Therefore, efficacy objectives were not analyzed for phase II. Discussion The current study was based Bicalutamide on the favorable toxicity profile and promising efficacy of enzastaurin in combination with cytotoxic agents in previous studies and the potential for synergistic activity between enzastaurin and pemetrexed . The addition of enzastaurin to cisplatin/pemetrexed as first line treatment in patients with advanced NSCLC was well tolerated, with no new or unexpected safety issues observed, and showed preliminary activity in the safety lead in phase with 8 partial responses . However, on the basis of the interim results from two other phase II, randomized trials of enzastaurin in patients with NSCLC , we decided to terminate the study early.
These studies showed that the addition of enzastaurin to pemetrexed and to carboplatin pemetrexed was well tolerated, with no new safety issues identified, but did not provide additional efficacy in patients Bortezomib clinical trial with advanced NSCLC, and both Bortezomib structure studies were subsequently closed. Our findings also suggest that enzastaurin is tolerable when administered with full dose cytotoxic chemotherapy, but because of the lack of additional efficacy with enzastaurin in the aforementioned studies , our patients remained in the study but continued treatment with cisplatin pemetrexed or an alternative therapy of the physician’s choice.Background. Rapamycin is an mTOR inhibitor with preclinical efficacy in squamous cell carcinoma of the head and neck . However, mTOR inhibitors also increase Akt activity in SCCHN cell lines, which would promote survival and oncogenesis.
Enzastaurin is an AGC kinase inhibitor with nanomolar inhibitory concentrations Bortezomib solubility for Akt and protein kinase C . Moreover, Akt and PKC inhibitors have demonstrated efficacy in SCCHN. Methods. We hypothesized that the combination of rapamycin and enzastaurin would be more effective than either agent alone. Results. Rapamycin and enzastaurin generally inhibited putative targets in SCCHN cell lines in culture. In mice xenografted with CAL27 cells, rapamycin and enzastaurin produced growth delay. In contrast, the combination of rapamycin and enzastaurin caused regression of CAL27 tumors with evidence of inhibition of putative targets, survival, angiogenesis and proliferation. Conclusion.
These data demonstrate that the combination of rapamycin and enzastaurin disrupts critical oncogenic pathways in SCCHN and has efficacy in preclinical models. VVC 2011 Wiley Periodicals, Inc. Head Neck 33: 1774 1782, 2011 Keywords: PKC, AKT, mTOR, Head and neck squamous cell carcinoma, rapamycin, welfare state enzastaurin Squamous cell carcinoma of the head and neck is the sixth leading cause of cancer related death worldwide, with an incidence of more than 500,000.1 Three major factors affect survival in this disease—recurrence, second malignancies, and comorbid illness. Patients diagnosed with recurrent or metastatic disease have a median survival of 6 to 8 months with currently available therapies.2 Molecular targeted therapy has made an impact on the standards of care in SCCHN, especially with respect to targeting the epidermal growth factor receptor. Nonetheless, all recurrent or metastatic SCCHN will become resistant to treatment resulting in the patient’s death.