Feature

Sex differences in glioblastoma could lead to tailored treatments, improved outcomes

Researchers at Washington University School of Medicine in St. Louis have identified distinct molecular signatures of glioblastoma that may explain differences in treatment responses and survival between men and women.

“[These results] 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,” Joshua B. Rubin, MD, PhD, professor of pediatrics, hematology and oncology, as well as professor of neuroscience, said in a press release. “The biology of sex differences and its applications in medicine are highly relevant but almost always ignored aspects of personalized treatments.”

HemOnc Today spoke with Rubin about his team’s research, as well as how stratifying patients and evaluating treatments in a sex-specific manner could enhance treatment quality and improve outcomes.

Question: Can you explain the study rationale?

Answer: I am a pediatric neuro-oncologist and my experience, as well as that of my colleagues who care for adults with brain tumors, prompted this research. We more frequently care for more males with malignant brain tumors. First, I looked into epidemiological data using the SEER and Central Brain Tumor Registry of the United States databases. Sure enough, more males than females are diagnosed with malignant brain tumors. Nearly everyone diagnosed with glioblastoma dies of the disease, but males tend to die faster than females. We then started examining sexual differentiation in the lab and the impact on malignant transformation. In parallel, we were working to rigorously describe the clinical observations.

 

Q: How did you conduct the study and what did you find?

A: We were fortunate to work with Kristin R. Swanson, PhD, a mathematical oncologist at Mayo Clinic, and colleagues and use an algorithm for interpreting standard MRI scans that allowed us to derive parameters related to tumor growth. Using this algorithm, we were able to establish that females with glioblastoma respond better to standard therapy than males, which we expected. We then applied a computational algorithm known as JIVE — which stands for Joint and Individual Variance Explained — to gene expression data sets. We were able to identify a significant number of genes whose expression differed between males and females and whose correlation with survival also differed. This allowed us to identify different molecular pathways in male and female patients with glioblastoma that appeared to predict survival.

 

Q: H ow could stratifying patients and evaluating treatments in a sex-specific manner help enhance treatment quality and improve outcomes?

A: I like to imagine eventually that — at the time of diagnosis — we will identify mutations, copy number variations and gene expression signatures that will allow us to think about personalized approaches to cancer treatment. However, these approaches will also incorporate patient sex, because the interpretation of how actionable something may be will likely depend on their sex. Even when genes are expressed at the same level between males and females, the correlation with survival could be different. For example, a low level may be associated with short or long survival for one sex and have no effect on survival for the other sex. What I hope comes out of this is an approach in which we incorporate sex into the kinds of decisions we make and for identifying drugs and treatment approaches that may be effective. This will require prospective clinical trials. The immediate impact of this study, I hope, is on the initiation of clinical trials that are appropriately powered to detect sex differences and response.

 

Q: What is next for research?

A: We opened a trial at St. Louis Children’s Hospital for children with recurrent brain tumors. We will use a combination of a ketogenic diet and chemotherapy. We will collect data for sex differences. This is based upon work that we published along with Joseph Ippolito, MD, PhD, instructor in radiology at Siteman Cancer Center, which — with the work of others — demonstrates that metabolism under normal conditions and cancer metabolism differ between males and females. This trial is possibly the first of its kind, with the aim of understanding how easy it is to induce ketosis in male and female patients, whether the depth of ketosis is equally achieved and how the depths of ketosis correlates with efficacy. I hypothesize that the ketogenic diet may be more effective in males compared with females because males tend to be more dependent upon glucose and glucose metabolism.

Q: Is there anything else that you would like to mention?

A: The NIH has a mandate to consider sex as a biological variable, which most grant writers and scientists take to mean that they have to conduct their experiments in equal numbers of male and female animals. However, what we are looking at is the interaction between sex and whatever the experiment is about. This means that we have to do a very specific power calculation that estimates the effect size for the sex difference and for the manipulation, and then calculate how many animals are needed of both sexes to detect that interaction. There is a lot of work being done where people are saying there is no sex difference, but they have not done an experiment to detect sex differences. They are just using equal numbers of male and female mice, which is inadequate. – by Jennifer Southall

 

References:

Rubin JB, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aao5253.

 

For more information:

Joshua B. Rubin, MD, PhD, can be reached at Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130; email: rubin_j@kids.wustl.edu.

 

Disclosure: Rubin reports no relevant financial disclosures.

Researchers at Washington University School of Medicine in St. Louis have identified distinct molecular signatures of glioblastoma that may explain differences in treatment responses and survival between men and women.

“[These results] 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,” Joshua B. Rubin, MD, PhD, professor of pediatrics, hematology and oncology, as well as professor of neuroscience, said in a press release. “The biology of sex differences and its applications in medicine are highly relevant but almost always ignored aspects of personalized treatments.”

HemOnc Today spoke with Rubin about his team’s research, as well as how stratifying patients and evaluating treatments in a sex-specific manner could enhance treatment quality and improve outcomes.

Question: Can you explain the study rationale?

Answer: I am a pediatric neuro-oncologist and my experience, as well as that of my colleagues who care for adults with brain tumors, prompted this research. We more frequently care for more males with malignant brain tumors. First, I looked into epidemiological data using the SEER and Central Brain Tumor Registry of the United States databases. Sure enough, more males than females are diagnosed with malignant brain tumors. Nearly everyone diagnosed with glioblastoma dies of the disease, but males tend to die faster than females. We then started examining sexual differentiation in the lab and the impact on malignant transformation. In parallel, we were working to rigorously describe the clinical observations.

 

Q: How did you conduct the study and what did you find?

A: We were fortunate to work with Kristin R. Swanson, PhD, a mathematical oncologist at Mayo Clinic, and colleagues and use an algorithm for interpreting standard MRI scans that allowed us to derive parameters related to tumor growth. Using this algorithm, we were able to establish that females with glioblastoma respond better to standard therapy than males, which we expected. We then applied a computational algorithm known as JIVE — which stands for Joint and Individual Variance Explained — to gene expression data sets. We were able to identify a significant number of genes whose expression differed between males and females and whose correlation with survival also differed. This allowed us to identify different molecular pathways in male and female patients with glioblastoma that appeared to predict survival.

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Q: H ow could stratifying patients and evaluating treatments in a sex-specific manner help enhance treatment quality and improve outcomes?

A: I like to imagine eventually that — at the time of diagnosis — we will identify mutations, copy number variations and gene expression signatures that will allow us to think about personalized approaches to cancer treatment. However, these approaches will also incorporate patient sex, because the interpretation of how actionable something may be will likely depend on their sex. Even when genes are expressed at the same level between males and females, the correlation with survival could be different. For example, a low level may be associated with short or long survival for one sex and have no effect on survival for the other sex. What I hope comes out of this is an approach in which we incorporate sex into the kinds of decisions we make and for identifying drugs and treatment approaches that may be effective. This will require prospective clinical trials. The immediate impact of this study, I hope, is on the initiation of clinical trials that are appropriately powered to detect sex differences and response.

 

Q: What is next for research?

A: We opened a trial at St. Louis Children’s Hospital for children with recurrent brain tumors. We will use a combination of a ketogenic diet and chemotherapy. We will collect data for sex differences. This is based upon work that we published along with Joseph Ippolito, MD, PhD, instructor in radiology at Siteman Cancer Center, which — with the work of others — demonstrates that metabolism under normal conditions and cancer metabolism differ between males and females. This trial is possibly the first of its kind, with the aim of understanding how easy it is to induce ketosis in male and female patients, whether the depth of ketosis is equally achieved and how the depths of ketosis correlates with efficacy. I hypothesize that the ketogenic diet may be more effective in males compared with females because males tend to be more dependent upon glucose and glucose metabolism.

Q: Is there anything else that you would like to mention?

A: The NIH has a mandate to consider sex as a biological variable, which most grant writers and scientists take to mean that they have to conduct their experiments in equal numbers of male and female animals. However, what we are looking at is the interaction between sex and whatever the experiment is about. This means that we have to do a very specific power calculation that estimates the effect size for the sex difference and for the manipulation, and then calculate how many animals are needed of both sexes to detect that interaction. There is a lot of work being done where people are saying there is no sex difference, but they have not done an experiment to detect sex differences. They are just using equal numbers of male and female mice, which is inadequate. – by Jennifer Southall

PAGE BREAK

 

References:

Rubin JB, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aao5253.

 

For more information:

Joshua B. Rubin, MD, PhD, can be reached at Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130; email: rubin_j@kids.wustl.edu.

 

Disclosure: Rubin reports no relevant financial disclosures.

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