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Journal Watch

December 6, 2016

VUMC study: current cancer drug discovery method flawed

The primary method used to test compounds for anti-cancer activity in cells is flawed, Vito Quaranta, M.D., and colleagues reported May 2 in Nature Methods. The scientists developed a new metric to evaluate a compound’s effect on cell proliferation. The old system counted how many cancer cells were alive after 72 hours, but all cells don’t proliferate at the same rate.


Finding the smoking gun for tumor formation in breast cancer

Many genes are associated with cancer. The trick is proving they actually promote tumor formation. One approach, detailed by Ian Macara, Ph.D., and colleagues May 26 in Cell Reports, is an in vivo “gain of function” screen. They used a gene library to increase the expression of nearly 1,000 different genes in mouse mammary glands. Five genes that promoted tumor formation were identified, four of which were not previously known to be breast cancer genes.


Improving natural killer cancer therapy

Natural killer cells are a type of white blood cell that specifically recognize and destroy tumor cells. Eric Sebzda, Ph.D., and colleagues showed in a study published April 25 in the Proceedings of the National Academy of Sciences that a transcription factor called KLF2 is critical for natural killer cell expansion and survival.


Drug combo may be more effective with gliobastoma

A combination of two inhibitor drugs, gefitinib and an InsR/IGF1R inhibitor, was more effective than either agent alone against glioblastoma xenograft tumors in a mouse model. The findings by Jialiang Wang, Ph.D., and colleagues, reported in April 1 Clinical Cancer Research, suggest that combining therapies that block both pathways may be a promising treatment for EGFR-dependent glioblastoma.


Algorithm developed to track genomic instability in cancers

Molecularly heterogenous cancers such as triple negative breast cancer are challenging to treat because of their genomic instability. Timothy Shaver and Brian Lehmann, Ph.D., working with Jennifer Pietenpol, Ph.D., developed a new algorithm to predict gene arrangements reported Aug. 15 in Cancer Research.


New breast cancer driver identified and studied

Approximately 20 percent of breast cancers have overexpression of the protein HER2, which drives signaling by the protein kinase Akt and is a marker of aggressive disease. The protein complex Rictor/mTORC2 is known activator of Akt, but its role in breast cancer formation, progression and treatment is unclear. Rebecca Cook, Ph.D., and colleagues demonstrated its role in a report Aug. 15 in Cancer Research.


Restore T cells to fight leukemia

Acute and chronic B cell leukemia can promote T cell “exhaustion,” which contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms by which leukemia promotes T cell dysfunction are poorly understood, however. Jeffrey Rathmell Ph.D., and Peter Siska, M.D., at Vanderbilt University and colleagues at Duke University and the Netherlands reasoned that impaired T cell function in leukemia may result from altered metabolism. In a study published Sept. 21 in Journal of Immunology, they show that T cells in leukemia patients and leukemia-bearing animals are metabolically suppressed partly through the upregulation of PD-1, which turns down T cell activation.


Proliferative capacity of neuroblastoma

Neuroblastoma is a neural crest cell-derived extracranial solid cancer that affects infants and young children. The most vigorous of these cancers spreads through self-renewing cancer stem cells. Knowing the nature of these cells is essential to understanding the progression of neuroblastoma and devising the right treatment strategy. Reporting in the journal Biochemical and Biophysical Research Communications, Dai Chung, M.D., and colleagues use a technique called “limiting dilution analysis” to show that the frequency with which neuroblastoma stem cells form spheres in suspension cultures accurately quantifies their stemness, or ability to “self-renew.” Cell lines formed spheres more frequently when the MYCN oncogene was overactive. Retinoic acid, used clinically to induce differentiation of residual disease after chemotherapy and radiation, almost blocked sphere formation entirely, while fibroblast growth factor (FGF) promoted sphere formation. Limiting dilution analysis is an accurate method of quantifying sphere-forming frequency, and should be adopted as an effective way to assess the stemness or proliferative capacity of neuroblastoma stem cells, they concluded.


Superior scan for tumors

While relatively rare, tumors of neuroendocrine cells, which release hormones in response to neuronal signals, have been difficult to diagnose and treat. Now Ronald C. Walker, M.D., and colleagues have reported that PET/CT imaging using the radionuclide Gallium-68 combined with DOTATATE, a compound that binds to these types of tumor cells, is safe and clearly superior to the current standard for imaging these tumors, Indium-111 combined with pentetreotide. Gallium-68/DOTATATE imaging has been in widespread clinical use outside the United States for nearly a decade. But the study, published last month in the Journal of Nuclear Medicine, is the first to report quantitative toxicity data establishing the safety of the technique.