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Yale researchers have found that Mendelian randomization, a widely used scientific method for analyzing experiments, can be reversed to yield a more robust predictive index in future trials of prostate cancer drugs. The work appears in Molecular & Cellular Prostate Cancer.

Years of mouse research in the laboratory of James Chaymor, senior author of the study, put him at the forefront of transforming biology. Over the past decade, he and Yoni Freedhoff, the study leader, have re-engineered human brain cells, or gliocytes, to produce the typical response to hormones such as androgen.

The novel combination of genetic manipulation, epigenetic changes, and drug delivery into the glial cell reservoir is called Mendelian randomization. Mendelian randomisation involves giving several genes, or genes that codes for proteins, specific factors that are more or less likely to be effective or toxic in each individual. Indeed, one gene that is more effective is multiplied less often than another, boosting the effect of a gene. By using Mendelian randomization as a model, researchers were able to precisely determine gene activity and cell responses by first trying different combinations until a gene mutation becomes random, leading to lower activation or activation of a drug. Ultimately, they were able to “reorder” the genes, producing a personalized test that could map malignity to a candidate gene.

Previous studies have shown that Mendelian randomization of cancer metabolism is highly effective and of both utility and ethical issues. In spite of this evidence of utility and cost savings over and above patient safety with programs of reduced FDA-required toxicology testing than what can currently be done in clinical trials, the technology needs to be adopted more widely in clinical trials.

To address this gap, a team of researchers led by Alfred Flouwen, senior author of the study and Head of the Flouwen Lab at Yale, previously treated human embryonic bone marrow and mesenchymal stromal cells with a final dose of estrogen (∆9-tetrahydrocorticosterone) as a first-line endocrine treatment for male breast cancer and pancreatic cancer in preclinical models.

They then tested the predictive accuracy of the assay with dose-controlled human prostate cancer cells.

We then performed similar assays on human glioblastoma cells which were treated with estradiol (α-estradiol), an estrogen hormone. The Nobel Prize-winning assay was initially created to test the detection of estrogen and pregnancy hormones in women, but we thoroughly rejected the idea of a universally used test to distinguish early embryo hormone from later hormone producing cells (derived cells from the testis), since estrogen cannot reliably detect endocrine-modulating hormones.”

James Chaymor, Senior Author, Yale Molecular & Cellular Prostate Cancer Center.

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