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This Week in Cancer Discovery: Apr 20, 2012


In Cancer Discovery this week, researchers in the UK and Switzerland report they performed a functional metabolic screen to identify the gene PFKFB4 as an important regulator of prostate cancer cell survival. The team analyzed the effect of silencing 222 different enzymes, transporters, and regulators on the survival of three metastatic prostate cancer cell lines and one non-malignant prostate cancer cell line and found that there are several genes required for the cells' survival. Among them was PFKFB4, which is required to "balance glycolytic activity and antioxidant production to maintain cellular redox balance in prostate cancer cells," the team writes. When the researchers depleted the gene in a xenograft model of prostate cancer, tumor growth was inhibited. "PFKFB4 mRNA expression was also found to be greater in metastatic prostate cancer compared with primary tumors," they add. "Taken together, these results indicate that PFKFB4 is a potential target for the development of antineoplastic agents."

Also in Cancer Discovery this week, researchers at the Institute of Cancer Research in the UK report that treatment of BRAFV600E-driven melanoma with metformin accelerates the cancer's growth through the up-regulation of VEGF-A. The team says that melanoma cells driven by oncogenic BRAF are resistant to the effects of metformin — which has been shown to inhibit tumor growth in a variety of cancers by inhibiting TORC1 — because TORC1 activity is sustained by the signal transducer RSK. Further, the team says, VEGF-A is also up-regulated, which drives angiogenesis and accelerates tumor growth. When VEGF signaling is inhibited, the researchers add, metformin inhibits tumor growth in mice. "VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients," they write.

Finally in Cancer Discovery this week, researchers in the US and Denmark report that allelic imbalance in the telomeres of cancer patients indicate they may be sensitive to DNA-damaging agents. The team analyzed various cancer cell lines and tumors to find genomic signatures of defective DNA repair. They found that the number of sub-chromosomal regions with allelic imbalance all the way to the telomere was predictive of cisplatin sensitivity in vitro in patients with triple-negative breast cancer. Further, in patients with serous ovarian cancer, higher levels of telomeric allelic imbalance predicted a better response to treatment with platinum-based chemotherapy, they add. "Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents," the team writes. "[The number of sub-chromosomal regions with allelic imbalance extending to the telomere], a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair."

The Scan

Enzyme Involved in Lipid Metabolism Linked to Mutational Signatures

In Nature Genetics, a Wellcome Sanger Institute-led team found that APOBEC1 may contribute to the development of the SBS2 and SBS13 mutational signatures in the small intestine.

Family Genetic Risk Score Linked to Diagnostic Trajectory in Psychiatric Disorders

Researchers in JAMA Psychiatry find ties between high or low family genetic risk scores and diagnostic stability or change in four major psychiatric disorders over time.

Study Questions Existence of Fetal Microbiome

A study appearing in Nature this week suggests that the reported fetal microbiome might be the result of sample contamination.

Fruit Fly Study Explores Gut Microbiome Effects on Circadian Rhythm

With gut microbiome and gene expression experiments, researchers in PNAS see signs that the microbiome contributes to circadian rhythm synchronicity and stability in fruit flies.