Bench to Bedside: From the Labratory to the Pharmacy

OSU 09120 – Phase I Trial of Vorinostat in the Treatment of Advanced Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Hypothesis: The addition of vorinostat to a standard chemoradiation therapy protocol for the treatment of unresectable or borderline resectable OPSCC will improve the toxicity of this effective regimen; improve tumor immune surveillance by activating adaptive and innate immune responses, especially in human papilloma virus (HPV)-positive tumors; and improve the methylation status of commonly methylated genes in OPSCC.

Study Design: Phase I clinical trial.

Rationale: Despite aggressive therapy that can include chemotherapy and concurrent chemoradiation, the overall five-year survival rate for advanced-stage OPSCC is less than 50 percent. Better treatment options are needed for this functionally and aesthetically sensitive area.

It has become evident in recent years that there exists an aggressive subtype of OPSCC characterized by female gender, a history of smoking, an anti-apoptotic phenotype and poor survival; and a subtype that is HPV-positive with low EGFR expression that is associated with good treatment response and survival.

In both cases, chemoradiation therapy protocols are very toxic, with radiation-related complications that include soft tissue fibrosis, muscle fibrosis and atrophy, dysphagia, and osteoradionecrosis and chondroradionecrosis. Improving therapeutic efficacy while minimizing toxicity to normal tissue is the overriding rationale for the use of vorinostat in this investigation.

Vorinostat (SAHA) inhibits the enzymatic activity of several histone deacetylases at nanomolar concentrations. These enzymes catalyze the removal of acetyl groups from proteins such as histones and transcription factors, altering gene expression.

Elevated histone deacetylase (HDAC) levels have been observed in head and neck cancer. HDAC inhibitors, such as vorinostat, regulate gene transcription, inhibit growth and induce apoptosis. Evidence indicates that these agents also preferentially induce both intrinsic and extrinsic apoptotic pathways in head and neck squamous cell carcinoma while sparing normal oral mucosa.

These characteristics—along with targeted cell-cycle disruption, inhibition of angiogenesis, inhibition of cell proliferation in tumor cells but not normal cells—is why vorinostat has been shown to sensitize head and neck cancer to radiotherapy while minimizing radiation-related damage. Vorinostat also suppresses the cutaneous radiation syndrome by decreasing production of TNF-alpha and TGF-beta.

Research has shown that vorinostat can be safely combined with platinum-based chemotherapy, and that it may sensitize head and neck cancer to this cytotoxic agent. Finally, evidence from our laboratories suggests that this agent modulates the immune system to better recognize virally induced tumors. Thus, the multiple effects of vorinostat indicate that this agentshould improve the response rates of HPV-positive and HPV-negative OPSCC to organ-preservation therapy, while reducing treatment toxicity.

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