0 at 12 weeks were randomized to either continue cabozantinib or receive placebo...
November 2016: Breast Cancer Research and Treatment
Steven S Yu, David I Quinn, Tanya B Dorff
Clear cell (cc) renal cell carcinoma (RCC) is the most common type of cancer found in the kidney accounting for ~90% of all kidney cancers. In 2012, there were ~337,000 new cases of RCC diagnosed worldwide with an estimated 143,000 deaths, with the highest incidence and mortality in Western countries. Despite improvements in cancer control achieved with VEGF- and mTOR-targeted therapy for RCC, progression remains virtually universal and additional therapies are needed. The pivotal results of the METEOR trial led to cabozantinib's designation as a breakthrough drug by the US Food and Drug Administration and its approval for treatment of advanced RCC in 2016...
2016: OncoTargets and Therapy
Jörg Trojan, Oliver Waidmann
Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016...
2016: J Hepatocell Carcinoma
Magda Bahcall, Taebo Sim, Cloud P Paweletz, Jyoti D Patel, Ryan S Alden, Yanan Kuang, Adrian G Sacher, Nam Doo Kim, Christine Lydon, Mark M Awad, Michael T Jaklitsch, Lynette M Sholl, Pasi A Jänne, Geoffrey R Oxnard
Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped and understanding of mechanisms of resistance to MET TKIs is limited. Here we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib, responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib...
September 30, 2016: Cancer Discovery
Samuel J Klempner, Ali Borghei, Behrooz Hakimian, Siraj M Ali, Sai-Hong Ignatius Ou
INTRODUCTION: A significant portion of non-small cell lung cancers with MET exon14 skipping alterations are sensitive to small molecule MET tyrosine kinase inhibitors. However, the incidence and management of brain metastases in this molecular subset is unknown and represents an unmet clinical need. METHODS: Hybrid capture based comprehensive genomic profiling identified a patient with a MET exon14 skipping alteration and serial MRI imaging was utilized to follow intracranial disease during crizotinib and subsequent cabozantinib therapy...
September 27, 2016: Journal of Thoracic Oncology
Haris Zahoor, Brian I Rini
The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas Covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials, which led to their approval, is presented...
October 3, 2016: Expert Opinion on Emerging Drugs
Emiliano Calvo, Manuela Schmidinger, Daniel Y C Heng, Viktor Grünwald, Bernard Escudier
Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab...
September 10, 2016: Cancer Treatment Reviews
Vinicius Ernani, Mukesh Kumar, Amy Y Chen, Taofeek K Owonikoko
Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival...
September 10, 2016: Cancer Treatment Reviews
Melissa Bersanelli, Sebastiano Buti
N/A (Letter to the Editor).
2016: Acta Bio-medica: Atenei Parmensis
Dan-Dan Wang, Ying Chen, Zi-Bo Chen, Fang-Jie Yan, Xiao-Yang Dai, Mei-Dan Ying, Ji Cao, Jian Ma, Peihua Luo, Yong-Xin Han, Yong Peng, Yinghui Sun, Hui Zhang, Qiao-Jun He, Bo Yang, Hong Zhu
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic anti-tumor effects against HCC in vitro and in vivo. Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the anti-tumor activity of cabozantinib...
September 16, 2016: Molecular Cancer Therapeutics
Mary Choy
Cabozantinib (Cabometyx) for advanced renal cell carcinoma; glycopyrrolate/formoterol fumarate (Bevespi Aerosphere) for chronic obstructive pulmonary disease; and ephedrine sulfate (Akovaz) for hypotension during anesthesia.
September 2016: P & T: a Peer-reviewed Journal for Formulary Management
Sebastiano Buti, Alessandro Leonetti, Alice Dallatomasina, Melissa Bersanelli
INTRODUCTION: Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, and its pathogenesis is strictly related to altered cellular response to hypoxia, in which mTOR signaling pathway is implicated. Everolimus, an mTOR serine/threonine kinase inhibitor, represents a therapeutic option for the treatment of advanced RCC. AIM: The objective of this article is to review the evidence for the treatment of metastatic RCC with everolimus. EVIDENCE REVIEW: Everolimus was approved for second- and third-line therapy in patients with advanced RCC according to the results of a Phase III pivotal trial that demonstrated a benefit in median progression-free survival of ~2 months compared to placebo after failure of previous lines of therapy, of which at least one was an anti-VEGFR tyrosine kinase inhibitor (TKI)...
2016: Core Evidence
Tatiana Kelil, Abhishek R Keraliya, Stephanie A Howard, Katherine M Krajewski, Marta Braschi-Amirfarzan, Jason L Hornick, Nikhil H Ramaiya, Sree Harsha Tirumani
Substantial improvement in the understanding of the oncogenic pathways in thyroid cancer has led to identification of specific molecular alterations, including mutations of BRAF and RET in papillary thyroid cancer, mutation of RAS and rearrangement of PPARG in follicular thyroid cancer, mutation of RET in medullary thyroid cancer, and mutations of TP53 and in the phosphatidylinositol 3'-kinase (PI3K)/AKT1 pathway in anaplastic thyroid cancer. Ultrasonography (US) and US-guided biopsy remain cornerstones in the initial workup of thyroid cancer...
September 2016: Radiographics: a Review Publication of the Radiological Society of North America, Inc
Julio Lambea, Urbano Anido, Olatz Etxániz, Luis Flores, Álvaro Montesa, Juan Manuel Sepúlveda, Emilio Esteban
Sequential targeted therapies are the standard of care for patients with metastatic renal cell carcinoma (mRCC). Several drugs are available for patients whose disease progresses while they receive initial tyrosine kinase inhibitor (TKI) therapy; these include nivolumab (an inhibitor of PD-1 receptor), everolimus (an inhibitor of the mechanistic target of rapamycin) or additional TKIs. Until now, there has been no clinical evidence to support the use of one strategy versus another, so investigators and physicians rely on experience, judgement and findings from molecular analyses to select the appropriate treatment...
November 2016: Current Oncology Reports
Elena Andreucci, Paola Francica, Antony Fearns, Lesley-Ann Martin, Paola Chiarugi, Clare M Isacke, Andrea Morandi
The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers...
September 2, 2016: Oncotarget
Bo Hyun Kim, In Joo Kim
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor derived from the thyroid C cells producing calcitonin. MTC accounts for 0.6% of all thyroid cancers and incidence of MTC increased steadily between 1997 and 2011 in Korea. It occurs either sporadically or in a hereditary form based on germline rearranged during transfection (RET) mutations. MTC can be cured only by complete resection of the thyroid tumor and any loco-regional metastases. The most appropriate treatment is still less clear in patients with residual or recurrent disease after initial surgery or those with distant metastases because most patients even with metastatic disease have indolent courses with slow progression for several years and MTC is not responsive to either radioactive iodine therapy or thyroid-stimulating hormone suppression...
September 2016: Endocrinology and Metabolism
Benjamin M Ellingson, Robert J Harris, Davis C Woodworth, Kevin Leu, Okkar Zaw, Warren P Mason, Solmaz Sahebjam, Lauren E Abrey, Dana T Aftab, Gisela M Schwab, Colin Hessel, Albert Lai, Phioanh L Nghiemphu, Whitney B Pope, Patrick Y Wen, Timothy F Cloughesy
BACKGROUND: The prognostic significance of baseline contrast enhancing tumor prior to second- or third-line therapy in recurrent glioblastoma (GBM) for overall survival (OS) remains controversial, particularly in the context of repeated surgical resection and/or use of anti-angiogenic therapy. In the current study, we examined recurrent GBM patients from both single and multicenter clinical trials to test whether baseline enhancing tumor volume, including central necrosis, is a significant prognostic factor for OS in recurrent GBM...
August 31, 2016: Neuro-oncology
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