Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer

Ma, Liang; Sato, Fuminori; Sato, Ryuta; Matsubara, Takanori; Hirai, Kenichi; Yamasaki, Mutsushi; Shin, Toshitaka; Shimada, Tatsuo; Nomura, Takeo; Mori, Koichi; Sumino, Yasuhiro; Mimata, Hiromitsu

doi:10.3892/or.2014.3132

Cited by 45 publications

(40 citation statements)

References 44 publications

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“…Preclinical studies suggest that Hsp90 inhibitors are able to enhance the efficacy of anticancer agents, and potentially overcome drug resistance. 28–30 Several studies have been conducted with Hsp90 inhibitors in combination with cytotoxic chemotherapies including the GALAXY-I study of ganetespib with docetaxel in advanced non–small-cell lung cancer, which demonstrated improved OS with docetaxel with ganetespib compared with docetaxel alone as second line therapy. 30 These data, along with unpublished preclinical data suggesting strong synergy of ganetespib with platinum in CRC cell lines and xenografts support our plans for a combination study in metastatic CRC particularly in KRAS-mutated CRC where we believe Hsp90 might have the most potential benefit based on preclinical data.…”

Section: Resultsmentioning

confidence: 99%

Ganetespib, a Novel Hsp90 Inhibitor in Patients With KRAS Mutated and Wild Type, Refractory Metastatic Colorectal Cancer

Cercek

Shia

Gollub

et al. 2014

Clinical Colorectal Cancer

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Seventeen patients with refractory KRAS mutated and wild type metastatic colorectal adenocarcinoma received single agent ganetespib in a single institution phase II study. The drug was well tolerated but did not yield any responses, although two patients achieved durable stable disease. 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. Patients received ganetespib 200 mg/m2 intravenously. Tumor tissue was collected before treatment and 48 hours after treatment for changes in expression of Hsp90 client proteins and other potential pharmacodynamics markers. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B, and phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutational status was also determined. Results Seventeen patients were treated (median age, 58; range, 44–79 years). No patients demonstrated objective regression of disease. Two patients had stable disease of 6.8 and 5.1 months duration. Serious adverse events that were potentially attributable to ganetespib included diarrhea (12%, n = 2), fatigue (17%, n = 3), and increased aspartate aminotransferase/alanine aminotransferase (12%, n = 2) and alkaline phosphatase (6%, n = 1) levels. Of the 17 evaluable patients, 9 (53%) including patients with stable disease as best response, had KRAS-mutant tumors. Conclusion In this first phase II investigation of an Hsp90 inhibitor in colorectal cancer, ganetespib as a single agent did not demonstrate activity in chemotherapy-refractory metastatic colorectal cancer. However, on the basis of the drug’s promising preclinical combination data and the relatively mild toxicity profile, further clinical investigation of this agent in combination with standard cytotoxic agents is planned.

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Section: Resultsmentioning

confidence: 99%

Ganetespib, a Novel Hsp90 Inhibitor in Patients With KRAS Mutated and Wild Type, Refractory Metastatic Colorectal Cancer

Cercek

Shia

Gollub

et al. 2014

Clinical Colorectal Cancer

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“…Furthermore, HSP70 overexpression possibly contributes to the avoidance of cell death, and HSP70 could be a key molecule for overcoming resistance to HSP90 inhibitors. Indeed, the combination of these two chaperones with conventional anti-cancer drugs is a promising therapeutic option for patients with advanced bladder cancer (Ma et al 2014). HSP70 is a potential biomarker for the detection of tumors and for monitoring the clinical outcome of radiotherapy in squamous cell carcinoma of the head and neck (SCCHN) patients (Gehrmann et al 2014b).…”

Section: Changes In the Significance Of Hsp70 Levels In Various Cancersmentioning

confidence: 98%

The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: a literature review

Qu¹,

Jia²,

Liu³

et al. 2015

Cell Stress and Chaperones

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As an intracellular polypeptide, heat shock protein 70 (HSP70) can be exposed on the plasma membrane and/or released into the circulation. However, the role of HSP70 in various nondisease and disease conditions remains unknown. Quantitative methods for the detection of HSP70 have been used in clinical studies, revealing that an increase in circulating HSP70 is associated with various types of exercise, elderly patients presenting with inflammation, mobile phones, inflammation, sepsis, chronic obstructive pulmonary disease, asthma, carotid intima-media thickness, glutamine-treated ill patients, mortality, diabetes mellitus, active chronic glomerulonephritis, and cancers. Circulating HSP70 decreases with age in humans and in obstructive sleep apnea, arteriosclerosis, atrial fibrillation (AF) following coronary artery bypass surgery, nonalcoholic fatty liver disease, moderate-to-severe alcoholic fatty liver disease, hepatic steatosis, and Helicobacter pylori infection. In conclusion, quantitative methods can be used to detect HSP70, particularly in determining circulating HSP70 levels, using more convenient and rapid screening methods. Studies have shown that changes in HSP70 are associated with various nondisease and disease conditions; thus, HSP70 might be a novel potential biomarker reflecting various nondisease conditions and also the severity of disease conditions. However, the reliability and accuracy, as well as the underlying mechanism, of this relationship remain poorly understood, and large-sample clinical research must be performed to verify the role.

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“…The chaperone-rich cytoplasm of the cancer cell thus contributes to the resistance to PCD and killing by cytotoxins [49]. Chaperones appear to act additively in the restraint of cell death and for instance dual targeting of Hsp70 and Hsp90 promoted chemotherapy-induced death in bladder cancer[50]. …”

Section: Hsps and The Defining Traits Of Cancer Cellsmentioning

confidence: 99%

Heat Shock Proteins Promote Cancer: It's a Protection Racket

Calderwood

Gong

2016

Trends in Biochemical Sciences

331

251

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Heat Shock Proteins (HSP) are expressed at high levels in cancer and form a fostering environment essential for tumor development. We have reviewed the recent data in this area, concentrating mainly on Hsp27, Hsp70 and Hsp90. The overriding role of the HSPs in cancer is to stabilize the active functions of overexpressed and mutated cancer gene. Elevated HSPs are thus required for many of the traits that underlie the morbidity of cancer, including increased growth, survival and formation of secondary cancers. In addition, HSPs participate in the evolution of cancer treatment resistance. HSPs are also released from cancer cells and influence malignant properties by receptor- mediated signaling. Current data strongly support efforts to target HSPs in cancer treatment.

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Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer

Cited by 45 publications

References 44 publications

Ganetespib, a Novel Hsp90 Inhibitor in Patients With KRAS Mutated and Wild Type, Refractory Metastatic Colorectal Cancer

Ganetespib, a Novel Hsp90 Inhibitor in Patients With KRAS Mutated and Wild Type, Refractory Metastatic Colorectal Cancer

The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: a literature review

Heat Shock Proteins Promote Cancer: It's a Protection Racket

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