Journal Watch
May 22, 2018
Novel anti-cancer drug resistance mechanism identified
Vanderbilt investigators have discovered a novel nongenetic cause of resistance to cetuximab, a mainstay of treatment for advanced colorectal cancer. The findings of Robert Coffey Jr., MD, and colleagues, published Oct. 16, 2017, in Nature Medicine, suggest a strategy for overcoming this resistance, which their research indicates is due to an epigenetic mode instead of a mutation in genes. They discovered that increased expression of an RNA molecule resulted in increased Wnt signaling, which is known to promote cell proliferation. Blocking Wnt may help avoid resistance to cetuximab.
A new way to starve cancer
Vanderbilt researchers have demonstrated for the first time that it is possible to starve a tumor and stop its growth with a newly discovered small compound that blocks uptake of the vital nutrient glutamine. The findings by Charles Manning, PhD, and colleagues, reported Jan. 15 in Nature Medicine, lay the groundwork for development of potential “paradigm shifting” therapies targeting cancer cell metabolism that could be monitored non-invasively by positron-emission tomography (PET) imaging. They went one step further by developing V-9302, the first highly potent small molecule inhibitor of a glutamine transporter.
Boosting breast tumor immune response
Scientists are trying to make breast tumors more responsive to immunotherapy by increasing their visibility to the immune system. Research by Justin Balko, PhD, PharmD, and colleagues, published Jan. 16, in Nature Communications suggests that targeting specific molecules in the tumor called methylating agents can turn up the immune response.
Targeting the receptors for colorectal cancer
Selective targeting of the Wnt pathway may be an effective therapy for the treatment for the vast majority of colorectal cancers, according to research by Kenyi Saito-Diaz, a postdoctoral trainee in the lab of Ethan Lee, MD, PhD, and colleagues. The research published March 12, in Developmental Cell sheds light on why mutations in the tumor suppressor adenomatous polyposis coli (APC) lead to such potent stimulation of the Wnt pathway and cancer, and how researchers could potentially target APC-mutant cancers.
Searching out pancreatic cancer risk
A prospective study by Wei Zheng, MD, PhD, MPH, and colleagues delivers the first direct epidemiological evidence that increased production of a chemical compound called prostaglandin E2 (PGE2), as measured by metabolites in urine (PGE-M), is associated with increased pancreatic cancer risk. The study, published Aug. 29, 2017, in International Journal of Cancer suggests this compound might serve as a biomarker to predict pancreatic cancer risk.
Boosting sarcoma cell death
Ewing sarcomas — rare, aggressive childhood cancers — are derived from mesenchymal cells in bone and soft tissues, and children with metastatic disease have poor survival. In a search for new therapeutic options for Ewing sarcoma, Dai Chung, MD, and colleagues tested a compound, ML327, previously identified at Vanderbilt that induces the expression of the cell adhesion protein E-cadherin. This protein, which binds cells together, is often lost as cancer cells become invasive. Now the investigators have demonstrated that ML327 increases E-cadherin in Ewing sarcoma cells. The compound also increased cell death and had additive effects with a cell death-inducing ligand called TRAIL that has been tested for Ewing sarcoma. The findings reported in the Sept. 16, 2017, issue of Biochemical and Biophysical Research Communications support further study.
Calcium intake and colorectal cancer
Previous studies exploring the relationship between dietary calcium intake and colorectal cancer have had contradictory results, perhaps due to no consideration of variation in calcium reabsorption by the kidney. Qi Dai, M.D., Ph.D., and colleagues examined how variation in genes involved in calcium reabsorption related to the risk of colorectal adenoma (pre-cancer lesion) in patients enrolled in the Tennessee Colorectal Polyp Study. They found that variants in a sodium-calcium exchanger protein interacted with calcium intake in colorectal adenoma risk. They further found that carriers of variants in two of three calcium reabsorption genes with calcium intake above 1000 mg/day were up to 57 percent less likely to have adenomas compared to those with lower calcium intake. The findings, reported in the October issue of Molecular Carcinogenesis, suggest a protective effect of calcium intake in individuals with certain gene variants and may provide a new approach for personalized prevention of colorectal adenoma and cancer.
New target for neuroblastoma
Neuroblastoma — a cancer that starts in nerve tissue outside of the brain — is the third most common cancer in children and accounts for about 15 percent of pediatric cancer-related deaths. Sirtuins, (SIRTs), a family of proteins with roles in metabolism, aging and genomic stability, have been linked to various cancers but their role in neuroblastoma has not been explored. Dai Chung, MD, and colleagues discovered that one type, SIRT6, promotes neuroblastoma cell growth. Their findings reported in the February 2018 issue of Anticancer Research suggest SIRT6 should be a target for new therapeutics for neuroblastoma.