No abstract

SUMMARY Chuvash polycythemia (CP) is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the von Hippel-Lindau (VHL) gene whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark features of CP such as hypersensitivity to erythropoietin are unclear. Here, we show that VHL directly binds suppressor of cytokine signalling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated (p)JAK2 for ubiquitin-mediated destruction. In contrast, CP-associated VHL mutants have altered affinity for SOCS1 and fail to engage and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reverses the disease phenotype in vhlR200W/R200W knock-in mice, a model that faithfully recapitulates human CP. These results reveal VHL as a SOCS1-cooperative negative regulator of JAK2 and provide compelling biochemical and preclinical evidence for JAK2- targeted therapy in CP patients.

Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2α levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2α is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2α and a mutant form of Kras (Kras G12D ) that induces lung tumors. Mice expressing both Hif2a and Kras G12D in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only Kras G12D . Additionally, tumors expressing both Kras G12D and Hif2a were more invasive, demonstrated features of epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2α causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2α can promote expression of markers of EMT, and define HIF2α as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2α and prognosis in patients with NSCLC.

The EGFR inhibitor erlotinib, when administered in the neoadjuvant setting, can have beneficial effects in terms of surgical pathology and short-term clinical outcomes in patients undergoing RC for invasive bladder cancer. Analyses are underway to examine the molecular correlates of the apparent clinical effect of neoadjuvant therapy in these patients.

After decades of therapeutic nihilism in the treatment of advanced renal cell carcinoma, remarkable therapeutic strides have been made over the last few years. Early forays into molecularly targeted therapy for this difficult-to-treat disease were based around the inhibition of gene products of the hypoxia-inducible factor (HIF) transcription factor (i.e., VEGF). Recent data suggest that inhibition of mTOR results in clinical benefit in patients with poor prognostic features, and in preclinical models this therapeutic effect involves downregulation of HIF. Intriguingly, patients with nonclear cell histology appeared to obtain clinical benefit when treated with mTOR inhibitors. This review will highlight the mTOR pathway, its relevance to both clear cell and nonclear cell renal cell carcinoma, and its place in the host of quickly expanding treatment options.