April 1 Clinical Cancer Research Highlights

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Selected Articles from the April 1, 2006 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Clinical Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the April 1 issue of Clinical Cancer Research.

Evaluation of Potential Targets for Chemoprevention of Lung Cancer

Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. No chemoprevention approaches have so far shown promise in lung cancer. The current study of 268 bronchoscopically obtained biopsies from 134 subjects show that epidermal growth factor receptor (EGFR) and HER-2 proteins were strongly expressed in bronchial dysplasias, and that EGFR protein expression increased with increased dysplastic change. Biopsies with co-expression of EGFR and HER-2 were associated with the highest levels of Ki-67 and MCM2 expression, suggesting a synergistic effect on proliferation. This study provides the rationale for exploring inhibition of EGFR signaling in lung cancer chemoprevention.

Effects of Smoking on the Pharmacokinetics of Erlotinib

Although the recommendation to consider smoking status in clinical studies was made decades ago, the effect of smoking on pharmacokinetics has been studied for only a limited number of drugs. An open label study of erlotinib, which is indicated for use in non–small cell lung cancer (NSCLC) and pancreatic cancer patients, in healthy male subjects shows current smokers achieved significantly less drug exposure following a single dose compared with nonsmokers. These results suggest further study to determine appropriate erlotinib dosing in smokers and are intriguing in light of the reduced benefit of erlotinib therapy that has been observed in advanced NSCLC patients who smoke.

Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs

The recent discovery of the erythropoietin receptor on breast cancer cells raises the concern that erythropoietin therapy for the prevention and treatment of chemotherapy-induced anemia might stimulate tumor growth and/or protect cancer cells from drug-induced apoptosis. Gewirtz et al. found that erythropoietin failed to stimulate the proliferation of MCF-7 or MDA-MB231 breast tumor cells and did not interfere with the antiproliferative and/or cytotoxic effects of Adriamycin, Taxol, or tamoxifen. Erythropoietin further failed to prevent apoptosis induced by Taxol or senescence induced by Adriamycin. These findings suggest that erythropoietin is unlikely to directly counteract the effectiveness of cancer chemotherapeutic drugs. Studies relating to the activation of ERK, p38, JNK, Akt, or STAT5 suggest that the lack of effect of erythropoietin in the breast tumor cell lines may be a consequence of either ineffective signaling through the erythropoietin receptor or drug-mediated suppression of erythropoietin signaling.

ST2146 Monoclonal Antibody Targets Tenascin-Expressing Tumors

Despite the clinical success of monoclonal antibodies in several pathologies, the immunotherapy of solid tumors still remains unsatisfactory. Pretargeted Antibody Guided RadioImmunoTherapy (PAGRIT) is a multi-treatment approach allowing restricted and amplified accumulation of the radioisotope in the tumor. The specificity and affinity of the antitumor monoclonal antibody, used as a first step, is fundamental for treatment efficacy. De Santis et al. report exceptionally high and specific accumulation of the ST2146 anti-tenascin monoclonal antibody in both low and high antigen-expressing human xenotransplanted tumors. The data support the use of ST2146 in PAGRIT currently in phase I/II clinical trials for glioblastoma treatment.

Phase II Trial of Celecoxib in Prostate-Specific Antigen Recurrent Prostate Cancer after Definitive Radiation Therapy or Radical Prostatectomy

Recent evidence has shown that Cox-2 inhibitors have antitumor activity in a variety of tumor types including prostate cancer, both in vitro and in vivo. However, human trials are absent. This study evaluated the efficacy of the Cox-2 inhibitor celecoxib in patients with prostate-specific antigen (PSA)-recurrent prostate cancer after radiation therapy or radical prostatectomy. PSA doubling times and the slope of PSA rise were significantly inhibited in patients treated with celecoxib as compared with pretreatment values. These results suggest that Cox-2 inhibitors may help delay or prevent disease progression in these patients, and thereby help extend the time until androgen-deprivation therapy.