Men and women may require different brain tumor therapy, study finds


Many cancers are known to have markedly different rates of incidence, and very different outcomes, in males and females. Among these are brain tumors, the most common of them being glioblastomas (GBM). These are the most aggressive tumors of the brain and occur at 60% higher rates in males, whether human or not. Now a startling new study published on the preprint server bioRxiv* in November 2020 tracks down these differences to a gene called Brd4, a transcriptome-wide regulator of gene expression.

Recently, it was recognized that disease susceptibility and clinical phenotype are determined not only by pathogenic and environmental factors but also by the sex of the patient. This is also true for lifestyle diseases, including metabolic conditions like cardiovascular and neurologic disease and cancer.

Sex-biased GBM biology

The new study explored differences in GBM biology in males and females to better understand underlying factors and pathways that drive the risk and course of tumors. Earlier, the researchers found that GBM cells in male mice were more vulnerable to cancerous change-inducing events and the effects of chemotherapy. Half of these differences were confirmed in human GBM.

A later study showed that differences in survival in treated human GBM patients were due to the underlying transcriptional programs modulated by sex-specific epigenetic changes, just as with normal sexual differentiation.

Brd4 and epigenetic modulation

The BET family of proteins is involved in regulating transcription by epigenetic reading and work together with target genes to which they recruit specific transcriptional complexes. Brd4 is a BET protein that reads acetylated histones H3 and H4 throughout the entire cell cycle and specifies its cell identity.

The enhancers bound to it may therefore be responsible for the fundamental sex-dependent differences in GBM. Moreover, Brd4 inhibition is being increasingly targeted by drugs for epigenetic modulation of growth in many cancers. It is found to be unregulated in many cancers. It enhances many processes such as epithelial-to-mesenchymal transition, conversion to a stem cell-like profile, and pluripotency.

Sex-dependent Brd4-bound enhancers

The current study shows that the sex differences in the tumor phenotype vary with the effect of the enhancer regulatory molecule bound to Brd4 on the course of stem cell-like differentiation in male and female GBM cells. Inhibition of Brd4 by genetic and pharmacological factors also varies in males and females, both in vivo and in vitro. Thus, GBM cells in males are less likely to form new clones and tumors are less likely to grow, following Brd4 inhibition. The opposite occurs in female cells and tumors.

The researchers found that Brd4 binding sites were at regions with a high density of H3 acetylation. Of the Brd4-bound enhancers, a fifth (around 2,800) bound more Brd4 in males, while the same proportion bound more of the protein in female GBM cells. Of the former, 0.13% were on the Y chromosome and 3.11% on the X chromosome. Of the latter, 4.29% were located on the X chromosome. The researchers comment, “The observed differences in Brd4-bound enhancers are not simply due to differential Brd4 enhancer enrichment on sex chromosomes.” In fact, this is the first time that male- and female-biased Brd4-bound enhancer use has been shown in any type of cell.

The researchers also found that Brd4-bound genes were regulated differently by males and females; in around 1,300 genes, about 52% were expressed more often in males. The pathways most often regulated by these genes involve core cancer pathways, which are therefore differently regulated in the sexes. Not only are the transcriptional programs leading to tumor formation different between males and females, but their binding by Brd4-enhancers is also dependent on the sex.

Response to BET- inhibitors

The response to small molecule inhibitors of BET proteins in male GBM cells was at reduced clonogenic cell frequency, but in females, it was increased. That is, the sex differences were reduced by Brd4 inhibition because of the responses which occurred in opposite directions. The drugs reduced tumor growth in males but increased it in females.

The authors point out, “These results demonstrate for the first time that the sex differences in the tumorigenic phenotype we observe in our murine GBM cells are mediated by differential Brd4-bound enhancers and that the response to BET inhibition is sex-dependent.”

Similar results were later obtained with human GBM cells. Thus, not only the biology of these tumors but their response to therapeutic drugs is sex-dependent.

Earlier studies showed that women with ER-positive breast or endometrial cancer had poor survival odds if Brd4 expression was low, but in men with prostate cancer, the same marker indicated better survival.

Transcription factors concerned with oncogenesis and stem cell-like development were enriched at male-biased Brd4-bound enhancers, but at female-biased Brd4-bound enhancers were bound to tumor suppressor genes such as p53. Thus, this gene is apparently able to promote tumor formation in male GBM but to suppress it in female GBD.

Implications

Further study will be needed to understand the master transcriptional regulators which bind to Brd4, directly or indirectly, to determine where it occurs in the genome. However, the study showed that Brd4 is found in the same location as Myc and p53, in male and female GBM cells, respectively.

The authors conclude: “We have identified sex-biased Brd4-regulated genes and pathways, which could translate into new and promising therapeutic targets to enhance survival for all GBM patients and potentially other cancers that exhibit substantial sex differences in incidence or outcome.”

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.



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Dartmouth receives $2.5 million to develop device for detecting tumor left behind during surgery



Dartmouth engineers have been awarded a $2.5 million grant from the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), to develop and test a device–a microendoscopic electrical impedance sensing probe– that could be used by surgeons to detect prostate cancer still left in the body during surgery.

Currently, 6.5 to 32 percent of patients undergoing radical prostatectomy each year come out of surgery with positive surgical margins (PSMs), according to a 2014 European Urology study, meaning cancer is still left in the body, increasing the likelihood of disease recurrence. These patients often choose to undergo radiation, hormonal therapy, or chemotherapy to treat the leftover disease, which can lead to physical and/or financial hardship.

We’re really trying to augment and improve a patient’s quality of life following surgery, and intraoperatively detecting positive surgical margins will help to make that a reality. One of the things this approach might allow is for surgeons to be more aggressive in nerve-sparing procedures because they can check that margin after they’ve done the procedure to see if there’s cancer left behind.”

Ryan Halter, Principal Investigator, Professor of Engineering and of Surgery at Dartmouth

Halter has developed similar technology at his private technical service company, RyTek Medical, and has previously won a grant award for an early prototype of this device. However, the new grant will fund the first large study in humans using an optimized version of the device, which will be miniaturized and integrated within a surgical probe to allow for a better signal and clearer data.

During the first year of the five-year grant period, Halter and the team, which includes Dartmouth engineering and medical colleagues and students, will optimize the device. Starting in the second year, the device will be deployed intraoperatively – meaning during surgery – in a cohort of 200 men. In the operating room, members of the Dartmouth team will conduct real-time data acquisition to identify possible PSMs while a surgeon manipulates the probe.

“Currently, there is no way to test for the presence of surgical margins in the operating room. The ability to identify, and subsequently address, positive surgical margins in real-time will be a game-changing advancement in the surgical treatment of prostate cancer,” said Lawrence Dagrosa, professor of surgery and a specialist in urological oncology at Dartmouth-Hitchcock Medical Center.

Halter believes the device will be especially helpful to patients with larger PSMs, who are more likely to have a reduced quality of life, but notes that the tool may not be able to provide the same level of resolution that can be determined microscopically, which is the approach normally used today. Importantly, microscopic evaluation can only determine PSMs after surgery has concluded, meaning a patient with cancer still left in the body might be encouraged to seek treatments such as chemotherapy.

Should the human studies be successful, Halter foresees conducting larger clinical trials and investigating further applications for the device beyond radical prostatectomy, such as for kidney, breast, and brain surgery.



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