Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors.

Background: Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities. Thus we are seeking alternative therapeutics to enhance PARP-directed outcomes.

xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction.

About 3 million US cancer patients and 1.7 million EU cancer patients received multiple doses of radiation therapy (RT) in 2012, with treatment duration limited by normal adjacent tissue damage. Tumor-specific sensitization could allow treatment with lower radiation doses, reducing normal tissue damage.

Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells.

Background: About 75-80% of breast tumors express the estrogen receptor alpha (ER-α) and are treated with endocrine-target therapeutics, making this the premier therapeutic modality in the breast cancer clinic. However, acquired resistance is common and about 20% of resistant tumors loose ER-α expression via unknown mechanisms. Inhibition of ER-α loss could improve endocrine therapeutic efficacy, benefiting a significant number of patients.

Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target.

A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs.

Lipoprotein lipase links dietary fat to solid tumor cell proliferation.

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake.

PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation.

Mutations in genes functioning in different pathways frequently occur together in the same cancer, whereas mutations in the same pathway tend to be mutually exclusive. However, the majority of colon, breast, and endometrial cancers that possess mutations in PIK3CA, the catalytic subunit p110alpha of phosphatidylinositol 3'-kinase (PI3K), also possess mutations or alterations in genes upstream of PI3K such as Ras, ERBB2/ERBB3, or PTEN. PIK3CA mutations occur almost exclusively in invasive tumors, whereas upstream mutations occur as frequently in early-stage and late-stage tumors, suggesting that PIK3CA mutation is a late-stage event that may augment earlier activation of the PI3K pathway.

Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw.

Notch is an ancient cell signaling system that regulates cell fate specification, stem cell maintenance and initiation of differentiation in embryonic and postnatal tissues.(1) Alteration of these functions in the adult have been associated to various types of cancer in which Notch may act as an oncogene or as a tumor suppressor. As occurs during development, Notch cooperates with other signaling pathways in the transformation process.

Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway.

Spitz nevi are benign melanocytic nevi that overlap histopathologically with melanoma. We previously found copy number increases of chromosome 11p frequently paralleled by mutations in the HRAS oncogene mapping to this region. In this study, we explored mechanisms that inhibit proliferation in the presence of HRAS activation.

Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.

Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types.