sta-9090 and Triple-Negative-Breast-Neoplasms

Pharmacological inhibition of Hsp90 shows great promise in breast cancer treatment. This is the first systematic review to synthesize all available data and to evaluate the efficacy and safety of Hsp90 inhibitors in breast cancer.. This study was performed in accordance with the PRISMA guidelines. Eligible articles were identified by a search of MEDLINE and ClinicalTrials.gov databases, using a predefined combination of the terms "breast", "cancer", "Hsp90", "inhibitors".. Overall, 19 articles (190 patients) were eligible. The greatest clinical activity has been observed on the field of HER2-positive metastatic breast cancer. However, accumulating data suggest that Hsp90 inhibitors may play a significant role in the treatment of triple negative and aromatase inhibitor-resistant breast cancer.. In the last decade, the development of Hsp90 inhibitors has moved forward rapidly; however, no phase III trials have been conducted and none agent has been approved for use in the clinical practice.

Topics: Adenine; Antineoplastic Agents; Benzamides; Benzoquinones; Biomarkers, Tumor; Female; Glycine; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Indazoles; Isoxazoles; Lactams, Macrocyclic; Pyridines; Resorcinols; Triazoles; Triple Negative Breast Neoplasms

Due to the lack of effective therapies and poor prognosis in TNBC (triple-negative breast cancer) patients, there is a strong need to develop effective novel targeted therapies for this subtype of breast cancer. Inhibition of heat shock protein 90 (HSP90), a conserved molecular chaperone that is involved in the regulation of oncogenic client proteins, has shown to be a promising therapeutic approach for TNBC. However, both intrinsic and acquired resistance to HSP90 inhibitors (HSP90i) limits their effectiveness in cancer patients.. We developed models of acquired resistance to HSP90i by prolonged exposure of TNBC cells to HSP90i (ganetespib) in vitro. Whole transcriptome profiling and a 328-compound bioactive small molecule screen were performed on these cells to identify the molecular basis of acquired resistance to HSP90i and potential therapeutic approaches to overcome resistance.. Among a panel of seven TNBC cell lines, the most sensitive cell line (Hs578T) to HSP90i was selected as an in vitro model to investigate acquired resistance to HSP90i. Two independent HSP90i-resistant clones were successfully isolated which both showed absence of client proteins degradation, apoptosis induction and G2/M cell cycle arrest after treatment with HSP90i. Gene expression profiling and pathway enrichment analysis demonstrate significant activation of the survival JAK-STAT signalling pathway in both HSP90i-resistant clones, possibly through IL6 autocrine signalling. A bioactive small molecule screen also demonstrated that the HSP90i-resistant clones showed selective sensitivity to JAK2 inhibition. Inhibition of JAK and HSP90 caused higher induction of apoptosis, despite prior acquired resistance to HSP90i.. Acquired resistance to HSP90i in TNBC cells is associated with an upregulated JAK-STAT signalling pathway. A combined inhibition of the JAK-STAT signalling pathway and HSP90 could overcome this resistance. The benefits of the combined therapy could be explored further for the development of effective targeted therapy in TNBC patients.

Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Interleukin-6; Janus Kinase 2; Signal Transduction; Small Molecule Libraries; Triazoles; Triple Negative Breast Neoplasms

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. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Mice; Paclitaxel; Receptors, Glucocorticoid; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

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.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Female; HSP90 Heat-Shock Proteins; Humans; Inflammation; Mice, SCID; Molecular Targeted Therapy; Protein Stability; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Treatment Outcome; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy.. The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment.. Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin-cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy.. The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC.

Topics: Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Disease Models, Animal; DNA Damage; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Synergism; Female; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Mice; Mitosis; Neoplasm Metastasis; Neoplasm Staging; Positron-Emission Tomography; Tomography, X-Ray Computed; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Targeted therapy against triple-negative breast cancers, which lack expression of the estrogen, progesterone, and HER2 receptors, is not available and the overall response to cytotoxic chemotherapy is poor. One of the molecular hallmarks of triple-negative breast cancers is increased expression of genes that are transcriptionally activated by hypoxia-inducible factors (HIFs), which are implicated in many critical aspects of cancer progression including metabolism, angiogenesis, invasion, metastasis, and stem cell maintenance. Ganetespib is a second-generation inhibitor of heat shock protein 90 (HSP90), a molecular chaperone that is essential for the stability and function of multiple client proteins in cancer cells including HIF-1α. In this study, human MDA-MB-231 and MDA-MB-435 triple-negative breast cancer cells were injected into the mammary fat pad of immunodeficient mice that received weekly intravenous injections of ganetespib or vehicle following the development of palpable tumors. Ganetespib treatment markedly impaired primary tumor growth and vascularization, and eliminated local tissue invasion and distant metastasis to regional lymph nodes and lungs. Ganetespib treatment also significantly reduced the number of Aldefluor-positive cancer stem cells in the primary tumor. Primary tumors of ganetespib-treated mice had significantly reduced levels of HIF-1α (but not HIF-2α) protein and of HIF-1 target gene mRNAs encoding proteins that play key roles in angiogenesis, metabolism, invasion, and metastasis, thereby providing a molecular basis for observed effects of the drug on the growth and metastasis of triple-negative breast cancer.. Triple-negative breast cancers (TNBCs) respond poorly to available chemotherapy. TNBCs overexpress genes regulated by hypoxia-inducible factors (HIFs). Ganetespib induces degradation of HSP90 client proteins, including HIF-1α. Ganetespib inhibited TNBC orthotopic tumor growth, invasion, and metastasis. Ganetespib inhibited expression of HIF-1 target genes involved in TNBC progression.

Topics: Animals; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; HSP90 Heat-Shock Proteins; Humans; Hypoxia-Inducible Factor 1; Immunoblotting; Immunohistochemistry; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Neovascularization, Pathologic; Neural Cell Adhesion Molecule L1; Reverse Transcriptase Polymerase Chain Reaction; Triazoles; Triple Negative Breast Neoplasms; Tumor Burden; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays