Glioblastoma with extreme nuclear enlargement.
Glioblastoma with extreme nuclear enlargement.

A new study by researchers at the Washington University School of Medicine in St. Louis suggest that tailoring treatments to men and women with glioblastoma, based on the molecular subtypes of their tumors, may help improve survival.

The study, supported by National Institutes of Health (NIH),? the Children?s Discovery Institute of Washington University, Joshua?s Great Things, the James S. McDonnell Foundation, Mayo Clinic and the Ben & Catherine Ivy Foundation, helped researchers identify distinct molecular signatures of glioblastoma in men and women that help explain such underlying disparities in between men and women and their response to treatment and survival.

Man vs. Woman
Sex differences are recognized as important determinants of human health and disease. And scientists have, for decades, recognized epidemiological data confirming sex differences the incidence of cardiovascular disease, disorders of the immune system, depression, addiction and asthma.

And while the differences in incidence, disease phenotype, and outcome are generally well described and recognized, the molecular bases, beyond acute hormone actions, are poorly understood.

Overall, scientists have also recognized that more man get cancer, and die of the disease, than women. This is true for many types of cancer, including the deadly brain tumor glioblastoma.

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The findings are published January 2. 2019 edition of Science Translational Medicine.

?It is our expectation that this study could have an immediate impact on the care of patients with glioblastoma and further research, as the findings indicate we should be stratifying male and female glioblastoma into risk groups and evaluating the effectiveness of treatment in a sex-specific manner,? said Joshua B. Rubin, MD, Ph.D, a Washington University professor of pediatrics and of neuroscience and the study?s co-senior author.

?The biology of sex differences and its applications in medicine are highly relevant but almost always ignored aspects of personalized treatments.?

Glioblastoma is the most common malignant brain tumor and kills about half of patients within 14 months of diagnosis. The disease It diagnosed nearly twice as often in men compared to women.

The tumor is most often diagnosed in people over age 50, and standard treatment is aggressive ? surgery, followed by chemotherapy and radiation. However, stubborn stem cells often survive and continue to divide, producing new tumor cells to replace the ones killed by treatment. Most tumors recur within six months.

Studying adults with glioblastoma, the researchers found that standard treatment for glioblastoma is more effective in women than men.

Understanding gender differences
To help understand such gender differences in treatment response, the researchers, including Kristin R. Swanson, Ph.D, a mathematical oncologist at the Mayo Clinic, measured tumor growth velocity in standard MRI scans.

?Basically, you can look at tumor growth velocity while patients are undergoing treatment and derive a value for how fast their tumors are growing,? said Rubin, who also is co-founder and co-director of the Pediatric Neuro-Oncology Program at St. Louis Children?s Hospital, where he treats patients. ?This gives you an opportunity to think more deeply about whether the drug you?re giving a patient is actually helping.?

The researchers culled patient MRI scans and survival data from a cancer research database. They then calculated tumor growth velocity every two months for the duration of therapy in 63 glioblastoma patients ? 40 males and 23 females ? who received standard chemo-radiation treatment following surgery. While initial tumor growth velocities were similar between females and males, only the females showed a steady and significant decline in tumor growth after treatment with temozolomide, the most common chemotherapy drug used to treat glioblastoma.

Response to treatment
?[Men] did not respond as well, and we wanted to understand why, so we looked at the underlying genetics of patients? tumors,? said Rubin, a co-leader of the Solid Tumor Therapeutics Program at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

The researchers tapped into The Cancer Genome Atlas (TCGA) ? a project launched in 2005 to pursue the genetic basis of cancer and funded by the National Cancer Institute and National Human Genome Research Institute, both of the National Institutes of Health (NIH).

Led by the study?s co-senior author Jingqin ‘Rosy’ Luo, Ph.D, a Washington University associate professor of surgery in the Division of Public Health Sciences, and the study?s lead author, Wei ‘Will’ Yang, Ph.D, a Washington University bioinformaticist in the Department of Genetics, the researchers applied sophisticated statistical algorithms to distinguish male- or female-specific gene expression patterns from such patterns that were shared among the male and female patients. The team then focused on the gender-specific gene expression to identify molecular subtypes that corresponded to differences in survival for males and for females.

Gender and survival
?We observed tremendous genetic sex differences in the tumors of glioblastoma patients that correlated with survival,? Luo noted.

?All evidence supports the need to define these distinctions and incorporate the sex differences into glioblastoma biology research and treatment,? he further explained.

The researchers were able to show that the tumors of patients with glioblastoma cluster into 10 distinct subtypes – five for tumors in men and five for tumors in women. The clusters are distinguished by gene activity and survival. For example, women with tumors in one such cluster survived longer than women with tumors in any of the other four clusters ? just over three years compared with just over one year. Similarly, they found a male cluster linked to longer survival ? just over 18 months compared with just over one year for men with tumors in the other clusters.

The researchers validated the clusters in three additional data sets and also showed that even genes activated at similar levels in tumors in males and females can result in substantial sex-specific effects on survival.

?[We also] identified genetic pathways that correlated with the longest survival, and they were very different in [men] compared [to women],? Rubin said.

?For example, in males survival was all about regulating cell division, which suggests that drugs that block cell-cycle progression may be more effective in men. For women, survival was all about regulating invasiveness, which suggests that drugs targeting integrin signaling may be more effective in women. This tells us it might be better to separate men and women and examine their gender-specific genetic signatures.,” Rubin explained

“We tested this hypothesis by doing a series of in vitro drug screens in which we took four relatively common chemo drugs and looked at how the expression of these genes correlated with response to those drugs. In both males and females, there was a clear correlation,” he added

Among diseases in general, gender differences are often tied to hormones. For example, the female hormone estrogen contributes significantly to more women getting breast cancer than men.

“However, with glioblastoma diagnosis and survival, sex hormones did not directly contribute to female and male differences,” Rubin said.

?The sex-specific genetic activity in glioblastoma is not dependent on the acute actions of circulating sex hormones as differences are evident across all stages of life,? he added.

?In a broader sense, I [hope that] our research [encourages] people to think more about how diseases affect men and women in different ways, making it the norm and not the exception,? Rubin observed.

?I hope the research will inspire more specific approaches to treatments. It may be that we shouldn?t be using the same criteria when treating diseases in males and females, and as a next step we should definitely develop and evaluate sex-specific treatment regimens for glioblastoma,? he added.

In addition to researchers at Washington University and the Mayo Clinic, scientists at the Cleveland Clinic, Case Western Reserve University and TGen, a genomics research institute, also contributed to the study.

Yang W, Warrington NM, Taylor SJ, Whitmire P, Carrasco E, Singleton KW, Wu N, Lathia JD, et al. Sex differences in GBM revealed by analysis of patient imaging, transcriptome and survival data. Science Translational Medicine. 2019 Jan 2;11(473). pii: eaao5253. doi: 10.1126/scitranslmed.aao5253. PMID: 30602536 [Article]

Last Editorial Review: January 4, 2019

Featured Image: Glioblastoma with extreme nuclear enlargement and very high magnification. Courtesy: ? 2010 ? 2019 Fotolia. Used with permission.

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