Highlights of This Issue

In this study, Hui and colleagues conducted global microRNA expression profiling of 51 archival samples of locally advanced head and neck squamous cell carcinomas (HNSCCs). They found that approximately one third of all miRNAs tested were deregulated, and chromosomal alterations were one mechanism that could lead to abnormal miRNA expression. Profiles were similar among laryngeal, oropharyngeal, and hypopharyngeal cancers. MiR-451 was significantly downregulated in relapsed patients, and functional analysis demonstrated the involvement of the miR-106b-25 cluster and miR-375 in HNSCC development and progression. Further study of these abnormally expressed miRNAs should lead to a better understanding of HNSCC biology.

The ERK pathway is upregulated in many human cancers, and specific blockade of the ERK pathway using the MEK inhibitor PD184352 induces mostly cytostatic effects. Watanabe and colleagues show that the therapeutic efficacy of microtubule-destabilizing agents is enhanced when combined with PD184352. In mice harboring tumor xenografts, PD184352 could sensitize tumor cells to the cytotoxic effects of the microtubule-destabilizing agents TZT-1027 and vinorelbine. The enhanced therapeutic efficacy of the drug combinations was achieved by a relatively transient blockade of the ERK pathway. These findings suggest that administration of both a MEK inhibitor and a microtubule-destabilizing agent could be an effective chemotherapeutic strategy.

Farnesyltransferase inhibitors (such as tipifarnib) appear to have additive or synergistic effects with cancer treatments, and preclinical data suggest they could help overcome hormone therapy resistance in breast cancer. Dalenc and colleagues conducted a phase II clinical trial with combined tipifarnib/tamoxifen as a rescue therapy for metastatic breast cancer patients with acquired tamoxifen resistance. Of 20 patients, one had an objective response and nine had stable disease, for an overall clinical benefit rate of 50%. Additionally, serum profiling was performed, and a peptide of fibrinogen α was identified as a possible therapeutic response marker.

Cancer cell proliferation depends upon ribonucleotide reductase, an enzyme needed for DNA synthesis. After ionizing radiation, ribonucleotide reductase activity increases, facilitating DNA repair and decreasing cancer cell sensitivity to this treatment. To explore the safety and efficacy of ribonucleotide reductase inhibition, Kunos and colleagues designed a phase 1 clinical study of daily radiation and weekly cisplatin chemotherapy plus three-times weekly 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a ribonucleotide reductase inhibitor, in patients with cervical cancer. The regimen was well tolerated and a 100% complete response rate was observed, with no disease progression documented through 18 months of median follow-up.