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David A Proia - One of the best experts on this subject based on the ideXlab platform.

  • ganetespib an Hsp90 Inhibitor kills epstein barr virus ebv infected b and t cells and reduces the percentage of ebv infected cells in the blood
    Leukemia & Lymphoma, 2017
    Co-Authors: Amber N Shatzer, Iman Elhariry, David A Proia, Mir A Ali, Mayra Chavez, Kennichi C Dowdell, Minjung Lee, Yusuke Tomita, Jane B Trepel, Jeffrey I Cohen
    Abstract:

    Hsp90 Inhibitors have been shown to kill Epstein-Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an Hsp90 Inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line. The former cell line showed lower levels of EBNA-1 after treatment with ganetespib in vitro. Treatment of a patient with T-cell chronic active EBV with ganetespib reduced the percentage of EBV-positive cells in the peripheral blood. These data indicate that Hsp90 Inhibitors may have a role in the therapy of certain EBV-associated diseases.

  • Hsp90 Inhibitor ganetespib sensitizes non small cell lung cancer to radiation but has variable effects with chemoradiation
    Clinical Cancer Research, 2016
    Co-Authors: David A Proia, Y Wang, Hui Liu, Lixia Diao, Adam Potter, Jianhu Zhang, Yawei Qiao, Jing Wang, Ramesh C Tailor
    Abstract:

    Purpose: Hsp90 inhibition is well known to sensitize cancer cells to radiation. However, it is currently unknown whether additional radiosensitization could occur in the more clinically relevant setting of chemoradiation (CRT). We used the potent Hsp90 Inhibitor ganetespib to determine whether it can enhance CRT effects in NSCLC. Experimental Design: We first performed in vitro experiments in various NSCLC cell lines combining radiation with or without ganetespib. Some of these experiments included clonogenic survival assay, DNA damage repair, and cell-cycle analysis, and reverse-phase protein array. We then determined whether chemotherapy affected ganetespib radiosensitization by adding carboplatin–paclitaxel to some of the in vitro and in vivo xenograft experiments. Results: Ganetespib significantly reduced radiation clonogenic survival in a number of lung cancer cell lines, and attenuated DNA damage repair with irradiation. Radiation caused G2–M arrest that was greatly accentuated by ganetespib. Ganetespib with radiation also dose-dependently upregulated p21 and downregulated pRb levels that were not apparent with either drug or radiation alone. However, when carboplatin–paclitaxel was added, ganetespib was only able to radiosensitize some cell lines but not others. This variable in vitro CRT effect was confirmed in vivo using xenograft models. Conclusions: Ganetespib was able to potently sensitize a number of NSCLC cell lines to radiation but has variable effects when added to platinum-based doublet CRT. For optimal clinical translation, our data emphasize the importance of preclinical testing of drugs in the context of clinically relevant therapy combinations. Clin Cancer Res; 22(23); 5876–86. ©2016 AACR.

  • abstract 267 preclinical investigation of the Hsp90 Inhibitor ganetespib in combination with fda approved cytotoxic agents for their potential anti tumor effects on human neuroendocrine tumors
    Cancer Research, 2016
    Co-Authors: Chung Wong, Evan Vosburgh, Arnold J Levine, David A Proia
    Abstract:

    The gastroenteropancreatic neuroendocrine tumor (GEP-NET) system is comprised of a heterogeneous group of tumors with increasing incidence. Current standard of care cytotoxic agents have limited efficacy, which necessitates the need for innovative therapeutic approaches. Heat shock protein 90 (Hsp90) is overexpressed in a wide range of tumor types including human pancreatic neuroendocrine tumors (PanNETs). Ganetespib is a second-generation Hsp90 Inhibitor that is well tolerated in cancer patients (dosed into >1500 patients) and is currently being evaluated in several investigator sponsored clinical trials including acute myeloid leukemia (AML), ovarian cancer, breast cancer, and other tumor types. Here, we show that ganetespib inhibits the proliferation of NET cells and induces apoptosis in vitro with potency comparable to another second-generation Hsp90 Inhibitor (NVP-AUY922), but with potency two- to seven-fold more than first generation Inhibitors (17-AAG, IPI-504) in BON-1, CM and H727 cell lines, and thirty-fold more in QGP-1 cell line. In mice bearing PanNET tumor xenografts, single agent ganetespib reduced the growth of tumors without signs of toxicity. Tumors from ganetespib treated animals demonstrated reduced phospho-AKT and phospho-ERK expression, and elevated HSP70 expression, supportive of exposures necessary for functional activity. In an effort to identify clinically meaningful agents that could further potentiate the antitumor activity of ganetespib, we performed in vitro combination screens evaluating proliferation in four NET cell lines with ganetespib and forty FDA approved anticancer agents. Ganetespib showed synergistic effects when combined with Inhibitors of mTOR, topoisomerase I or II, or DNA synthesis. Results from our ongoing in vivo combination studies with ganetespib and these three classes of anticancer agents will be presented. Citation Format: Chung Wong, Evan Vosburgh, Arnold Levine, David Proia, Eugenia Xu. Preclinical investigation of the Hsp90 Inhibitor, ganetespib, in combination with FDA-approved cytotoxic agents for their potential anti-tumor effects on human neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 267.

  • the Hsp90 Inhibitor ganetespib radiosensitizes human lung adenocarcinoma cells
    Cancers, 2015
    Co-Authors: Roberto Gomezcasal, David A Proia, Chitralekha Bhattacharya, Michael W Epperly, Per H Basse, Hong Wang, Xinhui Wang, Joel S Greenberger, Mark A Socinski, Vera Levina
    Abstract:

    The molecular chaperone Hsp90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of Hsp90 Inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, Hsp90 Inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.

  • ganetespib a novel Hsp90 Inhibitor in patients with kras mutated and wild type refractory metastatic colorectal cancer
    Clinical Colorectal Cancer, 2014
    Co-Authors: Andrea Cercek, David A Proia, Jinru Shia, Marc J Gollub, Joanne F Chou, Marinela Capanu, Pamela Joan Raasch, Diane Reidylagunes, Efsevia Vakiani, David B Solit
    Abstract:

    Abstract Background Heat shock protein 90 (Hsp90) is a cellular chaperone that is required for the maturation and stability of a variety of proteins that play key roles in colon cancer initiation and progression. The primary objective of the current study was to define the safety and efficacy of ganetespib, a novel, selective small-molecule Hsp90 Inhibitor, in patients with refractory metastatic colorectal cancer. Patients and Methods The study was a single-arm, Simon 2-stage, phase II trial for patients with chemotherapy-refractory, metastatic colorectal cancer. Patients received ganetespib 200 mg/m 2 intravenously. Tumor tissue was collected before treatment and 48 hours after treatment for changes in expression of Hsp90 client proteins and other potential pharmacodynamics markers. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B, and phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutational status was also determined. Results Seventeen patients were treated (median age, 58; range, 44-79 years). No patients demonstrated objective regression of disease. Two patients had stable disease of 6.8 and 5.1 months duration. Serious adverse events that were potentially attributable to ganetespib included diarrhea (12%, n = 2), fatigue (17%, n = 3), and increased aspartate aminotransferase/alanine aminotransferase (12%, n = 2) and alkaline phosphatase (6%, n = 1) levels. Of the 17 evaluable patients, 9 (53%) including patients with stable disease as best response, had KRAS-mutant tumors. Conclusion In this first phase II investigation of an Hsp90 Inhibitor in colorectal cancer, ganetespib as a single agent did not demonstrate activity in chemotherapy-refractory metastatic colorectal cancer. However, on the basis of the drug's promising preclinical combination data and the relatively mild toxicity profile, further clinical investigation of this agent in combination with standard cytotoxic agents is planned.

Michael Rugaard Jensen - One of the best experts on this subject based on the ideXlab platform.

  • the novel oral Hsp90 Inhibitor nvp hsp990 exhibits potent and broad spectrum antitumor activities in vitro and in vivo
    Molecular Cancer Therapeutics, 2012
    Co-Authors: Daniel Menezes, Michael Rugaard Jensen, Pietro Taverna, Tinya Abrams, Darrin Stuart, David Duhl, Timothy D Machajewski, William R Sellers, Nancy Pryer, Zhenhai Gao
    Abstract:

    A novel oral Hsp90 Inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.

  • 89zr bevacizumab pet of early antiangiogenic tumor response to treatment with Hsp90 Inhibitor nvp auy922
    The Journal of Nuclear Medicine, 2010
    Co-Authors: Wouter B Nagengast, Michael Rugaard Jensen, Cornelia Quadt, Maarten A De Korte, Thijs Oude H Munnink, Hetty Timmerbosscha, Wifred Den F Dunnen, Harry Hollema, Johan R De Jong, Carlos Garciaecheverria
    Abstract:

    Angiogenesis is a critical step in tumor development, in which vascular endothelial growth factor (VEGF) is a key growth aspect. Heat shock protein 90 (Hsp90), a molecular chaperone, is essential for the activity of key proteins involved in VEGF transcription. Currently, no biomarkers to predict the effect of, or monitor, Hsp90 inhibition therapy in individual patients exist. 89Zr-bevacizumab PET provides a noninvasive tool to monitor tumor VEGF levels. The aim of this study was to investigate 89Zr-bevacizumab PET for early antiangiogenic tumor response evaluation of treatment with the new Hsp90 Inhibitor NVP-AUY922. In xenografts of A2780 and its cisplatin-resistant CP70 human ovarian cancer subline, 89Zr-bevacizumab small-animal PET was performed before and after NVP-AUY922 treatment and verified with histologic response and ex vivo tumor VEGF levels. Compared with pretreatment values, 2 wk of NVP-AUY922 treatment decreased 89Zr-bevacizumab uptake by 44.4% (P = 0.0003) in A2780 xenografts, whereas tumor uptake was not affected in CP70 xenografts. The same pattern was observed in A2780 and CP70 tumor VEGF levels, measured with enzyme-linked immunosorbent assay, and mean vessel density after NVP-AUY922 treatment. These findings coincided with reduction in the proliferation rate, assessed by Ki67 staining, in A2780 tumor tissue only. Conclusion:89Zr-bevacizumab PET was in line with the antiangiogenic response and direct antitumor effects after NVP-AUY922 treatment, supporting the specificity of 89Zr-bevacizumab PET as a sensitive technique to monitor the antiangiogenic response of Hsp90 inhibition in vivo.

  • signalling profile and antitumour activity of the novel Hsp90 Inhibitor nvp auy922 in multiple myeloma
    Leukemia, 2008
    Co-Authors: Thorsten Stuhmer, Michael Rugaard Jensen, A Zollinger, Daniela Siegmund, Manik Chatterjee, Evelyn Grella, Stefan Knop, Martin Kortum, C Unzicker, Cornelia Quadt
    Abstract:

    We as well as others have recently shown that Hsp90 is overexpressed in multiple myeloma (MM) and critically contributes to tumour cell survival. Pharmacologic blockade of Hsp90 has consistently been found to induce MM cell death. However, most data have been obtained with MM cell lines whereas knowledge about the molecular effects of pharmacologic Hsp90 blockade in primary tumour cells is limited. Furthermore, these investigations have so far focused on geldanamycin derivatives. We analysed the biochemical effects of a novel diarylisoxazole-based Hsp90 Inhibitor (NVP-AUY922) on signalling pathways and cell death in a large set of primary MM tumour samples and in MM cell lines. Treated cells displayed the molecular signature and pharmacodynamic properties for abrogation of Hsp90 function, such as downregulation of multiple survival pathways and strong upregulation of Hsp70. NVP-AUY922 treatment efficiently induced MM cell apoptosis and revealed both sensitive and resistant subgroups. Sensitivity was not correlated with TP53 mutation or Hsp70 induction levels and stromal cells from the bone marrow microenvironment were unable to abrogate NVP-AUY922-induced apoptosis of MM cells. Thus, NVP-AUY922 may be a promising drug for treatment of MM and clinical studies are warranted.

  • nvp auy922 a small molecule Hsp90 Inhibitor with potent antitumor activity in preclinical breast cancer models
    Breast Cancer Research, 2008
    Co-Authors: Michael Rugaard Jensen, Andrew Massey, Joseph Schoepfer, Thomas Radimerski, Chantale T Guy, Josef Brueggen, Cornelia Quadt, Alan Buckler, Robert Cozens, Martin J Drysdale
    Abstract:

    Heat shock protein 90 (Hsp90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. Hsp90 has emerged in recent years as a promising new target for anticancer therapies. The concentrations of the Hsp90 Inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on Hsp90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation. We show that the novel small molecule Hsp90 Inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion – hallmarks of Hsp90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including Hsp90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels. NVP-AUY922 is a potent small molecule Hsp90 Inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials.

  • activity of new heat shock protein 90 Hsp90 Inhibitor nvp auy922 against myeloma cells sensitive and resistant to conventional agents
    Blood, 2007
    Co-Authors: Douglas W Mcmillin, Joseph Negri, Jake Delmore, Patrick Hayden, Melissa Ooi, Nicholas Mitsiades, Robert L Schlossman, Paul G Richardson, Nikhil C Munshi, Michael Rugaard Jensen
    Abstract:

    Context: The molecular chaperone Hsp90 is a major anti-cancer therapeutic target because it regulates the function of proteins with pivotal roles in tumor cell proliferation, survival and drug resistance, including mutated/chimeric oncoproteins or oncogenic kinases/receptors. Our preclinical studies on the ansamycin Hsp90 Inhibitor tanespimycin (17-AAG) provided the rationale for clinical trials, either alone or in combination with the proteasome Inhibitor bortezomib, for treatment of relapsed/refractory MM. In this study, we report preclinical studies of the new, non-ansamycin, Hsp90 Inhibitor NVP-AUY922. Methods/Results: We tested 36 human MM cell lines and observed with MTT colorimetric survival assays potent time- and dose-dependent anti-MM activity of NVP-AUY922. IC50 values were Conclusion: The new Hsp90 Inhibitor NVP-AUY922 has potent in vitro activity against MM cells resistant to conventional therapeutics, with selectivity for malignant compared to normal cells. Ongoing in vivo experiments and studies to identify biomarkers of pronounced sensitivity to NVP-AUY922 will help provide a framework for potential clinical trials of NVP-AUY922 in MM and other neoplasias.

Ajit K Verma - One of the best experts on this subject based on the ideXlab platform.

  • Topically applied Hsp90 Inhibitor 17AAG inhibits ultraviolet radiation-induced cutaneous squamous cell carcinomas
    2016
    Co-Authors: Anupama Singh, Samuel J Bauer, Bilal Bin Hafeez, Ashok Singh, Jordan M. S, Ajit K Verma
    Abstract:

    We present here that Heat shock protein 90 (Hsp90) Inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17AAG), when topically applied to mouse skin, inhibits ultraviolet radiation (UVR)-induced development of cutaneous squamous cell carcinoma (SCC). In these experiments, DMSO:acetone (1:40 v/v) solution of 17AAG (500nmol) was applied topically to mouse skin in conjunction with each UVR exposure (1.8 kJ/m2). The UVR source was Kodacel-filtered FS-40 sun lamps (approximately 60 % UVB and 40 % UVA). In independent experiments with three separate mouse lines (SKH-1 hairless mice, wild-type FVB, and PKCε overexpressing transgenic FVB mice), 17AAG treatment increased the latency and decreased both the incidence and multiplicity of UVR-induced SCC. Topical 17AAG alone or in conjunction with UVR treatments elicited neither skin nor systemic toxicity. 17AAG-caused inhibition of SCC induction was accompanied by decrease in UVR-induced: 1) hyperplasia, 2) Hsp90β-PKCε interaction, 3) expression levels of Hsp90β, Stat3, pStat3Ser727, pStat3Tyr705, pAktSer473 and matrix metalloproteinase (MMPs). The results presented here indicate that topical Hsp90 Inhibitor 17AAG is effective in prevention of UVR-induced epidermal hyperplasia and SCC. One may conclude from the preclinical data presented here that topical 17AAG may be useful for prevention of UVR-induced inflammation and cutaneous SCC either developed in UVR exposed or organ transplant population

  • topically applied Hsp90 Inhibitor 17aag inhibits uvr induced cutaneous squamous cell carcinomas
    Journal of Investigative Dermatology, 2015
    Co-Authors: Anupama Singh, Ashok K Singh, Jordan M Sand, Samuel J Bauer, Bilal Bin Hafeez, Louise Meske, Ajit K Verma
    Abstract:

    We present here that heat-shock protein 90 (Hsp90) Inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17AAG), when topically applied to mouse skin, inhibits UVR–induced development of cutaneous squamous cell carcinoma (SCC). In these experiments, DMSO:acetone (1:40 v/v) solution of 17AAG (500 nmol) was applied topically to mouse skin in conjunction with each UVR exposure (1.8 kJ m-2). The UVR source was Kodacel-filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). In independent experiments with three separate mouse lines (SKH-1 hairless mice, wild-type FVB, and protein kinase C epsilon (PKCe)-overexpressing transgenic FVB mice), 17AAG treatment increased the latency and decreased both the incidence and multiplicity of UVR-induced SCC. Topical 17AAG alone or in conjunction with UVR treatments elicited neither skin nor systemic toxicity. 17AAG-caused inhibition of SCC induction was accompanied by a decrease in UVR-induced (1) hyperplasia, (2) Hsp90β-PKCe interaction, and (3) expression levels of Hsp90β, Stat3, pStat3Ser727, pStat3Tyr705, pAktSer473, and matrix metalloproteinase (MMP). The results presented here indicate that topical Hsp90 Inhibitor 17AAG is effective in prevention of UVR-induced epidermal hyperplasia and SCC. One may conclude from the preclinical data presented here that topical 17AAG may be useful for prevention of UVR-induced inflammation and cutaneous SCC either developed in UVR-exposed or organ transplant population.

Elise Schmitt - One of the best experts on this subject based on the ideXlab platform.

A Seignez - One of the best experts on this subject based on the ideXlab platform.