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View the Table of Contents for the March 1 issue of Clinical Cancer Research.
Stanway et al. Page 1585
The steroid sulfatase (STS) pathway makes a major contribution to estrogen synthesis in breast tumors. To examine the effect of blocking this enzyme, Stanway et al. performed the first Phase I trial of an STS inhibitor and almost complete inhibition of activity was achieved in postmenopausal women with breast cancer. This resulted in significant reductions in serum estradiol and androstenediol concentrations. Unexpectedly, androstenedione concentrations also decreased by ≤86% indicating that peripheral conversion from dehydroepiandrosterone sulfate is the major source of this steroid. Four patients, who had previously progressed on aromatase inhibitor therapy, showed stable disease for up to 7 months.
Lara et al. Page 1556
Bone mass is dependent on the balance of osteoblast-mediated formation and osteoclast-mediated resorption. In advanced prostate cancer, osteoblasts predominate, leading to sclerotic bone metastases. As part of this randomized trial of a matrix metalloproteinase inhibitor (MMPI), BMS-275291, in hormone refractory prostate cancer (HRPC) patients with bone metastases, markers of bone turnover were prospectively assessed and correlated with patient outcome. Markers of bone formation (osteocalcin, procollagen N-terminal propeptides: PINP and PIIINP) and resorption (N-telopeptide, pyridinoline, deoxypyridinoline) in serum were measured using commercial enzyme immunoassays. Although BMS-275291 did not appear to have substantial activity in HRPC, the bone marker studies show that baseline serum levels of N-telopeptide, osteocalcin, PINP, and PICP had prognostic significance for progression-free and/or overall survival.
Page 1540
Primary malignant brain tumors in children and adolescents sometimes recur in the leptomeninges. Only a few chemotherapeutic agents are available in such instances for intrathecal therapy. Spartaject Busulfan is a lipid-encapsulated water-dispersable form of Busulfan that is suitable for intrathecal administration and has undergone extensive preclinical testing for toxicity and efficacy. Gururangan et al. have performed a Phase I study of this agent in children with neoplastic meningitis and have determined that the maximum tolerated dose is 13 mg when given by both the intraventricular and lumbar routes. Dose-limiting toxicities included headache and arachnoiditis.
Page 1441
Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) gene in several human solid tumors. In this issue, Qiu et al. reported four missense mutations in PIK3CA in 38 head and neck squamous cell carcinoma (HNSCC) specimens (11%). Three of the four mutations were shown to be somatic, whereas the fourth mutation was identified in a cell line. Interestingly, three of the four mutations identified were in pharyngeal cancer samples. These data provide evidence that the oncogenic properties of PIK3CA contribute to the carcinogenesis of human head and neck cancers. A specific kinase inhibitor to PIK3CA may potentially be an effective therapeutic reagent against HNSCC or pharyngeal cancer, in particular.