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Amber Shatzer, Mir A Ali, Mayra Chavez, Kennichi Dowdell, Min-Jung Lee, Yusuke Tomita, Iman El-Hariry, Jane B Trepel, David A Proia, Jeffrey I Cohen
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...
August 11, 2016: Leukemia & Lymphoma
Tim N Beck, Vladislav A Korobeynikov, Alexander E Kudinov, Rachel Georgopoulos, Nehal R Solanki, Magda Andrews-Hoke, Timothy M Kistner, David Pépin, Patricia K Donahoe, Emmanuelle Nicolas, Margret B Einarson, Yan Zhou, Yanis Boumber, David A Proia, Ilya G Serebriiskii, Erica A Golemis
Anti-Müllerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-β)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor κB (AKT-NF-κB) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC)...
July 19, 2016: Cell Reports
Yifan Wang, Hui Liu, Lixia Diao, Adam Potter, Jianhu Zhang, Yawei Qiao, Jing Wang, David A Proia, Ramesh Tailor, Ritsuko Komaki, Steven H Lin
PURPOSE: HSP90 inhibition is well known to sensitize cancer cells to radiation. However, it is currently unknown if additional radiosensitization could occur in the more clinically relevant setting of chemoradiation (CRT). We used the potent HSP90 inhibitor ganetespib to determine if 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...
June 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Christine Mall, Gail D Sckisel, David A Proia, Annie Mirsoian, Steven K Grossenbacher, Chien-Chun Steven Pai, Mingyi Chen, Arta M Monjazeb, Karen Kelly, Bruce R Blazar, William J Murphy
Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials...
February 2016: Oncoimmunology
Sivarajan T Chettiar, Reem Malek, Anvesh Annadanam, Katriana M Nugent, Yoshinori Kato, Hailun Wang, Jessica A Cades, Kekoa Taparra, Zineb Belcaid, Matthew Ballew, Sarah Manmiller, David Proia, Michael Lim, Robert A Anders, Joseph M Herman, Phuoc T Tran
Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance...
April 2, 2016: Cancer Biology & Therapy
Abena S Agyeman, Wesley J Jun, David A Proia, Caroline R Kim, Maxwell N Skor, Masha Kocherginsky, Suzanne D Conzen
Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood...
April 2016: Hormones & Cancer
Ganji Purnachandra Nagaraju, Anya Mezina, Walid L Shaib, Jerome Landry, Bassel F El-Rayes
BACKGROUND: Pancreatic cancer (PC) is an aggressive malignancy characterised by chemoresistance. HSP90 is important for stabilisation of proteins, cell signalling and malignant growth. We hypothesised that ganetespib, an HSP90 inhibitor, can inhibit PC cell growth by interfering with multiple signalling cascades, including the Janus-activated kinase (JAK)-STAT pathway, and act synergistically with chemotherapeutic drugs. METHODS: The effects of ganetespib were evaluated in ASPC-1, HPAC, MIA PaCA-2 and PANC-1 cell lines using a cell proliferation assay...
January 2016: European Journal of Cancer
Arjan Gower, Wei-Hsun Hsu, Shuo-Tse Hsu, Yisong Wang, Giuseppe Giaccone
ALK gene fusion occurs in approximately 3-7% of non-small cell lung cancer (NSCLC). For patients with ALK positive NCSLC, crizotinib and ceritinib are FDA approved ALK inhibitors, however, patients inevitably acquire resistance to such therapies typically within one to two years. Interrogation of in vitro ALK-positive NSCLC cell line models of acquired resistance to first and second-generation ALK inhibitors revealed acquired epithelial-to-mesenchymal transition (EMT) mechanisms. Here we demonstrated that knockdown of upregulated mesenchymal markers in acquired resistant lines decreased the invasive and migratory capabilities of the cells, however, it did not restore sensitivity to ALK inhibitors...
April 2016: Molecular Oncology
Manish K Thakur, Lance K Heilbrun, Shijie Sheng, Mark Stein, Glenn Liu, Emmanuel S Antonarakis, Ulka Vaishampayan, Sijana H Dzinic, Xiaohua Li, Stacy Freeman, Daryn Smith, Elisabeth I Heath
INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC)...
February 2016: Investigational New Drugs
Komal Jhaveri, Shanu Modi
Under stressful conditions, the heat shock protein 90 (HSP90) molecular chaperone protects cellular proteins (client proteins) from degradation via the ubiquitin-proteasome pathway. HSP90 expression is upregulated in cancers, and this contributes to the malignant phenotype of increased proliferation and decreased apoptosis and maintenance of metastatic potential via conservation of its client proteins, including human epidermal growth factor receptor 2, anaplastic lymphoma kinase, androgen receptor, estrogen receptor, Akt, Raf-1, cell cycle proteins, and B-cell lymphoma 2 among others...
2015: OncoTargets and Therapy
Roberto Gomez-Casal, Chitralekha Bhattacharya, Michael W Epperly, Per H Basse, Hong Wang, Xinhui Wang, David A Proia, Joel S Greenberger, Mark A Socinski, Vera Levina
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...
2015: Cancers
E M Alexandrova, A R Yallowitz, D Li, S Xu, R Schulz, D A Proia, G Lozano, M Dobbelstein, U M Moll
Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities. Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo...
July 16, 2015: Nature
S Ramalingam, G Goss, R Rosell, G Schmid-Bindert, B Zaric, Z Andric, I Bondarenko, D Komov, T Ceric, F Khuri, M Samarzija, E Felip, T Ciuleanu, V Hirsh, T Wehler, J Spicer, R Salgia, G Shapiro, E Sheldon, F Teofilovici, V Vukovic, D Fennell
BACKGROUND: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. PATIENTS AND METHODS: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS)...
August 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Yuan Liu, Josephine Ye, Luisa Shin Ogawa, Takayo Inoue, Qin Huang, John Chu, Richard C Bates, Weiwen Ying, Andrew J Sonderfan, Patricia E Rao, Dan Zhou
Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease with a diverse range of immunological and clinical manifestations. The introduction of broad spectrum immunosuppressive therapies and better management of acute disease exacerbations have improved outcomes for lupus patients over recent years. However, these regimens are burdened by substantial toxicities and confer significantly higher risks of infection, thus there remains a significant and unmet medical need for alternative treatment options, particularly those with improved safety profiles...
2015: PloS One
M Lazenby, R Hills, A K Burnett, J Zabkiewicz
HSP90 is a multi-client chaperone involved in regulating a large array of cellular processes and is commonly overexpressed in many different cancer types including hematological malignancies. Inhibition of HSP90 holds promise for targeting multiple molecular abnormalities and is therefore an attractive target for heterogeneous malignancies such as Acute Myeloid Leukemia (AML). Ganetespib is a highly potent second generation HSP90 inhibitor which we show is significantly more effective against primary AML blasts at nanomolar concentrations when compared with cytarabine (p<0...
June 2015: Leukemia Research
Andrew Lilja, Clare E Weeden, Kate McArthur, Thao Nguyen, Alastair Donald, Zi Xin Wong, Lovisa Dousha, Steve Bozinovski, Ross Vlahos, Christopher J Burns, Marie-Liesse Asselin-Labat, Gary P Anderson
Inflammation is an important component of cancer diathesis and treatment-refractory inflammation is a feature of many chronic degenerative lung diseases. HSP90 is a 90kDa protein which functions as an ATP-dependent molecular chaperone that regulates the signalling conformation and expression of multiple protein client proteins especially oncogenic mediators. HSP90 inhibitors are in clinical development as cancer therapies but the myeleosuppressive and neutropenic effect of first generation geldanamycin-class inhibitors has confounded studies on the effects on HSP90 inhibitors on inflammation...
2015: PloS One
H Liu, J Lu, Y Hua, P Zhang, Z Liang, L Ruan, C Lian, H Shi, K Chen, Z Tu
Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner...
2015: Cell Death & Disease
Andrea Cercek, Jinru Shia, Marc Gollub, Joanne F Chou, Marinela Capanu, Pamela Raasch, Diane Reidy-Lagunes, David A Proia, Efsevia Vakiani, David B Solit, Leonard B Saltz
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...
December 2014: Clinical Colorectal Cancer
Thomas E Stinchcombe
The identification of EGFR mutations and ALK rearrangements in nonsmall cell lung cancer (NSCLC) has led to the rapid development of targeted therapies and significant changes in the treatment paradigm. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and crizotinib are now standard therapies for patients with the appropriate molecular alteration. Current investigations are determining the mechanisms of resistance to targeted therapies and developing novel agents to combat resistance...
September 2014: Therapeutic Advances in Medical Oncology
Ganji Purnachandra Nagaraju, Olatunji B Alese, Jerome Landry, Roberto Diaz, Bassel F El-Rayes
Cell cycle progression and DNA synthesis are essential steps in cancer cell growth. Thymidylate synthase (TS) is a therapeutic target for 5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize colorectal cancer (CRC) cell lines to the effects of 5FU. Treatment with ganetespib (50 nM) for 24 hours inhibited cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29)...
October 30, 2014: Oncotarget
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