May 15 Clinical Cancer Research Highlights

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Selected Articles from the May 15, 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 15 issue of Clinical Cancer Research.

PTEN Hypermethylation, Dysregulation of PI3K/AKT Found in Medulloblastomas

Activation of the phosphatidylinositol 3’-kinase (PI3K)/AKT signaling pathway is a frequent event in many human cancers. Hartmann et al. investigated its role in human medulloblastomas. AKT was found to be frequently phosphorylated in medulloblastomas. Proliferation of cultured medulloblastoma cells was shown to be dependent on PI3K/AKT signaling. Mutations in the PTEN gene were ruled out. However, PTEN mRNA was significantly downregulated in the tumors, which was associated with PTEN promoter hypermethylation in a significant subset of the samples. The authors conclude that PI3K/AKT pathway activation and PTEN dysregulation constitute important steps in the molecular pathogenesis of medulloblastomas.

Tumor-Specific Antigen PRAME Useful in Antitumor T-Cell Therapies

The tumor antigen PRAME (preferentially expressed antigen on melanomas) is frequently overexpressed in different tumors, including 95% of melanomas, and has recently been shown to play a role in oncogenic transformation. To investigate whether PRAME can be used as target for T-cell therapy, Griffioen et al. screened healthy individuals and melanoma patients for circulating PRAME-specific T cells. Low frequencies of HLA-A*0201-restricted PRA^100-108-specific T cells were found in 30% to 40% of donors and patients. Moreover, PRA^100-108-specific T cells were shown to recognize and lyse PRAME-overexpressing tumor cells, supporting the usefulness of PRAME, and, in particular the PRA^100-108 epitope, as a target for antitumor T-cell therapies.

STK11/LKB1 Mutations in Peutz-Jeghers Syndrome Linked to Gastrointestinal and Breast Cancers

Although an increased cancer risk in Peutz-Jeghers syndrome (PJS) has been established, data on the spectrum of tumors associated with the disease and the influence of germline STK11/LKB1 (serine/threonine protein kinase 11) mutation status is limited. To study the frequency and spectrum of cancers in PJS, Hearle et al. analysed the incidence of cancer in 419 individuals with the syndrome, 297 of who were documented with STK11/LKB1 mutations. The risk for developing cancer by age 60 was 60%. The most common cancers in patients were gastrointestinal in origin. In women with PJS, the risk of breast cancer was substantially increased, being 31% at age 60. Cancer risks were similar in PJS patients with identified STK11/LKB1 mutations and those with no detectable mutation. Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk.

Artificial Antigen-Presenting Cells Increase Targeted Antitumor T-Cell Response

Presentation of synthetic peptides by antigen-presenting cells (APC) can sometimes generate ineffective immune responses both in vivo and in vitro. Hirano et al. developed artificial APC (aAPC) that endogenously present any HLA-A2-restricted peptide by processing a fusion protein that contains an antigenic peptide linked via a unique “LTK” sequence. aAPC engineered to naturally present the MART1-derived peptide successfully primed and expanded CD8⁺ CTL that target MART1-positive tumor cells. aAPC, constitutively expressing HLA-class I–restricted tumor-associated antigen–derived peptides, might serve as a versatile “off-the-shelf” reagent enabling the effective treatment of cancer by antigen-specific T cell–mediated immunotherapy.