Recent Publications by VICC Researchers
May 21, 2014
Vanderbilt-Ingram Cancer Center is committed to conducting innovative, high-impact, basic, translational and clinical research with the greatest potential for making a difference for cancer patients, today and in the future. Here’s a sampling of work published in peer-reviewed journals by Cancer Center investigators in 2013-2014:
Study sheds light on DNA replication
During the more than ten thousand trillion cell divisions over the course of a human lifetime, mistakes happen. These mistakes—and the failure to correct them—leave mutations in the genome, which cause cancer and other diseases, including inherited neurodegenerative and developmental diseases. David Cortez, Ph.D., and colleagues described how parts of the DNA replication machinery work in papers in the June 27, 2013, issue of Cell Reports and in the July 15, 2013, issue of Genes & Development. The investigators focused on the replication stress response machinery – the group of proteins that senses damage in the DNA and enables DNA repair so that copying can proceed. This machinery, and the master regulator protein ATR in particular, is considered a good target for cancer therapies.
Therapeutic target for gastric cancer
Chronic inflammation contributes to the development of gastric cancer, the second leading cause of cancer-related deaths worldwide. Aurora kinase A (AURKA) is frequently overexpressed in gastrointestinal and other cancers, but its roles in inflammation and tumorigenesis are unclear. Wael El-Rifai, M.D., Ph.D., and colleagues have linked AURKA overexpression to inflammation. They demonstrated that increased AURKA expression correlates with increased levels of pro-inflammatory molecules in a mouse model that develops gastric cancer, and in gastric tissue samples from patients with pre-malignant and malignant lesions. Inhibition of AURKA reversed the development of gastric tumors in the mouse model. The findings, reported in the December issue of Gastroenterology, highlight the importance of AURKA in gastric tumorigenesis and support the potential of AURKA inhibitors as therapeutic agents for gastric cancer.
Predictor of prostate cancer outcomes identified
Prostate cancer is the second leading cause of cancer-related deaths among North American men. Andries Zijlstra, Ph.D., and colleagues identified a biomarker for a cellular switch that accurately predicts prostate cancer progression and outcomes. In prostate cancer cell lines, the Vanderbilt team discovered CD151free, a form of the CD151 protein that is free of its normal adhesion partner (integrin). Reporting in the Jan. 1 issue of Cancer Research, the Vanderbilt team and their Alberta colleagues found that cancers recurred and spread earlier in patients who tested positive for CD151free, compared to those without detectable levels of the protein. This could be a universal mechanism important for cancer progression. An antibody test for clinical use is being developed.
VU study identifies new gene fusions in melanoma
Researchers, led by Jeffrey Sosman, M.D., William Pao, M.D., Ph.D., and Katherine Hutchinson, have identified two novel gene fusions in melanoma that may respond to existing cancer therapies. The study in the Dec. 15 issue of Clinical Cancer Research focused on the 35 percent of melanomas that do not have a driver gene mutation such as BRAF. Using a human melanoma, investigators found an unusual fusion between two genes, BRAF and PAPSS1. In melanomas from 51 additional patients, they found a second novel BRAF fusion, TRIM24-BRAF. Engineered fusion-bearing cells were treated the cells with a BRAF inhibitor and trametinib, a drug that inhibits the MEK protein. The fusion-induced signaling did not respond to the BRAF inhibitor but was inhibited by trametinib. This suggests that cells with novel fusions may respond to MEK inhibitors.
Cancer cells combine tools to increase invasiveness
Two features of invasive cancer cells—invadopodia and exosomes—are linked, Vanderbilt investigators reported in the Dec. 12 issue of Cell Reports. Alissa Weaver, M.D., Ph.D., and colleagues discovered that invadopodia—cell surface structures that “drill” into the surrounding matrix—act as docking and secretion sites for exosomes, bubble-like packets that carry tumor growth and survival factors. Recent studies have demonstrated that tumors secrete a lot of exosomes, and that they contribute to tumor survival and aggressive behavior. Weaver and her team linked exosome secretion to invadopodia and demonstrated that the two are interdependent. Blocking the formation of invadopodia reduced exosome secretion and vice versa. The findings may offer new therapeutic opportunities to limit the aggressiveness of tumors by targeting invadopodia formation to reduce exosome secretion.
New approach may halt glioblastoma’s ability to grow
H. Alex Brown, Ph.D., Craig Lindsley, Ph.D., and colleagues have discovered a “backdoor” approach to blocking an enzyme that fuels the growth of glioblastoma, the most common and fatal form of brain cancer. Their finding in glioma cell cultures, published Jan. 10 in the Journal of Biological Chemistry, could lead to more effective treatments with fewer side effects. The researchers developed the first isoenzyme-selective inhibitors of the enzyme phospholipase D, which regulates the oncogenic enzyme, Akt. When these small molecules bound to an allosteric, or secondary, binding site on the isoenzyme PLD2, the enzyme was blocked, the form of Akt most associated with tumor growth was not activated and the cells died. Additional work in mice showed the approach could shrink tumors without causing side effects elsewhere.
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