A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer

Goyal, Lipika; Chaudhary, Surendra Pal; Kwak, Eunice L.; Abrams, Thomas A.; Carpenter, Amanda; Wolpin, Brian M.; Wadlow, Raymond; Allen, Jill N.; Heist, Rebecca S.; McCleary, Nadine Jackson; Chan, Jennifer A.; Goessling, Wolfram; Schrag, Deborah; Ng, Kimmie; Enzinger, Peter C.; Ryan, David P.; Clark, Jeffrey W.

doi:10.1007/s10637-019-00889-y

Cited by 16 publications

(9 citation statements)

References 23 publications

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“…Early evidence that destabilization of mutant p53 had anti-cancer activity was obtained with HSP inhibitors in a range of experimental models [12]. However, in clinical trials, HSP inhibitors were found to be relatively toxic and lack efficacy [13,14]. Consequently, these trials were largely abandoned.…”

Section: Introductionmentioning

confidence: 99%

Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells

2022

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TP53 (p53) is mutated in 80–90% of cases of triple-negative breast cancer (TNBC). Statins, which are widely used to treat elevated cholesterol, have recently been shown to degrade mutant p53 protein and exhibit anti-cancer activity. The aim of this work was to evaluate the potential of statins in the treatment of TNBC. The anti-proliferative effects of 2 widely used statins were investigated on a panel of 15 cell lines representing the different molecular subtypes of breast cancer. Significantly lower IC50 values were found in triple-negative (TN) than in non-TN cell lines (atorvastatin, p < 0.01; simvastatin p < 0.05) indicating greater sensitivity. Furthermore, cell lines containing mutant p53 were more responsive to both statins than cell lines expressing wild-type p53, suggesting that the mutational status of p53 is a potential predictive biomarker for statin response. In addition to inhibiting proliferation, simvastatin was also found to promote cell cycle arrest and induce apoptosis. Using an apoptosis array capable of detecting 43 apoptosis-associated proteins, a novel protein shown to be upregulated by simvastatin was the IGF-signalling modulator, IGBP4, a finding we confirmed by Western blotting. Finally, we found synergistic growth inhibition between simvastatin and the IGF-1R inhibitor, OSI-906 as well as between simvastatin and doxorubicin or docetaxel. Our work suggests repurposing of statins for clinical trials in patients with TNBC. Based on our findings, we suggest that these trials investigate statins in combination with either doxorubicin or docetaxel and include p53 mutational status as a potential predictive biomarker.

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Section: Introductionmentioning

confidence: 99%

Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells

2022

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“…Our study provides fundamental evidence supporting future preclinical and clinical testing of STA-9090 in MYC-positive ESCC. Although the use of other HSP90 inhibitors in cancer patients has not shown impressive clinical activity at present, 38,44,45 it is possible that STA-9090 is an agent with high antitumor efficacy against MYC overexpressing ESCC, i.e. a subset of ESCC patients who could potentially benefit from this drug.…”

Section: Resultsmentioning

confidence: 99%

<p>HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma</p>

Guan¹,

Zou²,

Liu³

et al. 2020

OTT

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Purpose: Currently, the paucity of classical effective pharmacological drugs to treat esophageal squamous cell carcinoma (ESCC) is a major problem. The c-Myc (MYC) protein is a promising target as it is overexpressed in ESCC. MYC is a sensitive client protein of the heat shock protein 90 (HSP90) and, therefore, targeting the HSP90-MYC axis by inhibition of HSP90 is a potential therapeutic strategy for ESCC. Here, we evaluated the clinical application value of the HSP90 inhibitor (Ganetespib, STA-9090) as an anti-cancer agent for MYC-positive ESCC. Materials and Methods: We first analyzed ESCC tissue microarrays and clinical tissue samples to determine MYC expression. The relationship between MYC and HSP90 was analyzed by co-immunoprecipitation assays and immunofluorescence. In in vitro cell models, cell growth was analyzed using the CCK-8 kit, and MYC protein expression was analyzed by Western blot. The in vivo antitumor activity of STA-9090 was assessed in two xenograft animal models. Results: We demonstrated that MYC-overexpressing ESCC cells were highly sensitive to STA-9090 treatment through suppressing ESCC cell proliferation, cell cycle progression and survival. Moreover, STA-9090 treatment decreased MYC expression, reducing the half-life of the MYC protein. We further established two xenograft mouse models using ESCC cells and clinical ESCC samples to validate the effectiveness of STA-9090 in vivo. In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo. In contrast, STA-9090 treatment demonstrated no beneficial effects in mice with low-MYC expressing ESCC tumors. Conclusion: In conclusion, our data support that the HSP90 inhibitor, STA-9090, suppresses the expression of the MYC protein and interferes with HSP90-MYC protein-protein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion of apoptosis in ESCC cells in vitro and reduction of ESCC tumors in vivo. We propose, based on our findings, that STA-9090 is a potential novel therapeutic target for MYC-positive ESCC.

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“…In contrast to the findings in p53 mutant cells, the HSP inhibitors failed to block proliferation in p53-null cells [ 72 ]. However, in clinical trials, one of the most potent HSP90 inhibitors, i.e., ganestespib, was found to have unacceptable toxicity and to lack efficacy [ 77 , 78 , 79 ]. Thus, research into these compounds was largely abandoned.…”

Section: Mutant P53 Degrading Drugs Undergoing Clinical Trialsmentioning

confidence: 99%

Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

Duffy

Tang

Rajaram

et al. 2022

Cancers

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Mutant p53 is one of the most attractive targets for new anti-cancer drugs. Although traditionally regarded as difficult to drug, several new strategies have recently become available for targeting the mutant protein. One of the most promising of these involves the use of low molecular weight compounds that promote refolding and reactivation of mutant p53 to its wild-type form. Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. Of these, the most clinically advanced for targeting mutant p53 is eprenetapopt which has completed phase I, II and III clinical trials, the latter in patients with mutant TP53 myelodysplastic syndrome. Although no data on clinical efficacy are currently available for eprenetapopt, preliminary results suggest that the drug is relatively well tolerated. Other strategies for targeting mutant p53 that have progressed to clinical trials involve the use of drugs promoting degradation of the mutant protein and exploiting the mutant protein for the development of anti-cancer vaccines. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.

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A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer

Cited by 16 publications

References 23 publications

Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells

Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells

<p>HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma</p>

Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

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