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https://www.readbyqxmd.com/read/28901514/multimodal-actions-of-the-phytochemical-sulforaphane-suppress-both-ar-and-ar-v7-in-22rv1-cells-advocating-a-potent-pharmaceutical-combination-against-castration-resistant-prostate-cancer
#1
Namrata Khurana, Hogyoung Kim, Partha K Chandra, Sudha Talwar, Pankaj Sharma, Asim B Abdel-Mageed, Suresh C Sikka, Debasis Mondal
Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1)...
November 2017: Oncology Reports
https://www.readbyqxmd.com/read/28878208/hsp90-inhibition-enhances-cancer-immunotherapy-by-upregulating-interferon-response-genes
#2
Rina M Mbofung, Jodi A McKenzie, Shruti Malu, Min Zhang, Weiyi Peng, Chengwen Liu, Isere Kuiatse, Trang Tieu, Leila Williams, Seram Devi, Emily Ashkin, Chunyu Xu, Lu Huang, Minying Zhang, Amjad H Talukder, Satyendra C Tripathi, Hiep Khong, Nikunj Satani, Florian L Muller, Jason Roszik, Timothy Heffernan, James P Allison, Gregory Lizee, Sam M Hanash, David Proia, Rodabe Amaria, R Eric Davis, Patrick Hwu
T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28841232/inhibiting-heat-shock-protein-90-and-the-ubiquitin-proteasome-pathway-impairs-metabolic-homeostasis-and-leads-to-cell-death-in-human-pancreatic-cancer-cells
#3
Astrid Belalcazar, Walid L Shaib, Matthew R Farren, Chao Zhang, Zhengjia Chen, Lily Yang, Gregory B Lesinski, Bassel F El-Rayes, Ganji Purnachandra Nagaraju
BACKGROUND: Heat shock protein 90 (HSP90) and the ubiquitin-proteasome pathway play crucial roles in the homeostasis of pancreatic cancer cells. This study combined for the first time the HSP90 inhibitor ganetespib (Gan) and the proteasome inhibitor carfilzomib (Carf) to target key mechanisms of homeostasis in pancreatic cancer. It was hypothesized that Gan plus Carf would elicit potent antitumor activity by modulating complementary homeostatic processes. METHODS: In vitro and in vivo effects of this combination on mechanisms of cell growth and viability were evaluated with human pancreatic cancer cell lines (MIA PaCa-2 and HPAC)...
August 25, 2017: Cancer
https://www.readbyqxmd.com/read/28819369/in-vitro-cytotoxic-activities-of-the-oral-platinum-iv-prodrug-oxoplatin-and-hsp90-inhibitor-ganetespib-against-a-panel-of-gastric-cancer-cell-lines
#4
Lukas Klameth, Barbara Rath, Gerhard Hamilton
Gastric cancer exhibits a poor prognosis and is the third most common cause of cancer death worldwide. Chemotherapy of metastatic gastric cancer is based on combinations of platinum drugs and fluoropyrimidines, with added agents. Oxoplatin is a stable oral platinum(IV) prodrug which is converted to a highly active tetrachlorido(IV) complex under acidic conditions. In the present work, we studied the cytotoxic effects of oxoplatin against a panel of four gastric cancer cell lines in vitro. Furthermore, the role of HSP90 in chemoresistance of these lines was investigated using the specific inhibitor ganetespib...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28764748/a-phase-i-trial-of-ganetespib-in-combination-with-paclitaxel-and-trastuzumab-in-patients-with-human-epidermal-growth-factor-receptor-2-her2-positive-metastatic-breast-cancer
#5
Komal Jhaveri, Rui Wang, Eleonora Teplinsky, Sarat Chandarlapaty, David Solit, Karen Cadoo, James Speyer, Gabriella D'Andrea, Sylvia Adams, Sujata Patil, Sofia Haque, Tara O'Neill, Kent Friedman, Francisco J Esteva, Clifford Hudis, Shanu Modi
BACKGROUND: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer...
August 2, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28743892/dyrk1b-mutations-associated-with-metabolic-syndrome-impair-the-chaperone-dependent-maturation-of-the-kinase-domain
#6
Samira Abu Jhaisha, Esti W Widowati, Isao Kii, Rie Sonamoto, Stefan Knapp, Chrisovalantis Papadopoulos, Walter Becker
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28713919/ganetespib-induces-g2-m-cell-cycle-arrest-and-apoptosis-in-gastric-cancer-cells-through-targeting-of-receptor-tyrosine-kinase-signaling
#7
Harry Lee, Nipun Saini, Amanda B Parris, Ming Zhao, Xiaohe Yang
Heat shock protein 90 (HSP90) regulates several important cellular processes via its repertoire of 'client proteins'. These client proteins have been found to play fundamental roles in signal transduction, cell proliferation, cell cycle progression and survival, as well as other features of malignant cells, such as invasion, tumor angiogenesis and metastasis. Thus, HSP90 is an emerging target for cancer therapy. To this end, we evaluated ganetespib (STA-9090), a novel and potent HSP90 inhibitor, for its activity in gastric cancer cell lines...
September 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28624441/hsp90-inhibitor-geldanamycin-attenuates-the-cytotoxicity-of-sunitinib-in-cardiomyocytes-via-inhibition-of-the-autophagy-pathway
#8
Takayuki Kimura, Mai Uesugi, Kazuma Takase, Norimasa Miyamoto, Kohei Sawada
Sunitinib malate (sunitinib) is an orally available, multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Although sunitinib is effective for the treatment of patients with gastrointestinal stromal tumor, advanced renal cell carcinoma, or pancreatic neuroendocrine tumor, adverse cardiac events associated with sunitinib administration have been reported. Here, we examined the effect of geldanamycin, an inhibitor of heat shock protein (Hsp) 90, on sunitinib-induced cytotoxicity in cardiomyocytes...
August 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28583846/epigenetic-effects-of-inhibition-of-heat-shock-protein-90-hsp90-in-human-pancreatic-and-colon-cancer
#9
Ganji Purnachandra Nagaraju, Christina Wu, Neha Merchant, Zhengjia Chen, Gregory B Lesinski, Bassel F El-Rayes
Silencing of tumor suppressor and DNA repair genes through methylation plays a role in cancer development, growth and response to therapy in colorectal and pancreatic cancers. Heat shock protein 90 (HSP90) regulates transcription of DNA methyltransferase enzymes (DNMT). In addition, DNMTs are client proteins of HSP90. The aim of this study is to evaluate the effects of HSP90 inhibition on DNA methylation in colorectal and pancreatic cancer cell lines. Our data shows that inhibition of HSP90 using ganetespib resulted in downregulation of mRNA and protein expression of DNMT1, DNMT3A, and DNMT3B in HT-29 and MIA PaCa-2 cell lines...
August 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28566436/reactivation-of-the-p90rsk-cdc25c-pathway-leads-to-bypass-of-the-ganetespib-induced-g2-m-arrest-and-mediates-acquired-resistance-to-ganetespib-in-kras-mutant-nsclc
#10
Suman Chatterjee, Eric H-B Huang, Ian Christie, Timothy F Burns
A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit...
August 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28476040/efficacy-of-an-hsp90-inhibitor-ganetespib-in-preclinical-thyroid-cancer-models
#11
Shu-Fu Lin, Jen-Der Lin, Chuen Hsueh, Ting-Chao Chou, Chun-Nan Yeh, Ming-Huang Chen, Richard J Wong
Heat shock protein 90 is a molecular chaperon that maintains the correct folding and function of multiple client proteins. The inhibition of heat shock protein 90, which leads to the simultaneous degradation of multiple proteins involved in oncogenic signaling pathways, has revealed an innovative strategy to treat a variety of cancer types. We evaluated the therapeutic effects of ganetespib, a heat shock protein 90 inhibitor, in treating thyroid cancer. Ganetespib effectively inhibited cell proliferation in a dose-dependent manner in eight cell lines originating from four major histologic types of thyroid cancer (papillary, follicular, anaplastic and medullary)...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28301350/a-phase-ii-study-of-ganetespib-as-second-line-or-third-line-therapy-for-metastatic-pancreatic-cancer
#12
Dana B Cardin, Ramya Thota, Laura W Goff, Jordan D Berlin, Clyde M Jones, Gregory D Ayers, Jennifer G Whisenant, Emily Chan
OBJECTIVES: Heat shock protein 90 regulates multiple signaling proteins involved in key pathways of pancreatic cancer pathogenesis. Ganetespib binds to heat shock protein 90 and interferes with its binding to client proteins thus leading to inactivation and degradation of the signaling proteins that promote cancer progression. This phase II study was designed to evaluate the efficacy of ganetespib in patients with refractory metastatic pancreatic cancer (rMPC). METHODS: Patients with rMPC received 175 mg/m ganetespib intravenously once weekly for 3 weeks in 4-week cycles...
March 15, 2017: American Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28300840/ganetespib-synergizes-with-cyclophosphamide-to-improve-survival-of-mice-with-autochthonous-tumors-in-a-mutant-p53-dependent-manner
#13
Evguenia M Alexandrova, Sulan Xu, Ute M Moll
The DNA-alkylating cytotoxic agent cyclophosphamide (CTX) is commonly used in the clinic to treat hematological malignancies like lymphomas and leukemias as well as solid tumors, but shows dose-dependent potentially life-threatening toxicities and can induce secondary malignancies. Thus, the clinical utility of CTX would be improved if a companion drug could be identified that allows lowering the CTX dose, while maintaining or even increasing its antineoplastic therapeutic efficacy. In mouse models, high-dose CTX (300 mg/kg) is effective in treating T-lymphomas, while low dose (defined here as 100 mg/kg) is ineffective...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28298630/proteomic-analysis-of-proteome-and-histone-post-translational-modifications-in-heat-shock-protein-90-inhibition-mediated-bladder-cancer-therapeutics
#14
Qingdi Quentin Li, Jian-Jiang Hao, Zheng Zhang, L Spencer Krane, Kai H Hammerich, Thomas Sanford, Jane B Trepel, Len Neckers, Piyush K Agarwal
Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose- and time-dependent manner...
March 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28274158/heat-shock-protein-antagonists-in-early-stage-clinical-trials-for-nsclc
#15
REVIEW
Lizza E L Hendriks, Anne-Marie C Dingemans
Cancer cells have a higher need of chaperones than normal cells to prevent the toxic effects of intracellular protein misfolding and aggregation. Heat shock proteins (Hsps) belong to these chaperones; they are classified into families according to molecular size. Hsps are upregulated in many cancers and inhibition can inhibit tumor growth by destabilizing proteins necessary for tumor survival. In non-small cell lung cancer (NSCLC), there are three different Hsp antagonist classes that are in (early) clinical trials: Hsp90, Hsp70 and Hsp27 inhibitors...
May 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28167505/acquired-resistance-to-the-hsp90-inhibitor-ganetespib-in-kras-mutant-nsclc-is-mediated-via-reactivation-of-the-erk-p90rsk-mtor-signaling-network
#16
Suman Chatterjee, Eric H-B Huang, Ian Christie, Brenda F Kurland, Timothy F Burns
Approximately 25% of non-small cell lung cancer (NSCLC) patients have KRAS mutations, and no effective therapeutic strategy exists for these patients. The use of Hsp90 inhibitors in KRAS-mutant NSCLC appeared to be a promising approach, as these inhibitors target many KRAS downstream effectors; however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations, which may prevent and overcome resistance to Hsp90 inhibitors...
May 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28111726/ganetespib-overcomes-resistance-to-parp-inhibitors-in-breast-cancer-by-targeting-core-proteins-in-the-dna-repair-machinery
#17
Juhong Jiang, Yuanzhi Lu, Zhi Li, Liping Li, Daoli Niu, Wenwei Xu, Jing Liu, Lin Fu, Ziqing Zhou, Yingying Gu, Fen Xia
DNA damage repair plays essential roles in drug resistance, especially resistance to Poly (ADP-ribose) polymerase (PARP) inhibitors in the clinic. A subset of DNA repair proteins such as Breast cancer gene 1 (BRCA1), BRCA2 and RecA homolog (RAD51) are client proteins of heat shock protein 90 (Hsp90). Clearance of these DNA repair proteins by inhibition of Hsp90 is a promising strategy for overcoming resistance to PARP inhibitors. Here we report the pharmacological analysis of the highly potent second-generation Hsp90 inhibitor, ganetespib...
June 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28078663/inhibition-of-heat-shock-protein-90-exerts-an-antitumour-effect-in-angiosarcoma-involvement-of-the-vascular-endothelial-growth-factor-signalling-pathway
#18
S Yamada-Kanazawa, I Kajihara, S Fukushima, M Jinnin, M Masuzawa, M Masuzawa, Y Amoh, D Hoshina, R Abe, H Ihn
BACKGROUND: Angiosarcoma is a rare malignant neoplasm derived from endothelial cells, and because advanced angiosarcoma is resistant to standard chemotherapy its prognosis is poor. Therefore, new therapies are urgently needed. Heat shock protein (HSP)90 has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are currently testing the effectiveness of HSP90 inhibitors in various types of malignancies. OBJECTIVES: To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have antitumour activity...
August 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/28032595/prospective-identification-of-resistance-mechanisms-to-hsp90-inhibition-in-kras-mutant-cancer-cells
#19
Arefeh Rouhi, Christina Miller, Sarah Grasedieck, Stefanie Reinhart, Britta Stolze, Hartmut Döhner, Florian Kuchenbauer, Lars Bullinger, Stefan Fröhling, Claudia Scholl
Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/27922280/ganetespib-for-small-cell-lung-cancer
#20
REVIEW
Deepa S Subramaniam, Eiran A Warner, Giuseppe Giaccone
Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC)...
January 2017: Expert Opinion on Investigational Drugs
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