Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer

Proia, David A.; Zhang, Chaohua; Sequeira, Manuel; Jimenez, John-Paul; He, Suqin; Spector, Neil L.; Shapiro, Geoffrey I.; Tolaney, Sara M.; Nagai, Masazumi; Acquaviva, Jaime; Smith, Donald L.; Sang, Jim; Bates, Richard C.; El‐Hariry, Iman

doi:10.1158/1078-0432.ccr-13-2166

Cited by 56 publications

(54 citation statements)

References 51 publications

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“…Furthermore, it has been previously been shown that ganetespib can decrease lung metastasis in the 4T1. 42 An important consideration of this observation is how this may be translatable to clinical use of checkpoint blockade. Currently, treatments for irAEs associated with checkpoint blockade have been narrowed to discontinuation of treatment or management by corticosteroids or the addition of infliximab, a chimeric monoclonal antibody against the tumor necrosis factor alpha (TNFa).…”

Section: Discussionmentioning

confidence: 99%

“…23 Additionally, it has previously been shown that treatment with ganetespib results in a significant decrease in lung metastasis in the 4T1 tumor model. 42 Given its demonstrated efficacy in multiple cancer models including 4T1, its demonstrated immune modulating effects, and due to the lack of protection seen by anti-Gr-1 mAb therapy, we hypothesized that treatment of mice receiving repeated dosing of anti-PD-1 in combination with ganetespib would protect mice from hypersensitivity reactions. We treated mice with a combined therapy of ganetespib and anti-PD-1 to determine if fatal hypersensitivity reactions persist (Fig.…”

Section: Ganetespib Decreases Neutrophil Accumulation In Lung and Supmentioning

confidence: 99%

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Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

et al. 2015

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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. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30-60 min after 4-5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing noninflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1 high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation.

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Section: Discussionmentioning

confidence: 99%

Section: Ganetespib Decreases Neutrophil Accumulation In Lung and Supmentioning

confidence: 99%

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

et al. 2015

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“…Although the study did not meet its prespecified criteria for ORR in the first-stage of the Simon's 2-stage model in this heavily pretreated unselected population, activity was noted in trastuzumab refractory HER2-positive and triple-negative breast cancer (TNBC) [54]. Clinically, anecdotal evidence of single agent activity has been reported in TNBC patients treated on Phase I and Phase II trials including an ongoing Phase II monotherapy trial (ENCHANT, NCT01677455) [59]. Ganetespib also showed enhanced cytotoxic effects when combined with chemotherapeutic agents such as doxorubicin and taxanes [59] and the ENCHANT-1 trial has been expanded to evaluate the combination of ganetespib and weekly paclitaxel, and Synta Pharmaceuticals is planning another trial of ganetespib and docetaxel in TNBC.…”

Section: Hsp90 Clinical Agents: Second Generationmentioning

confidence: 99%

“…Clinically, anecdotal evidence of single agent activity has been reported in TNBC patients treated on Phase I and Phase II trials including an ongoing Phase II monotherapy trial (ENCHANT, NCT01677455) [59]. Ganetespib also showed enhanced cytotoxic effects when combined with chemotherapeutic agents such as doxorubicin and taxanes [59] and the ENCHANT-1 trial has been expanded to evaluate the combination of ganetespib and weekly paclitaxel, and Synta Pharmaceuticals is planning another trial of ganetespib and docetaxel in TNBC. A Phase I trial of ganetespib plus paclitaxel plus trastuzumab is ongoing in HER2-positive trastuzumab-refractory MBC (NCT020 60253).…”

Section: Hsp90 Clinical Agents: Second Generationmentioning

confidence: 99%

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

Jhaveri

Ochiana

Dunphy

et al. 2014

Expert Opinion on Investigational Drugs

148

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Introduction Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

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“…Also depleted were p-EGFR, p-AKT and p-STAT3 [22-24]. Ganetespib monotherapy decreased TNBC xenograft growth and metastases to the lung and ganetespib enhanced sensitivity of TNBC cells to taxane chemotherapy in vitro and in vivo [23]. Here we hypothesized that GR degradation and decreased GR transcriptional activity following treatment with Hsp90 inhibitors would allow enhanced TNBC sensitivity to chemotherapy-induced cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer

et al. 2016

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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.

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Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer

Cited by 56 publications

References 51 publications

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer

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