Clinical OMICS

MAR-APR 2019

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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Page 48 of 51 March/April 2019 Clinical OMICs 47 patients' tumors," said Rubin in the press release associated with the study. To do this, the researchers applied a computational algo- rithm to male and female GBM transcriptome data and identified sex-specific gene expression patterns of GBM. They determined that survival in males is correlated with the regulation of cell division through the expression of cell cycle regulators and the critical determinant in females was expression of integrin signaling pathway components to regulate invasiveness. The clinical relevance of these molecular signatures was further established through in vitro drug screens that looked at the effect of four commonly used chemotherapy drugs on gene expression in a panel of male and female patient-de- rived GBM cell lines. Both sexes showed a clear correlation. Rubin said that the impetus for studying sex differences in GBM comes from his own neuro-oncology practice, where he sees that improvements in GBM treatments are among the most pressing unmet needs in neuro-oncology. Although Rubin expected to find sex differences, he was surprised by how well each evaluation complemented the others, noting that "it made for a coherent story that increased my confi- dence in it." Ostrom's prior work, including a paper published on Jan. 1 in Neuro-oncology entitled, "Sex-specific gene and pathway modeling of inherited glioma risk," on which Rubin is also an author, focuses on the identification of genetic differences between males and females in susceptibility to glioma. One of the most exciting aspects of this work, accord- ing to Ostrom, is the finding of sex difference in treatment response as measured via MRI imaging. She explained that, "the results of gene expression analyses further suggest that females have increased sensitivity to chemotherapy." Taken together, the work suggests that there are both substantial incidence (risk of disease) and survival (clinical outcomes) differences by sex and that sex affects both sus- ceptibility to this disease as well as the disease process in individuals who develop these tumors. In Ostrom's own research, analyzing epidemiological data derived from state cancer registries, they have shown that sex differences in sur- vival are largest when the dataset is limited only to those that have received chemotherapy and radia- tion. These new findings suggest to her that the sex difference they have seen in those analyses may be due to biological treatment response that varies by sex. She was surprised to see that there were no differ- ences in survival by tumor growth velocity in males, especially considering that there are nearly twice as many males included in this study. These sex differences in treatment response have the potential to have significant clinical implications, and should be a topic for future study. Rubin is excited to be providing a strong rationale for prospectively evaluating sex differences in response to stan- dard and novel treatments for GBM and possibly other can- cers. The results also suggest to him that diagnostic criteria and disease response measures might need to be tailored to the sex of the patients and that lab-based investigations of cancer biology should be designed to detect sex differ- ences in mechanisms and response to therapeutics. His hope is that this work will change the way that doctors think about treating GBM and other cancers in a sex-specific way, improving outcomes for all. Rubin's team is actively pursuing both clinical and lab- based investigations with a large focus on sex differences in epigenetics and metabolism, the latter providing the ratio- nale for a new clinical trial they opened using ketogenic diet and chemotherapy for children with recurrent brain tumors. In the trial, they will be collecting data to determine whether there are differences in ketosis and disease response in boys and girls. "It is highly likely that by conducting experiments that do not incorporate sex, researchers are missing potentially important findings if these biological mechanisms vary by sex," noted Ostrom. She hopes that this work will encour- age people to consider the importance of sex in disease pro- cesses, noting that we are limiting ourselves by thinking of sex differences as being largely attributable to differences in circulating sex hormones, because there are numerous ways that sex affects biology—all of which are important to consider. Quinn Ostrom, Ph.D., Duncan Cancer Center at the Baylor Col- lege of Medicine "This analysis by Yang et al. demonstrates that there are identifiable biological differences between males and females with GBM that contribute to these differences." —Quinn Ostrom, Ph.D.

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