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David A Proia - One of the best experts on this subject based on the ideXlab platform.
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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, 2017Co-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 CohenAbstract: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.
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hsp90 inhibitor Ganetespib sensitizes non small cell lung cancer to radiation but has variable effects with chemoradiation
Clinical Cancer Research, 2016Co-Authors: David A Proia, Y Wang, Hui Liu, Lixia Diao, Adam Potter, Jianhu Zhang, Yawei Qiao, Jing Wang, Ramesh C TailorAbstract: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.
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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, 2016Co-Authors: Chung Wong, Evan Vosburgh, Arnold J Levine, David A ProiaAbstract: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.
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the hsp90 inhibitor Ganetespib potentiates the antitumor activity of egfr tyrosine kinase inhibition in mutant and wild type non small cell lung cancer
Targeted Oncology, 2015Co-Authors: Donald L Smith, Jim Sang, Jaime Acquaviva, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Richard C Bates, David A ProiaAbstract:Small molecule inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity, such as erlotinib and gefitinib, revolutionized therapy for non-small cell lung cancer (NSCLC) patients whose tumors harbor activating EGFR mutations. However, mechanisms to overcome the invariable development of acquired resistance to such agents, as well as realizing their full clinical potential within the context of wild-type EGFR (WT-EGFR) disease, remain to be established. Here, the antitumor efficacy of targeted EGFR tyrosine kinase inhibitors (TKIs) and the HSP90 inhibitor Ganetespib, alone and in combination, were evaluated in NSCLC. Ganetespib potentiated the efficacy of erlotinib in TKI-sensitive, mutant EGFR-driven NCI-HCC827 xenograft tumors, with combination treatment causing significant tumor regressions. In erlotinib-resistant NCI-H1975 xenografts, concurrent administration of Ganetespib overcame erlotinib resistance to significantly improve tumor growth inhibition. Ganetespib co-treatment also significantly enhanced antitumor responses to afatinib in the same model. In WT-EGFR cell lines, Ganetespib potently reduced cell viability. In NCI-H1666 cells, Ganetespib-induced loss of client protein expression, perturbation of oncogenic signaling pathways, and induction of apoptosis translated to robust single-agent activity in vivo. Dual Ganetespib/erlotinib therapy induced regressions in NCI-H322 xenograft tumors, indicating that the sensitizing properties of Ganetespib for erlotinib were conserved within the WT-EGFR setting. Mechanistically, combined Ganetespib/erlotinib exposure stabilized EGFR protein levels in an inactive state and completely abrogated extracellular-signal-regulated kinase (ERK) and AKT signaling activity. Thus, selective HSP90 blockade by Ganetespib represents a potentially important complementary strategy to targeted TKI inhibition alone for inducing substantial antitumor responses and overcoming resistance, in both the mutant and WT-EGFR settings.
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the hsp90 inhibitor Ganetespib radiosensitizes human lung adenocarcinoma cells
Cancers, 2015Co-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 LevinaAbstract: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.
Komal Jhaveri - One of the best experts on this subject based on the ideXlab platform.
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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
Breast Cancer Research, 2017Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, David B Solit, Karen Cadoo, James L Speyer, Gabriella Dandrea, Sylvia Adams, Rui Wang, S PatilAbstract: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. In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of Ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of Ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to Ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). The RP2D of Ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.
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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
BMC, 2017Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, David B Solit, Karen Cadoo, Sylvia Adams, Rui Wang, James Speyer, Gabriella D’andrea, S PatilAbstract:Abstract 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. Methods In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of Ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of Ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Results Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to Ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). Conclusion The RP2D of Ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. Trial registration ClinicalTrials.gov NCT02060253 . Registered 30 January 2014
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abstract p4 14 21 a phase i trial of Ganetespib heat shock protein 90 inhibitor in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 positive her2 metastatic breast cancer mbc
Cancer Research, 2016Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, David B Solit, Karen Cadoo, James L Speyer, Gabriella Dandrea, Sylvia Adams, S Patil, Sofia HaqueAbstract:Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent Ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of Ganetespib plus paclitaxel and trastuzumab in HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m 2 ) with Ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of Ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with Ganetespib plus docetaxel in NSCLC, only 3 dose levels of Ganetespib were explored: 100mg/m 2 , 150mg/m 2 and a 3 rd cohort of 125mg/m 2 , if needed . Secondary endpoints include evaluation of effects of Ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment. Results: The dosing cohorts (100 mg/m 2 (n=3) and 150 mg/m 2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to Ganetespib. Most common AEs related to Ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m 2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD>24 weeks) was 50% (4/8). 3 patients remain on study. Conclusion: The RP2D of Ganetespib is 150mg/m 2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent Ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of Ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting. Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D9Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of Ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-21.
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abstract p5 19 23 a phase i clinical trial of Ganetespib heat shock protein 90 inhibitor in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor 2 positive her2 metastatic breast cancer
Cancer Research, 2015Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, Karen Cadoo, James L Speyer, S Patil, Sofia Haque, Gabriella D Andrea, Kent Friedman, Scott HeeseAbstract:Introduction: Targeted therapies in HER2+ metastatic breast cancer (MBC) have significantly improved survival, however efficacy is limited by development of therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Ganetespib is a novel, synthetic HSP90 inhibitor with increased potency and tolerability compared with earlier agents. Our group has conducted a single agent Ganetespib trial in unselected patients which showed anti-tumor activity in HER2+ and triple negative breast cancer. In addition, preclinical data suggests HSP90 inhibition is synergistic with taxanes with potential for significant clinical activity. Ganetespib has been combined with docetaxel in non-small cell lung cancer, it has not previously been combined with paclitaxel and trastuzumab. This study will define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Ganetespib when given with paclitaxel and trastuzumab for patients with HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab resistant HER2+ MBC receive trastuzumab (4mg/kg loading dose, then 2mg/kg) and paclitaxel weekly (80mg/m2) with Ganetespib day 1, 8 ,15 of 28 day cycle. Patients are required to have prior pertuzumab and T-DM1 (prior pertuzumab and T-DM1 are not mandated if heavily pretreated prior to their respective FDA approvals). Hormone receptor positive patients are required to have at least one prior line of endocrine therapy. The single agent dose limiting toxicity (DLT) of Ganetespib is diarrhea and therefore patients receive prophylactic anti-motility agents. The anticipated MTD of Ganetespib in this combination has been informed by experience with docetaxel and based on this only three dose levels of Ganetespib are being explored 100mg/m2, 150mg/m2 and a third intermediate cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of Ganetespib on the pharmacokinetics of paclitaxel and preliminary assessment of efficacy of the combination (scans at 8 weeks and every 12 weeks thereafter, RECIST 1.1). Results: The first dosing cohort has fully enrolled and there were no significant toxicities or DLTs reported. Median age was 48 years (range 39-49), median prior lines of chemotherapy were 4 (range 3-7) and included prior pertuzumab and T-DM1 in all 3 patients. 5 adverse events have been defined as possibly/probably related to Ganetespib – grade 2 anemia and leukopenia, grade 1 diarrhea (2 patients), fatigue, and rash. Enrollment to the second and potentially final cohort is underway. Conclusion: This study will define the RP2D of Ganetespib in combination with paclitaxel and trastuzumab. Final safety, pharmacokinetic and preliminary response data for all patients will be presented. This combination, with a novel anti-HER2 agent, has encouraging potential for activity in HER2+ breast cancer which is refractory to other HER2 targeting agents. Citation Format: Komal Jhaveri, Karen Cadoo, Sarat Chandarlapaty, Eleonora Teplinsky, James Speyer, Gabriella D9 Andrea, Sujata Patil, Sofia Haque, Kent Friedman, Scott Heese, Deirdre Neville, Francisco Esteva, Clifford Hudis, Shanu Modi. A phase I clinical trial of Ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-23.
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a phase ii open label study of Ganetespib a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer
Clinical Breast Cancer, 2014Co-Authors: Komal Jhaveri, Sarat Chandarlapaty, Diana Lake, Teresa Gilewski, Mark E Robson, Shari GoldfarbAbstract:Abstract Background Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested Ganetespib in an unselected cohort of patients with MBC. Patients and Methods Patients were treated with single agent Ganetespib at 200 mg/m2 once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. Results Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). Conclusion The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.
Sarat Chandarlapaty - One of the best experts on this subject based on the ideXlab platform.
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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
Breast Cancer Research, 2017Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, David B Solit, Karen Cadoo, James L Speyer, Gabriella Dandrea, Sylvia Adams, Rui Wang, S PatilAbstract: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. In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of Ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of Ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to Ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). The RP2D of Ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.
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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
BMC, 2017Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, David B Solit, Karen Cadoo, Sylvia Adams, Rui Wang, James Speyer, Gabriella D’andrea, S PatilAbstract:Abstract 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. Methods In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of Ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of Ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Results Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to Ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). Conclusion The RP2D of Ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. Trial registration ClinicalTrials.gov NCT02060253 . Registered 30 January 2014
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abstract p4 14 21 a phase i trial of Ganetespib heat shock protein 90 inhibitor in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 positive her2 metastatic breast cancer mbc
Cancer Research, 2016Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, David B Solit, Karen Cadoo, James L Speyer, Gabriella Dandrea, Sylvia Adams, S Patil, Sofia HaqueAbstract:Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent Ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of Ganetespib plus paclitaxel and trastuzumab in HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m 2 ) with Ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of Ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with Ganetespib plus docetaxel in NSCLC, only 3 dose levels of Ganetespib were explored: 100mg/m 2 , 150mg/m 2 and a 3 rd cohort of 125mg/m 2 , if needed . Secondary endpoints include evaluation of effects of Ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment. Results: The dosing cohorts (100 mg/m 2 (n=3) and 150 mg/m 2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to Ganetespib. Most common AEs related to Ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m 2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD>24 weeks) was 50% (4/8). 3 patients remain on study. Conclusion: The RP2D of Ganetespib is 150mg/m 2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent Ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of Ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting. Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D9Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of Ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-21.
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abstract p5 19 23 a phase i clinical trial of Ganetespib heat shock protein 90 inhibitor in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor 2 positive her2 metastatic breast cancer
Cancer Research, 2015Co-Authors: Komal Jhaveri, Eleonora Teplinsky, Sarat Chandarlapaty, Karen Cadoo, James L Speyer, S Patil, Sofia Haque, Gabriella D Andrea, Kent Friedman, Scott HeeseAbstract:Introduction: Targeted therapies in HER2+ metastatic breast cancer (MBC) have significantly improved survival, however efficacy is limited by development of therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Ganetespib is a novel, synthetic HSP90 inhibitor with increased potency and tolerability compared with earlier agents. Our group has conducted a single agent Ganetespib trial in unselected patients which showed anti-tumor activity in HER2+ and triple negative breast cancer. In addition, preclinical data suggests HSP90 inhibition is synergistic with taxanes with potential for significant clinical activity. Ganetespib has been combined with docetaxel in non-small cell lung cancer, it has not previously been combined with paclitaxel and trastuzumab. This study will define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Ganetespib when given with paclitaxel and trastuzumab for patients with HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab resistant HER2+ MBC receive trastuzumab (4mg/kg loading dose, then 2mg/kg) and paclitaxel weekly (80mg/m2) with Ganetespib day 1, 8 ,15 of 28 day cycle. Patients are required to have prior pertuzumab and T-DM1 (prior pertuzumab and T-DM1 are not mandated if heavily pretreated prior to their respective FDA approvals). Hormone receptor positive patients are required to have at least one prior line of endocrine therapy. The single agent dose limiting toxicity (DLT) of Ganetespib is diarrhea and therefore patients receive prophylactic anti-motility agents. The anticipated MTD of Ganetespib in this combination has been informed by experience with docetaxel and based on this only three dose levels of Ganetespib are being explored 100mg/m2, 150mg/m2 and a third intermediate cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of Ganetespib on the pharmacokinetics of paclitaxel and preliminary assessment of efficacy of the combination (scans at 8 weeks and every 12 weeks thereafter, RECIST 1.1). Results: The first dosing cohort has fully enrolled and there were no significant toxicities or DLTs reported. Median age was 48 years (range 39-49), median prior lines of chemotherapy were 4 (range 3-7) and included prior pertuzumab and T-DM1 in all 3 patients. 5 adverse events have been defined as possibly/probably related to Ganetespib – grade 2 anemia and leukopenia, grade 1 diarrhea (2 patients), fatigue, and rash. Enrollment to the second and potentially final cohort is underway. Conclusion: This study will define the RP2D of Ganetespib in combination with paclitaxel and trastuzumab. Final safety, pharmacokinetic and preliminary response data for all patients will be presented. This combination, with a novel anti-HER2 agent, has encouraging potential for activity in HER2+ breast cancer which is refractory to other HER2 targeting agents. Citation Format: Komal Jhaveri, Karen Cadoo, Sarat Chandarlapaty, Eleonora Teplinsky, James Speyer, Gabriella D9 Andrea, Sujata Patil, Sofia Haque, Kent Friedman, Scott Heese, Deirdre Neville, Francisco Esteva, Clifford Hudis, Shanu Modi. A phase I clinical trial of Ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-23.
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a phase ii open label study of Ganetespib a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer
Clinical Breast Cancer, 2014Co-Authors: Komal Jhaveri, Sarat Chandarlapaty, Diana Lake, Teresa Gilewski, Mark E Robson, Shari GoldfarbAbstract:Abstract Background Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested Ganetespib in an unselected cohort of patients with MBC. Patients and Methods Patients were treated with single agent Ganetespib at 200 mg/m2 once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. Results Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). Conclusion The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.
Jim Sang - One of the best experts on this subject based on the ideXlab platform.
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the hsp90 inhibitor Ganetespib potentiates the antitumor activity of egfr tyrosine kinase inhibition in mutant and wild type non small cell lung cancer
Targeted Oncology, 2015Co-Authors: Donald L Smith, Jim Sang, Jaime Acquaviva, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Richard C Bates, David A ProiaAbstract:Small molecule inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity, such as erlotinib and gefitinib, revolutionized therapy for non-small cell lung cancer (NSCLC) patients whose tumors harbor activating EGFR mutations. However, mechanisms to overcome the invariable development of acquired resistance to such agents, as well as realizing their full clinical potential within the context of wild-type EGFR (WT-EGFR) disease, remain to be established. Here, the antitumor efficacy of targeted EGFR tyrosine kinase inhibitors (TKIs) and the HSP90 inhibitor Ganetespib, alone and in combination, were evaluated in NSCLC. Ganetespib potentiated the efficacy of erlotinib in TKI-sensitive, mutant EGFR-driven NCI-HCC827 xenograft tumors, with combination treatment causing significant tumor regressions. In erlotinib-resistant NCI-H1975 xenografts, concurrent administration of Ganetespib overcame erlotinib resistance to significantly improve tumor growth inhibition. Ganetespib co-treatment also significantly enhanced antitumor responses to afatinib in the same model. In WT-EGFR cell lines, Ganetespib potently reduced cell viability. In NCI-H1666 cells, Ganetespib-induced loss of client protein expression, perturbation of oncogenic signaling pathways, and induction of apoptosis translated to robust single-agent activity in vivo. Dual Ganetespib/erlotinib therapy induced regressions in NCI-H322 xenograft tumors, indicating that the sensitizing properties of Ganetespib for erlotinib were conserved within the WT-EGFR setting. Mechanistically, combined Ganetespib/erlotinib exposure stabilized EGFR protein levels in an inactive state and completely abrogated extracellular-signal-regulated kinase (ERK) and AKT signaling activity. Thus, selective HSP90 blockade by Ganetespib represents a potentially important complementary strategy to targeted TKI inhibition alone for inducing substantial antitumor responses and overcoming resistance, in both the mutant and WT-EGFR settings.
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abstract 5108 the hsp90 inhibitor Ganetespib is a potent chemosensitizer in preclinical colorectal cancer models
Cancer Research, 2014Co-Authors: Don Smith, Jim Sang, Jaime Acquaviva, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Richard C Bates, Masazumi Nagai, Timothy Korbut, David A ProiaAbstract:Background: More than half of all individuals diagnosed with colorectal cancer (CRC) will develop metastases and require chemotherapy. These treatments have significantly improved overall patient survival; however, drug resistance is a frequent cause of treatment failure often due to alteration in cell cycle regulators or DNA damage repair. The molecular chaperone HSP90 plays an important role in both processes by stabilizing proteins required for pathway activation and maintenance. Here, we sought to determine if HSP90 inhibition by the investigational drug Ganetespib could enhance the activity of standard chemotherapeutics utilized in CRC in order to extend responses and bypass/delay drug resistance. Results: Western blot analyses revealed that low nanomolar Ganetespib treatment promoted the degradation of a number of proteins involved in proliferation (EGFR, PDGFR, PI3-K/AKT/p70 S6 kinase, cMET and MAPK), survival (MCL1), anigiogenesis (VEGFR), cell cycle check points and DNA repair (CDK1, CHK1, Survivin, WEE1) in a panel of CRC cell lines. This activity directly correlated with G0/G1 cell cycle arrest and loss of CRC cell viability (average IC 50 in 19 CRC cell lines = 43 nM). In vitro combination of Ganetespib with conventional chemotherapies (cisplatin, oxaliplatin, 5-FU) augmented the accumulation of DNA damage (phospho-H2AX) and mitotic catastrophe more effectively over monotherapy alone in HCT116, HT29 and LoVo CRC cells. Ganetespib also sensitized CRC cells to ionizing radiation by inducing aberrant mitosis and enhanced DNA damage/fragmentation, resulting in a significant increase in apoptosis. In vivo, Ganetespib displayed comparable antitumor activity as capecitabine, cisplatin, and bevacizumab in human CRC tumor xenografts, with treatment/control values of ∼50 indicative of slowly progressive disease. Combining Ganetespib with capecitabine resulted in significant tumor regression (T/C = -52, p Conclusions: The HSP90 inhibitor Ganetespib promotes the destabilization of numerous proteins essential for tumor growth and survival as well as those involved in chemotherapeutic resistance. As a result, Ganetespib sensitizes colon cancer tumor models to chemotherapy and targeted agents, including VEGF inhibitors. Ganetespib is currently being evaluated in combination with capecitabine and radiation in patients with locally-advanced rectal cancer as part of an open-label, investigator-sponsored Phase 1 clinical study. Citation Format: Suqin He, Don Smith, Manuel Sequeira, John-Paul Jimenez, Chaohua Zhang, Jim Sang, Timothy Korbut, Jaime Acquaviva, Masazumi Nagai, Richard Bates, David A. Proia. The Hsp90 inhibitor Ganetespib is a potent chemosensitizer in preclinical colorectal cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5108. doi:10.1158/1538-7445.AM2014-5108
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The HSP90 inhibitor Ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer
Investigational New Drugs, 2014Co-Authors: Donald L Smith, Jim Sang, Manuel Sequeira, Richard C Bates, David A ProiaAbstract:The integration of targeted agents to standard cytotoxic regimens has improved outcomes for patients with colorectal cancer (CRC) over recent years; however this malignancy remains the second leading cause of cancer mortality in industrialized countries. Small molecule inhibitors of heat shock protein 90 (HSP90) are one of the most actively pursued classes of compounds for the development of new cancer therapies. Here we evaluated the activity of Ganetespib, a second-generation HSP90 inhibitor, in models of CRC. Ganetespib reduced cell viability in a panel of CRC cell lines in vitro with low nanomolar potency. Mechanistically, drug treatment exerted concomitant effects on multiple oncogenic signaling pathways, cell cycle regulation, and DNA damage repair capacity to promote apoptosis. Combinations of Ganetespib and low-dose ionizing radiation enhanced the radiosensitivity of HCT 116 cells and resulted in superior cytotoxic activity over either treatment alone. In vivo, the single-agent activity of Ganetespib was relatively modest, suppressing HCT 116 xenograft tumor growth by approximately half. However, Ganetespib significantly potentiated the antitumor efficacy of the 5-Fluorouracil (5-FU) prodrug capecitabine in HCT 116 xenografts, causing tumor regressions in a model that is intrinsically resistant to fluoropyrimidine therapy. This demonstration of combinatorial benefit afforded by an HSP90 inhibitor to a standard CRC adjuvant regimen provides an attractive new framework for the potential application of Ganetespib as an investigational agent in this disease.
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fgfr3 translocations in bladder cancer differential sensitivity to hsp90 inhibition based on drug metabolism
Molecular Cancer Research, 2014Co-Authors: Jaime Acquaviva, Jim Sang, Donald L Smith, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Masazumi Nagai, Luisa Shin Ogawa, Suqin He, Takayo InoueAbstract:Activating mutations and/or overexpression of FGFR3 are common in bladder cancer, making FGFR3 an attractive therapeutic target in this disease. In addition, FGFR3 gene rearrangements have recently been described that define a unique subset of bladder tumors. Here, a selective HSP90 inhibitor, Ganetespib, induced loss of FGFR3-TACC3 fusion protein expression and depletion of multiple oncogenic signaling proteins in RT112 bladder cells, resulting in potent cytotoxicity comparable with the pan-FGFR tyrosine kinase inhibitor BGJ398. However, in contrast to BGJ398, Ganetespib exerted pleiotropic effects on additional mitogenic and survival pathways and could overcome the FGFR inhibitor–resistant phenotype of FGFR3 mutant–expressing 97-7 and MHG-U3 cells. Combinatorial benefit was observed when Ganetespib was used with BGJ398 both in vitro and in vivo. Interestingly, two additional FGFR3 fusion-positive lines (RT4 and SW480) retained sensitivity to HSP90 inhibitor treatment by the ansamycins 17-AAG and 17-DMAG yet displayed intrinsic resistance to Ganetespib or AUY922, both second-generation resorcinol-based compounds. Both cell lines, compared with RT112, expressed considerably higher levels of endogenous UGT1A enzyme; this phenotype resulted in a rapid glucuronidation-dependent metabolism and subsequent efflux of Ganetespib from SW780 cells, thus providing a mechanism to account for the lack of bioactivity. Implications: Pharmacologic blockade of the molecular chaperone HSP90 represents a promising approach for treating bladder tumors driven by oncogenic gene rearrangements of FGFR3. Furthermore, UDP-glucuronosyltransferase enzyme expression may serve as a predictive factor for clinical response to resorcinol-based HSP90 inhibitors. Mol Cancer Res; 12(7); 1042–54. ©2014 AACR.
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Targeted inhibition of Hsp90 by Ganetespib is effective across a broad spectrum of breast cancer subtypes
Investigational New Drugs, 2014Co-Authors: Julie C Friedland, Jim Sang, Donald L Smith, Jaime Acquaviva, Chaohua Zhang, Suqin He, David A ProiaAbstract:Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the stability and function of multiple cellular client proteins, a number of which have been implicated in the pathogenesis of breast cancer. Here we undertook a comprehensive evaluation of the activity of Ganetespib, a selective Hsp90 inhibitor, in this malignancy. With low nanomolar potency, Ganetespib reduced cell viability in a panel of hormone receptor-positive, HER2-overexpressing, triple-negative and inflammatory breast cancer cell lines in vitro. Ganetespib treatment induced a rapid and sustained destabilization of multiple client proteins and oncogenic signaling pathways and even brief exposure was sufficient to induce and maintain suppression of HER2 levels in cells driven by this receptor. Indeed, HER2-overexpressing BT-474 cells were comparatively more sensitive to Ganetespib than the dual HER2/EGFR tyrosine kinase inhibitor lapatinib in three-dimensional culture. Ganetespib exposure caused pleiotropic effects in the inflammatory breast cancer line SUM149, including receptor tyrosine kinases, MAPK, AKT and mTOR signaling, transcription factors and proteins involved in cell cycle, stress and apoptotic regulation, as well as providing combinatorial benefit with lapatinib in these cells. This multimodal activity translated to potent antitumor efficacy in vivo, suppressing tumor growth in MCF-7 and MDA-MB-231 xenografts and inducing tumor regression in the BT-474 model. Thus, Ganetespib potently inhibits Hsp90 leading to the degradation of multiple clinically-validated oncogenic client proteins in breast cancer cells, encompassing the broad spectrum of molecularly-defined subtypes. This preclinical activity profile suggests that Ganetespib may offer considerable promise as a new therapeutic candidate for patients with advanced breast cancers.
Jaime Acquaviva - One of the best experts on this subject based on the ideXlab platform.
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the hsp90 inhibitor Ganetespib potentiates the antitumor activity of egfr tyrosine kinase inhibition in mutant and wild type non small cell lung cancer
Targeted Oncology, 2015Co-Authors: Donald L Smith, Jim Sang, Jaime Acquaviva, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Richard C Bates, David A ProiaAbstract:Small molecule inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity, such as erlotinib and gefitinib, revolutionized therapy for non-small cell lung cancer (NSCLC) patients whose tumors harbor activating EGFR mutations. However, mechanisms to overcome the invariable development of acquired resistance to such agents, as well as realizing their full clinical potential within the context of wild-type EGFR (WT-EGFR) disease, remain to be established. Here, the antitumor efficacy of targeted EGFR tyrosine kinase inhibitors (TKIs) and the HSP90 inhibitor Ganetespib, alone and in combination, were evaluated in NSCLC. Ganetespib potentiated the efficacy of erlotinib in TKI-sensitive, mutant EGFR-driven NCI-HCC827 xenograft tumors, with combination treatment causing significant tumor regressions. In erlotinib-resistant NCI-H1975 xenografts, concurrent administration of Ganetespib overcame erlotinib resistance to significantly improve tumor growth inhibition. Ganetespib co-treatment also significantly enhanced antitumor responses to afatinib in the same model. In WT-EGFR cell lines, Ganetespib potently reduced cell viability. In NCI-H1666 cells, Ganetespib-induced loss of client protein expression, perturbation of oncogenic signaling pathways, and induction of apoptosis translated to robust single-agent activity in vivo. Dual Ganetespib/erlotinib therapy induced regressions in NCI-H322 xenograft tumors, indicating that the sensitizing properties of Ganetespib for erlotinib were conserved within the WT-EGFR setting. Mechanistically, combined Ganetespib/erlotinib exposure stabilized EGFR protein levels in an inactive state and completely abrogated extracellular-signal-regulated kinase (ERK) and AKT signaling activity. Thus, selective HSP90 blockade by Ganetespib represents a potentially important complementary strategy to targeted TKI inhibition alone for inducing substantial antitumor responses and overcoming resistance, in both the mutant and WT-EGFR settings.
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abstract 5108 the hsp90 inhibitor Ganetespib is a potent chemosensitizer in preclinical colorectal cancer models
Cancer Research, 2014Co-Authors: Don Smith, Jim Sang, Jaime Acquaviva, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Richard C Bates, Masazumi Nagai, Timothy Korbut, David A ProiaAbstract:Background: More than half of all individuals diagnosed with colorectal cancer (CRC) will develop metastases and require chemotherapy. These treatments have significantly improved overall patient survival; however, drug resistance is a frequent cause of treatment failure often due to alteration in cell cycle regulators or DNA damage repair. The molecular chaperone HSP90 plays an important role in both processes by stabilizing proteins required for pathway activation and maintenance. Here, we sought to determine if HSP90 inhibition by the investigational drug Ganetespib could enhance the activity of standard chemotherapeutics utilized in CRC in order to extend responses and bypass/delay drug resistance. Results: Western blot analyses revealed that low nanomolar Ganetespib treatment promoted the degradation of a number of proteins involved in proliferation (EGFR, PDGFR, PI3-K/AKT/p70 S6 kinase, cMET and MAPK), survival (MCL1), anigiogenesis (VEGFR), cell cycle check points and DNA repair (CDK1, CHK1, Survivin, WEE1) in a panel of CRC cell lines. This activity directly correlated with G0/G1 cell cycle arrest and loss of CRC cell viability (average IC 50 in 19 CRC cell lines = 43 nM). In vitro combination of Ganetespib with conventional chemotherapies (cisplatin, oxaliplatin, 5-FU) augmented the accumulation of DNA damage (phospho-H2AX) and mitotic catastrophe more effectively over monotherapy alone in HCT116, HT29 and LoVo CRC cells. Ganetespib also sensitized CRC cells to ionizing radiation by inducing aberrant mitosis and enhanced DNA damage/fragmentation, resulting in a significant increase in apoptosis. In vivo, Ganetespib displayed comparable antitumor activity as capecitabine, cisplatin, and bevacizumab in human CRC tumor xenografts, with treatment/control values of ∼50 indicative of slowly progressive disease. Combining Ganetespib with capecitabine resulted in significant tumor regression (T/C = -52, p Conclusions: The HSP90 inhibitor Ganetespib promotes the destabilization of numerous proteins essential for tumor growth and survival as well as those involved in chemotherapeutic resistance. As a result, Ganetespib sensitizes colon cancer tumor models to chemotherapy and targeted agents, including VEGF inhibitors. Ganetespib is currently being evaluated in combination with capecitabine and radiation in patients with locally-advanced rectal cancer as part of an open-label, investigator-sponsored Phase 1 clinical study. Citation Format: Suqin He, Don Smith, Manuel Sequeira, John-Paul Jimenez, Chaohua Zhang, Jim Sang, Timothy Korbut, Jaime Acquaviva, Masazumi Nagai, Richard Bates, David A. Proia. The Hsp90 inhibitor Ganetespib is a potent chemosensitizer in preclinical colorectal cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5108. doi:10.1158/1538-7445.AM2014-5108
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fgfr3 translocations in bladder cancer differential sensitivity to hsp90 inhibition based on drug metabolism
Molecular Cancer Research, 2014Co-Authors: Jaime Acquaviva, Jim Sang, Donald L Smith, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Masazumi Nagai, Luisa Shin Ogawa, Suqin He, Takayo InoueAbstract:Activating mutations and/or overexpression of FGFR3 are common in bladder cancer, making FGFR3 an attractive therapeutic target in this disease. In addition, FGFR3 gene rearrangements have recently been described that define a unique subset of bladder tumors. Here, a selective HSP90 inhibitor, Ganetespib, induced loss of FGFR3-TACC3 fusion protein expression and depletion of multiple oncogenic signaling proteins in RT112 bladder cells, resulting in potent cytotoxicity comparable with the pan-FGFR tyrosine kinase inhibitor BGJ398. However, in contrast to BGJ398, Ganetespib exerted pleiotropic effects on additional mitogenic and survival pathways and could overcome the FGFR inhibitor–resistant phenotype of FGFR3 mutant–expressing 97-7 and MHG-U3 cells. Combinatorial benefit was observed when Ganetespib was used with BGJ398 both in vitro and in vivo. Interestingly, two additional FGFR3 fusion-positive lines (RT4 and SW480) retained sensitivity to HSP90 inhibitor treatment by the ansamycins 17-AAG and 17-DMAG yet displayed intrinsic resistance to Ganetespib or AUY922, both second-generation resorcinol-based compounds. Both cell lines, compared with RT112, expressed considerably higher levels of endogenous UGT1A enzyme; this phenotype resulted in a rapid glucuronidation-dependent metabolism and subsequent efflux of Ganetespib from SW780 cells, thus providing a mechanism to account for the lack of bioactivity. Implications: Pharmacologic blockade of the molecular chaperone HSP90 represents a promising approach for treating bladder tumors driven by oncogenic gene rearrangements of FGFR3. Furthermore, UDP-glucuronosyltransferase enzyme expression may serve as a predictive factor for clinical response to resorcinol-based HSP90 inhibitors. Mol Cancer Res; 12(7); 1042–54. ©2014 AACR.
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Targeted inhibition of Hsp90 by Ganetespib is effective across a broad spectrum of breast cancer subtypes
Investigational New Drugs, 2014Co-Authors: Julie C Friedland, Jim Sang, Donald L Smith, Jaime Acquaviva, Chaohua Zhang, Suqin He, David A ProiaAbstract:Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the stability and function of multiple cellular client proteins, a number of which have been implicated in the pathogenesis of breast cancer. Here we undertook a comprehensive evaluation of the activity of Ganetespib, a selective Hsp90 inhibitor, in this malignancy. With low nanomolar potency, Ganetespib reduced cell viability in a panel of hormone receptor-positive, HER2-overexpressing, triple-negative and inflammatory breast cancer cell lines in vitro. Ganetespib treatment induced a rapid and sustained destabilization of multiple client proteins and oncogenic signaling pathways and even brief exposure was sufficient to induce and maintain suppression of HER2 levels in cells driven by this receptor. Indeed, HER2-overexpressing BT-474 cells were comparatively more sensitive to Ganetespib than the dual HER2/EGFR tyrosine kinase inhibitor lapatinib in three-dimensional culture. Ganetespib exposure caused pleiotropic effects in the inflammatory breast cancer line SUM149, including receptor tyrosine kinases, MAPK, AKT and mTOR signaling, transcription factors and proteins involved in cell cycle, stress and apoptotic regulation, as well as providing combinatorial benefit with lapatinib in these cells. This multimodal activity translated to potent antitumor efficacy in vivo, suppressing tumor growth in MCF-7 and MDA-MB-231 xenografts and inducing tumor regression in the BT-474 model. Thus, Ganetespib potently inhibits Hsp90 leading to the degradation of multiple clinically-validated oncogenic client proteins in breast cancer cells, encompassing the broad spectrum of molecularly-defined subtypes. This preclinical activity profile suggests that Ganetespib may offer considerable promise as a new therapeutic candidate for patients with advanced breast cancers.
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overcoming acquired braf inhibitor resistance in melanoma via targeted inhibition of hsp90 with Ganetespib
Molecular Cancer Therapeutics, 2014Co-Authors: Jaime Acquaviva, Jim Sang, Donald L Smith, Manuel Sequeira, Johnpaul Jimenez, Chaohua Zhang, Richard C Bates, David A ProiaAbstract:Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF(V600E) inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of Ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF(V600E) mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF(V600E) provided combinatorial benefit in vemurafenib-sensitive melanoma cells in vitro and in vivo. Importantly, Ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF(V600E) by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with Ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, Ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of Ganetespib as a single-agent or combination treatment in BRAF(V600E)-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors.
