BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. The ansamycin-based Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in Phase III clinical testing. However, 17-AAG is difficult to formulate and associated with dose-limited toxicity issues. A fully synthetic and bioavailable Hsp90 inhibitor, BIIB021, was evaluated for antitumor activity in a variety of head and neck squamous cell carcinoma (HNSCC) cell lines and HNSCC xenograft models, either as a single agent or in combination with fractionated radiation and the results were compared with that of 17-AAG. BIIB021 showed strong antitumor activity, comparable with, and in certain instances, superior to 17-AAG. BIIB021 enhanced the in vitro radiosensitivity of HNSCCA cell lines with a corresponding reduction in the expression of key radioresponsive proteins, increased apoptotic cells and enhance G2 arrest. In xenograft studies, BIIB021 exhibited a strong antitumor effect outperforming 17-AAG, either as a single agent and or in combination with radiation, thereby improved the efficacy of radiation. These results suggest that this synthetic and bioavailable Hsp90 inhibitor affects multiple pathways involved in tumor development and progression in the HNSCC setting and may represent a better strategy for the treatment of HNSCC patients, either as a monotherapy or a radiosensitizer. Furthermore, it also demonstrates the benefits of using preclinical models of chemosensitization to radiotherapy to explore clinically relevant radiation dosing schemes.Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with approximately 600,000 new cases reported each year. More than 50% of newly diagnosed patients will eventually relapse with either local recurrence or distant metastases. Unfortunately, in the relapse setting prognosis is poor, with median overall survival limited to about 1 year. Current treatment paradigms depend upon the stage of the disease at presentation. The standard treatment for loco-regional disease involves surgery and/or radiotherapy in either the neo-or adjuvant setting. Radiotherapy almost always employed with locally advanced disease, with a variety of fractionation regimens currently in clinical practice. Efforts to increase the efficacy of radiotherapy have included combination with chemotherapy, initially in the concomitant setting with platinum-containing regimens (chemoradiotherapy) and most recently as adjuvant treatment. [1][2][3] Although the locoregional control and survival rates associated with chemoradiotherapy are higher than those for radiation alone, these intensive regimens are frequently associated with severe toxicities, leading to significant comorbidities. Targeted biological therapies that selectively interfere with cancer cell growth signals may improve patient survival by enhancing the effects of radiation, with the added b...

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

“…The synthetic Hsp90 inhibitor BIIB021 revealed a strong antitumor effect in head and neck squamous cell carcinoma cells in vitro and in vivo. Its antitumor effect was higher than the effect of ansamycin-based Hsp90 inhibitor 17-AAG and when combined with radiation sensitized the efficacy of radiation therapy (146). The activation of multichaperone complex could be a resistance mechanism to the antiproliferative and apoptotic effects induced by tipifarnib (farnesyl transferase inhibitor) and that the combination of The symbol ↑ means at least the additive effect of the combination compared to single therapies.…”

EC144, a Synthetic Inhibitor of Heat Shock Protein 90, Blocks Innate and Adaptive Immune Responses in Models of Inflammation and Autoimmunity

“…Recently, novel fully synthetic Hsp90 inhibitors have been produced that have activity comparable to the natural antibiotics yet do not share their pharmacologic liabilities (3). Several compounds are currently in phase II clinical trials for cancer indications (4,5).…”

HSP90 and its inhibitors (Review)

“…BIIB021 has shown potent antitumor activity both in vivo and in vitro research of many kinds of tumors (127)(128)(129). BIIB021 is currently undergoing phase I/II clinical trials and exhibits superior pharmaceutical properties and bioavailability (130).…”