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Cabozantinib

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https://www.readbyqxmd.com/read/28330784/vascular-endothelial-growth-factor-vegf-and-vegf-receptor-inhibitors-in-the-treatment-of-renal-cell-carcinomas
#1
REVIEW
Robert Roskoski
One Von Hippel-Lindau (VHL) tumor suppressor gene is lost in most renal cell carcinomas while the nondeleted allele exhibits hypermethylation-induced inactivation or inactivating somatic mutations. As a result of these genetic modifications, there is an increased production of VEGF-A and pro-angiogenic growth factors in this disorder. The important role of angiogenesis in the pathogenesis of renal cell carcinomas and other tumors has focused the attention of investigators on the biology of VEGFs and VEGFR1-3 and to the development of inhibitors of the intricate and multifaceted angiogenic pathways...
March 18, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28321130/effective-combinatorial-immunotherapy-for-castration-resistant-prostate-cancer
#2
Xin Lu, James W Horner, Erin Paul, Xiaoying Shang, Patricia Troncoso, Pingna Deng, Shan Jiang, Qing Chang, Denise J Spring, Padmanee Sharma, John A Zebala, Dean Y Maeda, Y Alan Wang, Ronald A DePinho
A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance...
March 20, 2017: Nature
https://www.readbyqxmd.com/read/28318881/targeted-therapy-in-thyroid-cancer-state-of-the-art
#3
L Valerio, L Pieruzzi, C Giani, L Agate, V Bottici, L Lorusso, V Cappagli, L Puleo, A Matrone, D Viola, C Romei, R Ciampi, E Molinaro, R Elisei
Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation for differentiated tumours and treatment with thyrotropine hormone-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Cytotoxic chemotherapy or external beam radiotherapy has a low efficacy in these patients. 'Target therapy' with tyrosine kinase inhibitors (TKIs) represent an important therapeutic option for the treatment of advanced cases of radioiodine refractory (RAI-R) differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC) and possibly for cases of poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC)...
March 16, 2017: Clinical Oncology: a Journal of the Royal College of Radiologists
https://www.readbyqxmd.com/read/28303494/current-management-strategy-for-metastatic-renal-cell-carcinoma-and-future-directions
#4
REVIEW
Hussein Merza, Marijo Bilusic
PURPOSE OF REVIEW: Major strides have been made in the treatment of kidney cancer in the last several years with checkpoint immunotherapies and novel targeted agents. This manuscript will review current treatment strategies for metastatic renal cell carcinoma and will discuss future directions. RECENT FINDINGS: Most recently, several new drugs including nivolumab, cabozantinib, and a combination of lenvatinib and everolimus have demonstrated acceptable toxicity and significantly improved overall survival, but evidence-based guidelines for sequencing of the approved treatment options and treatment selection based on biomarkers are still missing...
April 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28296822/the-different-effects-of-vegfa121-and-vegfa165-on-regulating-angiogenesis-depend-on-phosphorylation-sites-of-vegfr2
#5
Wang Shiying, Sun Boyun, Yuan Jianye, Zhang Wanjun, Tao Ping, Lin Jiang, Hu Hongyi
The effects of VEGFA isoforms on the vascular permeability and structure are still unclear. In this study, we found that VEGFA121 and VEGFA165, 2 isoforms of VEGFA, exerted the opposing effects of antiangiogenesis and proangiogenesis on regulating vascular endothelia cells proliferation and tube formation. The 2 isoforms affected the protein expression of Ras-related protein 1-GTPase-activating protein 1 (Rap1GAP) and thrombospondin 1, 2 important signal molecules of Rap1GAP/thrombospondin 1 signal pathway in primary human umbilical vein endothelial cells by regulating 2 different phosphorylating sites of VEGFR2, Tyr(1175) and Tyr(1214)...
April 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28286925/cabozantinib-for-renal-cell-carcinoma-current-and-future-paradigms
#6
REVIEW
Ahmed Abdelaziz, Ulka Vaishampayan
Cabozantinib was approved by the FDA in April 2016 for the treatment of advanced renal cancer, pretreated with at least one prior antiangiogenic therapy. This is the first agent in the therapy of kidney cancer to show a statistically significant improvement in all three endpoints of clinical efficacy, response rate, progression free survival, and overall survival (OS), in a phase III randomized trial. The reporting of METEOR coincided with that of the Checkmate 025 study which randomized similarly eligible patients to receive nivolumab or everolimus 10 mg daily...
March 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28276433/renal-cell-carcinoma
#7
REVIEW
James J Hsieh, Mark P Purdue, Sabina Signoretti, Charles Swanton, Laurence Albiges, Manuela Schmidinger, Daniel Y Heng, James Larkin, Vincenzo Ficarra
Renal cell carcinoma (RCC) denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney. The disease encompasses >10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is most common and accounts for most cancer-related deaths. Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance...
March 9, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/28274958/cabozantinib-eradicates-advanced-murine-prostate-cancer-by-activating-anti-tumor-innate-immunity
#8
Akash Patnaik, Kenneth D Swanson, Eva Csizmadia, Aniruddh Solanki, Natalie Landon-Brace, Marina P Gehring, Katja Helenius, Brian M Olson, Athalia R Pyzer, Lily C Wang, Olivier Elemento, Jesse Novak, Thomas B Thornley, John M Asara, Laleh Montaser, Joshua J Timmons, Todd M Morgan, Yugang Wang, Elena Levantini, John G Clohessy, Kathleen Kelly, Pier Paolo Pandolfi, Jacalyn M Rosenblatt, David E Avigan, Huihui Ye, Jeffrey M Karp, Sabina Signoretti, Steven P Balk, Lewis C Cantley
Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor...
March 8, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28252459/renal-cell-carcinoma-molecular-characterization-and-evolving-treatment-paradigms
#9
Mark W Ball, Eric A Singer, Ramaprasad Srinivasan
PURPOSE OF REVIEW: The treatment landscape of advanced renal cell carcinoma (RCC) continues to shift as both new targeted therapies and immunotherapies show efficacy in treating the disease. Contemporary insights into the molecular characterization of RCC are likely to fuel the development of additional therapies. This review summarizes recent advancements in the biologic characterization of RCC and discusses newly approved therapies and ongoing studies in the treatment of advanced RCC...
March 1, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28247252/cabozantinib-an-active-novel-multikinase-inhibitor-in-renal-cell-carcinoma
#10
REVIEW
Nizar M Tannir, Gisela Schwab, Viktor Grünwald
Clear cell renal cell carcinoma (RCC) is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL loss drives tumor angiogenesis and accounts for the clinical activity of VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs), the first-line standard of care for advanced RCC. Within the last year, three new second-line treatments have received FDA approval for use after anti-angiogenic therapy: the immune checkpoint inhibitor nivolumab, the TKI cabozantinib, and the combination of the TKI lenvatinib and the mTOR inhibitor everolimus...
February 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28224821/lenvatinib-for-use-in-combination-with-everolimus-for-the-treatment-of-patients-with-advanced-renal-cell-carcinoma-following-one-prior-anti-angiogenic-therapy
#11
REVIEW
Aine O'Reilly, James Larkin
In patients with mRCC options for second line therapies, following progression on anti-angiogenic agents, that demonstrate a survival advantage in clinical trials have been limited. Recently a number of agents have demonstrated efficacy in this setting. Here in we profile one such therapy, the combination of lenvatinib and everolimus, and discuss the expanded options for therapy available in this setting. Areas covered: In this review, we discuss current algorithms for treatment of mRCC in both the first-line and second-line setting...
March 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28223547/cabozantinib-targets-bone-microenvironment-modulating-human-osteoclast-and-osteoblast-functions
#12
Marco Fioramonti, Daniele Santini, Michele Iuliani, Giulia Ribelli, Paolo Manca, Nicola Papapietro, Filippo Spiezia, Bruno Vincenzi, Vincenzo Denaro, Antonio Russo, Giuseppe Tonini, Francesco Pantano
Cabozantinib, a c-MET and vascular endothelial growth factor receptor 2 inhibitor, demonstrated to prolong progression free survival and improve skeletal disease-related endpoints in castration-resistant prostate cancer and in metastatic renal carcinoma. Our purpose is to investigate the direct effect of cabozantinib on bone microenvironment using a total human model of primary osteoclasts and osteoblasts.Osteoclasts were differentiated from monocytes isolated from healthy donors; osteoblasts were derived from human mesenchymal stem cells obtained from bone fragments of orthopedic surgery patients...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28199818/cabozantinib-versus-sunitinib-as-initial-targeted-therapy-for-patients-with-metastatic-renal-cell-carcinoma-of-poor-or-intermediate-risk-the-alliance-a031203-cabosun-trial
#13
Toni K Choueiri, Susan Halabi, Ben L Sanford, Olwen Hahn, M Dror Michaelson, Meghara K Walsh, Darren R Feldman, Thomas Olencki, Joel Picus, Eric J Small, Shaker Dakhil, Daniel J George, Michael J Morris
Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria...
February 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28192597/a-phase-2-and-biomarker-study-of-cabozantinib-in-patients-with-advanced-cholangiocarcinoma
#14
Lipika Goyal, Hui Zheng, Matthew B Yurgelun, Thomas A Abrams, Jill N Allen, James M Cleary, Michelle Knowles, Eileen Regan, Amanda Reardon, Anna Khachatryan, Rakesh K Jain, Valentina Nardi, Darrell R Borger, Dan G Duda, Andrew X Zhu
BACKGROUND: Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond first-line gemcitabine/platinum-based chemotherapy. A single-arm, phase 2 and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET, was performed for patients with advanced refractory cholangiocarcinoma. METHODS: Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib (60 mg orally and daily on a continuous schedule)...
February 13, 2017: Cancer
https://www.readbyqxmd.com/read/28153029/new-treatment-options-for-metastatic-renal-cell-carcinoma-with-prior-anti-angiogenesis-therapy
#15
REVIEW
Kevin Zarrabi, Chunhui Fang, Shenhong Wu
Angiogenesis is a critical process in the progression of advanced renal cell carcinoma. Agents targeting angiogenesis have played a primary role in the treatment of metastatic renal cell carcinoma. However, resistance to anti-angiogenesis therapy almost always occurs, and major progress has been made in understanding its underlying molecular mechanism. Axitinib and everolimus have been used extensively in patients whom have had disease progression after prior anti-angiogenesis therapy. Recently, several new agents have been shown to improve overall survival in comparison with everolimus...
February 2, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28152932/national-comprehensive-cancer-network-petitions-submissions-and-outcomes
#16
Dinah Faith Huff, William J Hrushesky, Charles Lee Bennett, Kevin Knopf, Michael Baum
248 Background: The National Comprehensive Cancer Network (NCCN) invites petitions to its scientific panels. Most ( > 95%) are from the pharmaceutical industry lobbying to include their products in the NCCN Guidelines. Rarely, physicians request scientific scrutiny of the guidelines. We report the experience of Oncology Analytics (OA) with petition submissions and the possible impact on guidelines. METHODS: From 2011-2015, OA made 7 petitions to NCCN. The content of each was tracked into subsequent NCCN Guidelines to ascertain whether any changes resulted...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28152689/comparative-effectiveness-research-in-renal-cell-carcinoma-lenvatinib-with-everolimus-as-a-potential-new-treatment-option
#17
Corey Pelletier, Unnati Majethia, Anna Forsythe
27 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer and represents about 90% of all kidney cancers. As comprehensive comparison of the efficacy associated with mRCC treatments is not available, the goal of this research was to provide a comparative effectiveness analysis including overall survival (OS) and progression free survival (PFS) for first and second line treatments. METHODS: Systematic literature review yielded the following randomized active-controlled studies: lenvatinib + everolimus (LEN+EVE) versus everolimus (EVE), axinitib (AXI) versus sorafenib (SOR), cabozantinib (CAB) versus EVE, nivolumab (NIV) versus EVE, and pazopanib (PAZ) versus sunitinib (SUN)...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28137742/cabozantinib-targeted-therapy-back-to-the-future
#18
EDITORIAL
Ghassan Abou-Alfa
No abstract text is available yet for this article.
January 30, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28131876/modulating-the-function-of-atp-binding-cassette-subfamily-g-member-2-abcg2-with-inhibitor-cabozantinib
#19
Guan-Nan Zhang, Yun-Kai Zhang, Yi-Jun Wang, Anna Maria Barbuti, Xi-Jun Zhu, Xin-Yue Yu, Ai-Wen Wen, John N D Wurpel, Zhe-Sheng Chen
Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2...
January 25, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28123517/role-of-free-testosterone-levels-in-patients-with-metastatic-castration-resistant-prostate-cancer-receiving-second-line-therapy
#20
Christoph A von Klot, Markus A Kuczyk, Alena Boeker, Christoph Reuter, Florian Imkamp, Thomas R W Herrmann, Hossein Tezval, Mario W Kramer, Sven Perner, Axel S Merseburger
A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only...
January 2017: Oncology Letters
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