May 1 Clinical Cancer Research Highlights

PDF Version for Printing

Selected Articles from the May 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 May 1 issue of Clinical Cancer Research.

PUMA Deficiency in Lung Cancer Cells May Contribute to Chemo Resistance

PUMA is a BH3-only protein and an essential mediator of DNA damage-induced apoptosis. Yu et al. found that the induction of PUMA by chemotherapeutic agents is abrogated in p53-deficient lung cancer cells. PUMA is a potent inducer of apoptosis and growth suppression in lung cancer cells in vitro and in vivo. Adenoviral PUMA expression significantly sensitized lung cancer cells to chemotherapeutic agents and radiation through induction of apoptosis. These data suggest that deficiency in PUMA regulation contributes to the development of resistance to anticancer therapy, and that PUMA might be useful as a target in cancer gene therapy.

Parameters Defined for Mictotubule Targeting at Colchicine-Binding Site

Drugs which target microtubules are some of the most effective antineoplastic agents currently available. The vinca alkaloids and the taxanes each have a distinct binding site on beta-microtubulin. Colchicine binds to a separate site on beta-tubulin. No colchicine-site binders are currently approved for cancer chemotherapy. A study by Hande et al. describes the toxicity, pharmacology and suggests the appropriate treatment dose of ABT-751, a novel agent that targets the colchicine binding site on beta-tubulin. Primary dose-limiting toxicities encountered included ileus, constipation, abdominal pain and fatigue. ABT-751 was metabolized by glucuronidation and sulfation. Plasma ABT-751 drug concentrations found to be effective in pre-clinical models were noted in patients. No responses were seen in this Phase I trial but have been noted in other Phase I trials. Four of 39 patients had stable disease lasting at least 6 months.

Improved PCR Tests for Effect of Less Toxic Agents against Hairy Cell Leukemia

Purine analogs, effective standard agents for hairy cell leukemia (HCL), do not eliminate minimal residual disease (MRD) by PCR and Southern blot tests. To determine if new agents with less cumulative toxicity like recombinant immunotoxin BL22 and rituximab can eradicate HCL-MRD, Arons et al. designed an improved PCR test. They cloned the monoclonal surface immunoglobulin sequences and designed clone-specific primers and probes for real-time quantitative PCR. They could detect 1/10⁶ cells and quantify otherwise undetectable MRD in HCL patients completing therapy. This test could determine the optimal number of cycles of these agents and whether they can eradicate HCL in some patients.

Inflammatory Responses Mark Cancer-Related Fatigue

Persistent, medically unexplained fatigue is one of the most common and disabling complaints among breast cancer survivors, affecting as many as 30% of survivors up to 5 years after successful treatment. Collado-Hidalgo et al. evaluated the inflammatory basis for persistent cancer-related fatigue and present evidence of a functional alteration in innate immune response characterized by altered pro-inflammatory cytokine response to LPS stimulation. The study also examines multiple inflammatory parameters to define a highly prognostic biomarker of behavioral fatigue. These results provide new mechanistic insights into the inflammatory basis for post-cancer fatigue, and define biological markers for use in large-scale clinical studies.

GM-CSF Enhances CD8+ T Cell Targeting of Melanomas

Cutaneous melanoma is the most aggressive type of skin cancer for which complete surgical excision at an early stage remains the only curative treatment option. Impaired immune functions in the sentinel lymph node may facilitate early metastatic events during melanoma development. In this study Vuylsteke et al. demonstrate that anti-tumor CD8+ T cells can already be primed in the sentinel lymph node in the earliest stages of melanoma development and that these CD8+ T cell responses appear to be enhanced by the immunostimulatory agent GM-CSF. Such local potentation of tumor-specific T cell reactivity may present a valuable adjuvant treatment option.