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Kinase targeting and clear cell carcinoma

Magdalena Lukamowicz-Rajska, Christiane Mittmann, Michael Prummer, Qing Zhong, Jens Bedke, Jörg Hennenlotter, Arnulf Stenzl, Axel Mischo, Svenja Bihr, Manuela Schmidinger, Ursula Vogl, Iris Blume, Christoph Karlo, Peter Schraml, Holger Moch
A number of treatments targeting VEGF or mTOR pathways have been approved for metastatic clear cell Renal Cell Carcinoma (ccRCC), but the majority of patients show disease progression after first line therapy with a very low rate of complete or long-term responders. It has been shown that miRs may play a role in prediction of treatment response in various cancer types. The aim of our study was to identify a miR signature predictive for RCC patients' response to antiangiogenic tyrosine kinase inhibitor (TKI) treatment in the first line therapy...
October 12, 2016: Oncotarget
Yongkun Sun, Wei Niu, Feng Du, Chunxia Du, Shuting Li, Jinwan Wang, Li Li, Fengqing Wang, Yu Hao, Chuan Li, Yihebali Chi
BACKGROUND: Anlotinib is a novel multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. We aimed to evaluate the safety, pharmacokinetics, and antitumor activity of anlotinib in patients with advanced refractory solid tumors. METHODS: Anlotinib (5-16 mg) was orally administered in patients with solid tumor once a day on two schedules: (1) four consecutive weeks (4/0) or (2) 2-week on/1-week off (2/1)...
October 4, 2016: Journal of Hematology & Oncology
Aaron M Udager, Rohit Mehra
Molecular and morphologic interrogation has driven a much-needed reexamination of renal cell carcinoma (RCC). Indeed, the recently released 2016 World Health Organization classification now recognizes 12 distinct RCC subtypes, as well as several other emerging/provisional RCC entities. From a clinical perspective, accurate RCC classification may have important implications for patients and their families, including prognostic risk stratification, targeted therapeutics selection, and identification for genetic testing...
October 2016: Archives of Pathology & Laboratory Medicine
Junya Furukawa, Hideaki Miyake, Masato Fujisawa
The aim of the present study was to investigate the role of the Hedgehog signaling pathway in the progression of metastatic clear cell renal cell carcinoma (m-ccRCC) as well as the molecular targets of sunitinib, an inhibitor of multiple tyrosine kinases. A total of 39 patients subjected to radical nephrectomy who were diagnosed with m-ccRCC and were subsequently treated with sunitinib were enrolled in the present study. The expression levels of the Hedgehog signaling proteins (GLI1, GLI2, cyclin D1, cyclin E and transforming growth factor-β) and major molecular targets of sunitinib [vascular endothelial growth factor receptor (VEGFR)-1 and -2, and platelet-derived growth factor receptor-α and -β] in primary RCC specimens were assessed by immunohistochemical staining...
September 2016: Molecular and Clinical Oncology
Pooja Ghatalia, Eddy S Yang, Brittany N Lasseigne, Ryne C Ramaker, Sara J Cooper, Dongquan Chen, Sunil Sudarshan, Shi Wei, Arjun S Guru, Amy Zhao, Tiffiny Cooper, Deborah L Della Manna, Gurudatta Naik, Richard M Myers, Guru Sonpavde
Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets...
2016: PloS One
Basma Greef, Tim Eisen
Renal cell carcinoma (RCC) makes up 2-3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti-programmed cell death 1 ligand monoclonal antibody, nivolumab...
August 23, 2016: British Journal of Cancer
Kozo Kuribayashi, Norihiko Funaguchi, Takashi Nakano
Lung cancers are broadly divided into small-cell lung cancer (SCLC) and non-SCLC (NSCLC), and the treatments for each differ. NSCLC includes squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and others. However, because there is little difference in treatment efficacy between these histological types, they have collectively been treated as a single entity. Cytotoxic anti-cancer agents, mainly platinum-based drugs, are the first-line treatment for unresectable advanced NSCLC, and the standard therapy is combination chemotherapy with two drugs, usually involving one platinum-based and one unrelated cytotoxic drug...
April 2016: Journal of Cancer Research and Therapeutics
James Liu, Caleb Abshire, Connor Carry, Andrew B Sholl, Sree Harsha Mandava, Amrita Datta, Manish Ranjan, Cameron Callaghan, Donna V Peralta, Kristen S Williams, Weil R Lai, Asim B Abdel-Mageed, Matthew Tarr, Benjamin R Lee
OBJECTIVE: To investigate tyrosine kinase inhibitors (TKI) and gold nanorod (AuNR) paired with photothermal ablation in a human metastatic clear cell renal cell carcinoma mouse model. Nanoparticles have been successful as platform for targeted drug delivery in the treatment of urologic cancers. Likewise, the use of nanoparticles in photothermal tumor ablation, though early in its development, has provided promising results. Our previous in vitro studies of nanoparticles loaded with both TKI and gold nanorods and activated with photothermal ablation have demonstrated significant synergistic cell kill greater than each individual arm alone...
July 19, 2016: BJU International
S Zhang, M Ulrich, A Gromnicka, L Havlíček, V Kryštof, R Jorda, M Strnad, A M Vollmar, S Zahler
BACKGROUND AND PURPOSE: Cyclin-dependent kinase 5 (CDK5) has recently emerged as an attractive target in several tumour entities. Inhibition of CDK5 has been shown to have anti-angiogenic effects in vitro and in vivo. However, potent inhibitors of CDK5, which can be applied in vivo, are still scarce. We have recently developed a new series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines that show a preference for inhibiting CDK5 and tested them in vitro and in vivo in a murine model of hepatocellular carcinoma...
September 2016: British Journal of Pharmacology
Rowan E Miller, Rachel Brough, Ilirjana Bajrami, Chris T Williamson, Simon McDade, James Campbell, Asha Kigozi, Rumana Rafiq, Helen Pemberton, Rachel Natrajan, Josephine Joel, Holly Astley, Claire Mahoney, Jonathan D Moore, Chris Torrance, John D Gordan, James T Webber, Rebecca S Levin, Kevan M Shokat, Sourav Bandyopadhyay, Christopher J Lord, Alan Ashworth
New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction...
July 2016: Molecular Cancer Therapeutics
R S Al-Lamki, W Lu, P Manalo, J Wang, A Y Warren, A M Tolkovsky, J S Pober, J R Bradley
We previously reported that renal clear cell carcinoma cells (RCC) express both tumor necrosis factor receptor (TNFR)-1 and -2, but that, in organ culture, a TNF mutein that only engages TNFR1, but not TNFR2, causes extensive cell death. Some RCC died by apoptosis based on detection of cleaved caspase 3 in a minority TUNEL-positive cells but the mechanism of death in the remaining cells was unexplained. Here, we underpin the mechanism of TNFR1-induced cell death in the majority of TUNEL-positive RCC cells, and show that they die by necroptosis...
2016: Cell Death & Disease
Amy Prawira, Irene Brana-Garcia, Anna Spreafico, Andrew Hope, John Waldron, Albiruni R Abdul Razak, Eric X Chen, Raymond Jang, Brian O'Sullivan, Meredith Giuliani, Andrew Bayley, John Cho, Lisa Wang, Bayardo Perez-Ordonez, Ilan Weinreb, Lillian L Siu, Aaron R Hansen
Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg)...
October 2016: Investigational New Drugs
Jens Bedke, Thomas Gauler, Viktor Grünwald, Axel Hegele, Edwin Herrmann, Stefan Hinz, Jan Janssen, Stephan Schmitz, Martin Schostak, Hans Tesch, Stefan Zastrow, Kurt Miller
PURPOSE: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC). METHODS: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing...
June 9, 2016: World Journal of Urology
Joana R Costa, Krisna Prak, Sarah Aldous, Christina Anja Gewinner, Robin Ketteler
The cellular stress response autophagy has been implicated in various diseases including neuro-degeneration and cancer. The role of autophagy in cancer is not clearly understood and both tumour promoting and tumour suppressive effects of autophagy have been reported, which complicates the design of therapeutic strategies based on targeting the autophagy pathway. Here, we have systematically analyzed gene expression data for 47 autophagy genes for deletions, amplifications and mutations in various cancers. We found that several cancer types have frequent autophagy gene amplifications, whereas deletions are more frequent in prostate adenocarcinomas...
May 31, 2016: Oncotarget
Scott M Haake, Jiannong Li, Yun Bai, Fumi Kinose, Bin Fang, Eric A Welsh, Roy Zent, Jasreman Dhillon, Julio M Pow-Sang, Y Ann Chen, John M Koomen, W Kimryn Rathmell, Mayer Fishman, Eric B Haura
PURPOSE: Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes. EXPERIMENTAL DESIGN: Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. In order to describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors...
May 24, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rana R McKay, Guillermo De Velasco, Lillian Werner, Joaquim Bellmunt, Lauren Harshman, Christopher Sweeney, Jonathan E Rosenberg, Michelle Hirsch, Sabina Signoretti, Eliezer M Van Allen, Meghara Walsh, Ulka Vaishampayan, David F McDermott, Toni K Choueiri
BACKGROUND: The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity...
August 1, 2016: Cancer
Małgorzata Domagała-Haduch, Ida Cedrych, Marek Jasiówka, Maciej Niemiec, Piotr Skotnicki
INTRODUCTION: Treatment of the metastatic stage of renal cell carcinoma is specific because classical chemotherapy is not applicable here. The treatment is mainly based on molecularly targeted drugs, including inhibitors of tyrosine kinases. In many cases the therapy takes many months, and patients often report to general practitioners due to adverse events. In this article, the effectiveness and side effects of one of these drugs are presented. The aim of the study was to analyse of the toxicity and safety of treatment with sunitinib malate in patients with clear cell renal cell carcinoma in the metastatic stage...
April 1, 2016: Archives of Medical Science: AMS
Gabriel G Malouf, Ronan Flippot, David Khayat
Metastases are present in one third of renal cell carcinomas at diagnosis. The overall survival duration in metastatic renal cell carcinoma is approximately 22 months, which underlines the need for more effective systemic treatments. Therapies on the basis of antiangiogenic agents and inhibitors of the mammalian target of rapamycin have been approved for treatment of metastatic renal cell carcinoma, but only benefits for progression-free survival were demonstrated in the second-line setting. Fortunately, promising treatments are emerging, from new antiangiogenic agents to immune checkpoint inhibitors...
May 2016: Journal of Oncology Practice
Ofer N Gofrit, Marina Orevi
PURPOSE: Positron emission tomography-computerized tomography is a leading imaging modality for many types of solid tumors. The ability to characterize molecular processes noninvasively during a relatively fast whole-body scan is the major advantage of this technology. We reviewed the literature in an attempt to clarify the usefulness of positron emission tomography-computerized tomography in patients with a renal mass. MATERIALS AND METHODS: We searched PubMed® for articles published from 2004 through September 2015 using the keywords "renal," "kidney," "mass," "tumor," "cancer," and "PET/CT...
September 2016: Journal of Urology
Miguel A De la Cruz-Morcillo, Julien Berger, Ricardo Sánchez-Prieto, Sofiane Saada, Thomas Naves, Angélique Guillaudeau, Aurélie Perraud, Philippe Sindou, Aurélie Lacroix, Aurélien Descazeaud, Fabrice Lalloué, Marie-Odile Jauberteau
p75NTR, a member of TNF receptor family, is the low affinity receptor common to several mature neurotrophins and the high affinity receptor for pro-neurotrophins. Brain-Derived Neurotrophic Factor (BDNF), a member of neurotrophin family has been described to play an important role in development and progression of several cancers, through its binding to a high affinity tyrosine kinase receptor B (TrkB) and/or p75NTR. However, the functions of these two receptors in renal cell carcinoma (RCC) have never been investigated...
June 7, 2016: Oncotarget
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