Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced non-small-cell lung cancer.

We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non-small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m) and everolimus (5 mg orally once daily on days 1-19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

Sequence dependence of cell growth inhibition by EGFR-tyrosine kinase inhibitor ZD1839, docetaxel, and cisplatin in head and neck cancer.

BACKGROUND: This study was to explore whether the efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Z, Iressa, gefitinib) plus chemotherapeutic agents docetaxel (D) and cisplatin (P) may benefit from sequencing of the combination. METHODS: Three head and neck cancer cell lines were used to study the effect of various combinations of and relative sequencing of D, P, and Z in cell growth inhibition. A population pharmacokinetic stimulation study was conducted on Z in silico and used together with the growth inhibition data to derive principles for future in vivo use of this drug combination. RESULTS: The inhibitory effects of Z on combinations of D and P were sequence dependent. Treatment simultaneously with DPZ or with DP followed by Z (DP-->Z) showed synergistic effects in all 3 cell lines. However, sequencing with Z followed by DP (Z-->DP), gave an antagonistic effect, suggesting that D and P should be administered when the effect of Z is low. The induction of apoptosis was also sequence dependent. The in silico pharmacokinetic study suggested the feasibility of deriving a 5-day-on/2-day-off regimen for Z, in which D and P administration commences when levels of Z are low, allowing levels of Z to accumulate sufficiently during the remainder of the cycle. CONCLUSION: These data suggests that it is feasible to design clinical trials with these settings to maximize the efficacy of this combined drug regimen.

Current status and future perspectives of chemoprevention in head and neck cancer.

The incidence of SCCHN is expected to be approximately 42,800 new cases in the United States with more than 12,000 deaths from this disease for the year 2006. The five-year survival rate for patients with SCCHN in the United States and other developed countries is still poor, approximately 40%, and even those patients who do not experience recurrence of the original cancer, have a high risk of developing a second primary malignancy. Thus, a preventative approach before the development of invasive cancer is highly desirable and novel strategies to reduce cancer incidence in SCCHN and other tobacco-carcinogen related malignancies are being pursued. Ever since the last two decades have seen the rise and fall of the results of clinical trials using carotinoids and retinoids as chemopreventive agents, new treatment strategies are needed. Selective and nonselective COX-1/2 inhibitors and EGFR tyrosine kinase inhibitors have shown promising results in cancer therapy and are currently evaluated in chemoprevention trials. However, associated high costs and side effects make these less attractive to patients with premalignant lesions. Phytochemical containing foods like green tea, pomegranate juice and other natural compounds are attractive since they are less costly, nontoxic and widely available. While small trials have shown promising results using these agents, larger trials have yet to be conducted to establish chemopreventive effects. Since premalignant lesions of the oral cavity are easily accessible for topical treatments, it remains to be seen if there is a role for topical treatments. Current clinical trials using these novel agents for prevention of second primary tumors or treatment of premalignant lesions will further elucidate which agents should be used but also will help to establish the role of chemoprevention in head and neck cancer.

Enhancement of docetaxel-induced cytotoxicity by blocking epidermal growth factor receptor and cyclooxygenase-2 pathways in squamous cell carcinoma of the head and neck.

PURPOSE: The addition of molecular targeted agents to enhance the cytotoxicity of chemotherapeutic agents is a promising strategy in cancer treatment. The combination of cyclooxygenase-2 inhibitors and epidermal growth factor receptor tyrosine kinase inhibitors, such as celecoxib and ZD1839 (gefitinib), was reported to achieve synergistic cell growth inhibition in squamous cell carcinoma of the head and neck. Therefore, we postulated that the addition of celecoxib and ZD1839 to docetaxel, a cytotoxic agent, might further increase antitumor activity. EXPERIMENTAL DESIGN: The combination of celecoxib, ZD1839, and docetaxel was studied for its effect on cell growth and apoptosis by cell growth inhibition and Annexin V assays. The relevant molecular targets of these agents and apoptotic markers were examined by immunoblotting analyses in the presence or absence of these three drugs. Morphologic changes of the microtubule cytoskeleton, a known target of docetaxel, were also evaluated by staining for alpha-tubulin after the combination treatment. RESULTS: We showed that this triple combination significantly enhanced cell growth inhibition and docetaxel-induced apoptosis. Docetaxel mainly induced caspase-8 activation, whereas the addition of celecoxib and ZD1839 augmented the caspase-8 activation and enhanced caspase-9 activation. One of the underlying mechanisms for augmentation of docetaxel-induced apoptosis by celecoxib and ZD1839 is to further inhibit the activation of prosurvival pathway molecules, such as extracellular signal-regulated kinase and AKT, and the promotion of aberrant apoptosis. CONCLUSIONS: Our studies suggest that the combination of docetaxel with a cyclooxygenase-2 inhibitor and an epidermal growth factor receptor tyrosine kinase inhibitor may further improve efficacy of docetaxel and other taxane-based therapies in squamous cell carcinoma of the head and neck.

The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production.

Primary effusion lymphoma (PEL) is a B-cell lymphoma in which human herpesvirus-8 (HHV-8) is found within all tumor cells and represents a target for selectively destroying tumor cells. HHV-8 is latent in most PEL cells and, hence, resistant to antiviral agents that inhibit lytic replication. We demonstrate that PEL cell lines containing HHV-8 without and with coinfection with Epstein-Barr virus responded to the antiseizure medication valproate with entry into the lytic cascade and production of infectious virus. Minimal cell death occurred when noninfected BL-41 cells were incubated with valproate, whereas apoptosis occurred in response to valproate in PELs that supported lytic replication of HHV-8. The anti-viral agents ganciclovir and phosphonoformic acid (PFA) blocked valproate-induced production of infectious virus without blocking entry into the lytic cascade, and apoptosis occurred at levels that were as high as when virus production was not blocked. Ganciclovir and PFA also prevented most valproate-induced expression of the late lytic viral transcript open reading frame 26 (ORF-26), but they did not block the induction of either viral interleukin-6 (vIL-6) or viral G protein-coupled receptor (vGPCR). These studies provide evidence that incubation of PELs with valproate in the presence of ganciclovir or PFA can selectively target tumor cells for apoptosis without increasing viral load.