sta-9090 and Neoplasms

Heat-shock proteins are upregulated in cancer and protect several client proteins from degradation. Therefore, they contribute to tumorigenesis and cancer metastasis by reducing apoptosis and enhancing cell survival and proliferation. These client proteins include the estrogen receptor (ER), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), human epidermal growth factor receptor 2 (HER-2), and cytokine receptors. The diminution of the degradation of these client proteins activates different signaling pathways, such as the PI3K/Akt/NF-κB, Raf/MEK/ERK, and JAK/STAT3 pathways. These pathways contribute to hallmarks of cancer, such as self-sufficiency in growth signaling, an insensitivity to anti-growth signals, the evasion of apoptosis, persistent angiogenesis, tissue invasion and metastasis, and an unbounded capacity for replication. However, the inhibition of HSP90 activity by ganetespib is believed to be a promising strategy in the treatment of cancer because of its low adverse effects compared to other HSP90 inhibitors. Ganetespib is a potential cancer therapy that has shown promise in preclinical tests against various cancers, including lung cancer, prostate cancer, and leukemia. It has also shown strong activity toward breast cancer, non-small cell lung cancer, gastric cancer, and acute myeloid leukemia. Ganetespib has been found to cause apoptosis and growth arrest in these cancer cells, and it is being tested in phase II clinical trials as a first-line therapy for metastatic breast cancer. In this review, we will highlight the mechanism of action of ganetespib and its role in treating cancer based on recent studies.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Triazoles

As with many physiologic processes that become subverted during tumorigenesis, the chaperoning activity of heat shock protein 90 (HSP90) is often exploited by cancer cells to confer aberrant proliferative, survival, and/or metastatic potential. Functional inhibition of HSP90 results in the degradation of its client proteins, in turn providing a means to concomitantly disrupt multiple oncogenic signaling cascades through one molecular target. Pharmacologic blockade of HSP90 has, therefore, emerged as an innovative and multifaceted approach for the development of new antineoplastic agents. However, no HSP90 inhibitors are currently approved for cancer therapy and the full promise of this class of agents is yet to be realized. This review focuses on the preclinical activity profile of ganetespib, a potent small-molecule inhibitor of HSP90, the characterization of which has provided important frameworks for the optimal design and application of HSP90 inhibitor-based strategies in a variety of cancer types. Beyond client protein-driven tumors, ganetespib can also potentiate the effects of other molecularly targeted and standard-of-care therapeutics while simultaneously overcoming drug resistance in multiple tumor types, thereby positioning this compound as the leading HSP90 inhibitor currently under clinical development.

Topics: Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Triazoles

Heat shock protein 90 (Hsp90) plays a critical role in the maintenance of multiple oncogenic pathways and is a required protein for folding and stability of many oncoproteins that are related to the growth, proliferation, and survival of many kinds of cancers. Ganetespib (STA-9090) is a potent, synthetic, small molecule inhibitor of Hsp90, and its binding to Hsp90 is known to result in the degradation of its client proteins and subsequent death of cancer cells. This article provides a review of ganetespib as one of the leading Hsp90 inhibitors, which is under investigation in a broad range of clinical stages for the treatment of cancer.

Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Clinical Trials as Topic; Drug Design; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Protein Folding; Triazoles

STA-9090 is a second-generation Hsp90 inhibitor in clinical development by Synta Pharmaceuticals for the intravenous treatment of hematological and solid malignancies. It is a resorcinol-containing triazole compound, with a novel chemical structure that is unrelated to the geldanamycin class of Hsp90 inhibitors. STA-9090 binds to the ATP-binding domain at the N-terminus of Hsp90 and acts as a potent Hsp90 inhibitor by inducing degradation of multiple oncogenic Hsp90 client proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2, c-Met, and Wilms' tumor 1. STA-9090, at low nanomolar concentrations, potently arrested cell proliferation and induced apoptosis in a wide variety of human cancer cell lines, including many receptor tyrosine kinase inhibitor- and tanespimycin-resistant cell lines. Moreover, administration of STA-9090 led to significant tumor shrinkage in several tumor xenograft models in mice and appeared to be less toxic. Furthermore STA-9090 demonstrated better tumor penetration compared with tanespimycin. In initial phase I clinical trials, STA-9090 was well tolerated and has demonstrated activity. The further development of this agent, and the other Hsp90 inhibitors, may be dependent on the tumor type and the primary oncogenic driving forces.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Drug Evaluation, Preclinical; HSP90 Heat-Shock Proteins; Humans; Mice; Neoplasms; Structure-Activity Relationship; Triazoles

The combination of the antiangiogenic agent ziv-aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected adverse events and was not tolerable on the dosing schedule tested.Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens.. Although inhibition of angiogenesis is an effective strategy for cancer treatment, acquired resistance to antiangiogenic therapy is common. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates various oncogenic signaling pathways involved in acquired resistance and has been shown to play a role in angiogenesis. Combining an antiangiogenic agent with an Hsp90 inhibitor has therefore been proposed as a strategy for preventing resistance and improving antitumor activity. We conducted a single-arm phase I study evaluating the combination of ziv-aflibercept, an antiangiogenic drug, with the Hsp90 inhibitor ganetespib.. Adult patients were eligible if they had recurrent or metastatic gastrointestinal carcinomas, nonsquamous non-small cell lung carcinomas, urothelial carcinomas, or sarcomas that had progressed after at least one line of standard therapy. Ziv-aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28-day cycle.. Five patients were treated with the combination. Although three patients achieved stable disease, study treatment was associated with several serious and unexpected adverse events.. The dose escalation phase of this study was not completed, but the limited data obtained suggest that this combination may be too toxic when administered on this dosing schedule.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Neoplasms; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Sarcoma; Triazoles

This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies.. Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity.. Fifty-three patients were treated at doses escalating from 7 to 259 mg/m(2). The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m(2)), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m(2)). The MTD was 216 mg/m(2) and the recommended phase 2 dose was established at 200 mg/m(2) given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%.. Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m(2), and is associated with an acceptable tolerability profile.. NCT00687934.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Female; HSP90 Heat-Shock Proteins; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Treatment Outcome; Triazoles

Hypersensitivity towards proton versus photon irradiation was demonstrated in homologous recombination repair (HRR)-deficient cell lines. Hence, combined treatment concepts targeting HRR provide a rational for potential pharmaceutical exploitation. The HSP90 inhibitor ganetespib (STA-9090) downregulates a multitude of HRR-associated proteins and sensitizes for certain chemotherapeutics. Thus, the radiosensitizing effect of HSP90-inhibiting ganetespib was investigated for reference photon irradiation and proton irradiation at a proximal and distal position in a spread-out Bragg peak (SOBP).. Our findings illustrate a proton-specific sensitizing effect of low-dosed ganetespib in both employed cell lines and at both investigated SOBP positions. We provide additional experimental data on cellular response and a rational for future combinatorial approaches with proton radiotherapy.

Topics: Dose-Response Relationship, Radiation; Humans; Neoplasms; Protons; Relative Biological Effectiveness; Triazoles

The molecular chaperone TRAP1 is the mitochondrial paralog of Hsp90 and is overexpressed in many cancer cells. The orthosteric ATP-binding site of TRAP1 has been considered the primary inhibitor binding location, but TRAP1 allosteric modulators have not yet been investigated. Here, we generated and characterized the Hsp90 inhibitor PU-H71, conjugated to the mitochondrial delivery vehicle triphenylphosphonium (TPP) with a C

Topics: Allosteric Site; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Molecular Docking Simulation; Neoplasms; Protein Conformation; Purines

Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71. All cell lines retained dependence on HSP90 function, as evidenced by sensitivity to short hairpin RNA-mediated suppression of HSP90AA1 or HSP90AB1 (also called HSP90α and HSP90β, respectively), and exhibited two types of genomic alterations that interfere with the effects of PU-H71 on cell viability and proliferation: (i) a Y142N missense mutation in the ATP-binding domain of HSP90α that co-occurred with amplification of the HSP90AA1 locus, (ii) genomic amplification and overexpression of the ABCB1 gene encoding the MDR1 drug efflux pump. In support of a functional role for these alterations, exogenous expression of HSP90α Y142N conferred PU-H71 resistance to HSP90-dependent cells, and pharmacologic MDR1 inhibition with tariquidar or lowering ABCB1 expression restored sensitivity to PU-H71 in ABCB1-amplified cells. Finally, comparison with structurally distinct HSP90 inhibitors currently in clinical development revealed that PU-H71 resistance could be overcome, in part, by ganetespib (also known as STA9090) but not tanespimycin (also known as 17-AAG). Together, these data identify potential mechanisms of acquired resistance to small molecules targeting HSP90 that may warrant proactive screening for additional HSP90 inhibitors or rational combination therapies.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; Benzoquinones; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Amplification; Genetic Predisposition to Disease; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mutation; Mutation, Missense; Neoplasms; Phenotype; Proto-Oncogene Proteins p21(ras); Purines; RNA Interference; Transfection; Triazoles

The clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor-drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Camptothecin; Cell Line, Tumor; Female; HSP90 Heat-Shock Proteins; Humans; Irinotecan; Mice, Inbred ICR; Mice, SCID; Microscopy, Fluorescence; Molecular Targeted Therapy; Neoplasms; Resorcinols; Topoisomerase I Inhibitors; Treatment Outcome; Triazoles; Tumor Burden; Xenograft Model Antitumor Assays

The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic resistance. Circumventing this problem remains a key challenge to improving durable responses in patients receiving MET-targeted therapy. MET is an HSP90-dependent kinase, and in this report we show that HSP90 preferentially interacts with and stabilizes activated MET, regardless of whether the activation is ligand-dependent or is a consequence of kinase domain mutation. In contrast, many MET-TKI show a preference for the inactive form of the kinase, and activating mutations in MET can confer resistance. Combining the HSP90 inhibitor ganetespib with the MET-TKI crizotinib achieves synergistic inhibition of MET, its downstream signaling pathways, and tumor growth in both TKI-sensitive and -resistant MET-driven tumor models. These data suggest that inclusion of an HSP90 inhibitor can partially restore TKI sensitivity to previously resistant MET mutants, and they provide the foundation for clinical evaluation of this therapeutic combination in patients with MET-driven cancers.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Transformation, Neoplastic; Cells, Cultured; Crizotinib; Drug Resistance, Neoplasm; Drug Synergism; Female; HEK293 Cells; HSP90 Heat-Shock Proteins; Humans; Mice; Mice, Nude; Neoplasms; NIH 3T3 Cells; Proto-Oncogene Mas; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Triazoles; Xenograft Model Antitumor Assays

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzoquinones; Blotting, Western; Cell Line, Tumor; Cell Survival; Chemical and Drug Induced Liver Injury; Crystallography, X-Ray; Female; Heart; HL-60 Cells; HSP90 Heat-Shock Proteins; Humans; K562 Cells; Lactams, Macrocyclic; Male; Mice; Mice, Nude; Mice, SCID; Neoplasms; Rabbits; Rats; Rats, Sprague-Dawley; Triazoles; Xenograft Model Antitumor Assays

The novel water soluble compound STA-1474 is metabolized to ganetespib (formerly STA-9090), a potent HSP90 inhibitor previously shown to kill canine tumor cell lines in vitro and inhibit tumor growth in the setting of murine xenografts. The purpose of the following study was to extend these observations and investigate the safety and efficacy of STA-1474 in dogs with spontaneous tumors.. This was a Phase 1 trial in which dogs with spontaneous tumors received STA-1474 under one of three different dosing schemes. Pharmacokinetics, toxicities, biomarker changes, and tumor responses were assessed. Twenty-five dogs with a variety of cancers were enrolled. Toxicities were primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Upregulation of HSP70 protein expression was noted in both tumor specimens and PBMCs within 7 hours following drug administration. Measurable objective responses were observed in dogs with malignant mast cell disease (n = 3), osteosarcoma (n = 1), melanoma (n = 1) and thyroid carcinoma (n = 1), for a response rate of 24% (6/25). Stable disease (>10 weeks) was seen in 3 dogs, for a resultant overall biological activity of 36% (9/25).. This study provides evidence that STA-1474 exhibits biologic activity in a relevant large animal model of cancer. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 activation, it is likely that STA-1474 and ganetespib will demonstrate comparable anti-cancer activity in human patients.

Topics: Animals; Antineoplastic Agents; Chromatography, High Pressure Liquid; Dogs; Female; HSP90 Heat-Shock Proteins; Indoles; Male; Neoplasms; Prodrugs; Tandem Mass Spectrometry; Triazoles