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This Week in Cancer Discovery: Jun 27, 2012

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In Cancer Discovery, a team of US researchers reports a first-in-human trial of a STAT3 decoy oligonucleotide in patients with head and neck tumors. Transcription factors like STAT3 have been considered undruggable, the team says. For this study, the researchers developed a decoy targeting STAT3 and performed a phase 0 trial in which they injected it into patients with head and neck cancers. They found that expression levels of STAT3 target genes were decreased in these cancers after injection, compared with tumors receiving the saline control. To overcome the instability that usually prevents decoys from being administered systemically, the team linked the oligonucleotide strands using hexa-ethyleneglycol spacers. "This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells," they write. "Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development."

Also in Cancer Discovery, MIT researchers report that the outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. In studying the biochemical and cell-biological mechanisms that enable disseminated cancer cells to interact with a tissue's extracellular matrix to form metastases, the team found that "the formation of elongated, integrin β1-containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these cells via activation of focal adhesion kinase." The plaques only appear after filopodium-like protrusions have formed that harbor integrin β1. "The cytoskeleton-regulating proteins Rif and mDia2 contribute critically to the formation of these protrusions and thereby enable the proliferation of extravasated cancer cells," the team adds.

And finally in Cancer Discovery, a team led by researchers at the University of California, San Francisco, reports that the transcription factor ZNF217 has use as both a prognostic biomarker and a therapeutic target for breast cancer progression. Using in silico screening, the team identified candidate therapeutics that can inhibit the growth of cancer cells expressing high levels of ZNF217, the overexpression of which can drive aberrant differentiation and signaling events, and promote increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis. "The nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events in vivo," the team writes. "Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217."

The Scan

Mosquitos Genetically Modified to Prevent Malaria Spread

A gene drive approach could be used to render mosquitos unable to spread malaria, researchers report in Science Advances.

Gut Microbiomes Allow Bears to Grow to Similar Sizes Despite Differing Diets

Researchers in Scientific Reports find that the makeup of brown bears' gut microbiomes allows them to reach similar sizes even when feasting on different foods.

Finding Safe Harbor in the Human Genome

In Genome Biology, researchers present a new approach to identify genomic safe harbors where transgenes can be expressed without affecting host cell function.

New Data Point to Nuanced Relationship Between Major Depression, Bipolar Disorder

Lund University researchers in JAMA Psychiatry uncover overlapping genetic liabilities for major depression and bipolar disorder.