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This Week in Cancer Research: Apr 6, 2012

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In Cancer Research this week, researchers at the University of Michigan explore PARP-1 inhibition as a targeted treatment for Ewing's sarcoma. The team found that the products of gene fusions that characterize Ewing's sarcoma interact with PARP-1, and that the sarcoma's cells are sensitive to PARP-1 inhibition. "Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1–driven mouse xenograft model of [Ewing's sarcoma]," the authors write." Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines."

Also in Cancer Research this week, researchers in Japan report the tumor cell–derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis. In mice, ANGPTL2 has been implicated in inflammatory carcinogenesis, and elevated levels of ANGPTL2 in patients with lung cancer are associated with reduction in disease-free survival after surgical resection, the team writes. "Transcription factors NFATc, ATF2, and c-Jun upregulated in aggressive tumor cells promoted increased ANGPTL2 expression," the researchers add. "Most notably, tumor cell–derived ANGPTL2 increased in vitro motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype." These findings suggest that ANGPTL2 drives metastasis, and inhibiting it could inhibit the metastatic process, they write.

Finally in Cancer Research this week, researchers in the US and Greece report an association between resistance to rapamycin and defective regulation of Skp2, a subunit of the ubiquitin protein ligase complex. "The ability of rapamycin to downregulate Skp2 … identifies tumors that are sensitive to rapamycin," the authors write. "RNA interference–mediated silencing of Skp2 in human tumor cells increased their sensitivity to rapamycin in vitro and inhibited the growth of tumor xenografts in vivo." These findings suggest that Skp2 levels are important in determining response to mTOR inhibitors like rapamycin, which could be an important pharmacogenomic marker, they add.

The Scan

Drug Response Variants May Be Distinct in Somatic, Germline Samples

Based on variants from across 21 drug response genes, researchers in The Pharmacogenomics Journal suspect that tumor-only DNA sequences may miss drug response clues found in the germline.

Breast Cancer Risk Gene Candidates Found by Multi-Ancestry Low-Frequency Variant Analysis

Researchers narrowed in on new and known risk gene candidates with variant profiles for almost 83,500 individuals with breast cancer and 59,199 unaffected controls in Genome Medicine.

Health-Related Quality of Life Gets Boost After Microbiome-Based Treatment for Recurrent C. Diff

A secondary analysis of Phase 3 clinical trial data in JAMA Network Open suggests an investigational oral microbiome-based drug may lead to enhanced quality of life measures.

Study Follows Consequences of Early Confirmatory Trials for Accelerated Approval Indications

Time to traditional approval or withdrawal was shorter when confirmatory trials started prior to accelerated approval, though overall regulatory outcomes remained similar, a JAMA study finds.