Tumorigenesis

Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma Ligon, K. L. et al. Neuron 53, 503–517 (2007)

Ligon and colleagues have identified a mechanism regulating the growth of normal and cancer stem cells in the brain. The brain-specific transcriptional repressor OLIG2 represses the cell-cycle inhibitor p21 in both neural progenitors and gliomas. Its function is required for tumour formation in a mouse model of glioma. As the OLIG2 pathway is lineage-restricted, targeting OLIG2 could be a promising brain-specific therapeutic approach.

Therapeutics

A prostate-specific antigen-activated channel forming toxin as therapy for prostatic disease Williams, S. A et al. J. Natl Cancer Inst. 99, 376–385 (2007)

Prostate cancer is often associated with high levels of the prostate-specific antigen (PSA). Williams and colleagues engineered a bacterial toxin to produce a PSA-activated prototoxin (PRX302) which, when cleaved by PSA, generates stable pores in the plasma membrane and causes rapid cell death. Intratumoral injection of PRX302 reduced the growth of PSA-secreting tumours in mouse xenografts, and complete regression was achieved in 23% of cases. PRX302 specificity and toxicity were assessed in different animal models, including monkeys, and gave encouraging results. A phase I clinical trial is now underway to test intraprostatic treatment with PRX302 in patients with recurring prostate cancer.

DNA repair

DNA repair and transcriptional deficiencies caused by mutations in the Drosophila p52 subunit of TFIIH generate developmental defects and chromosome fragility Fregoso, M. et al. Mol. Cell. Biol. 5 March 2007 (doi: 10.1128/MCB.00030-07)

Mutations in some subunits of the transcription factor IIH (TFIIH) complex are associated with cancer, the cancer-prone disorder xeroderma pigmentosum (XP) and other hereditary syndromes. Fregoso and colleagues show that mutations in the Drosophila melanogaster homologue of the p52 subunit of TFIIH results in UV sensitivity, chromosomal instability and increased tumour incidence. It is possible that p52 mutations might account for a new complementation group of XP.

Tumor suppression

p38α MAP kinase as a sensor of reactive oxygen species in tumorigenesis Dolado, I. et al. Cancer Cell 11, 191–205 (2007)

Activation of the stress-activated kinase p38α inhibits malignant transformation and is therefore prevented in many cancer cells. Dolado and colleagues now show that p38α is activated in response to oncogenes, such as HRAS, that induce the production of reactive oxygen species. This indicates that targeting mechanisms that sense oxidative stress could be important for anticancer drug development.