Investigators at Cedar-Sinai Cancer are spearheading a project, funded by a five-year, $11.2 million grant from the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), to advance scientific knowledge of how biological differences between men and women affect bladder cancer.[1]

Xue Li, Ph.D.

Based on the outcome of the study, the investigators hope to use this knowledge to shape therapies and improve patient outcomes.

“As part of this work, we also hope to define the fundamental principles that influence cancer risk, and to promote cancer research so that investigators begin to take male and female differences into consideration,” said Xue Li, Ph.D., principal investigator of the project and co-leader of the Cancer Biology Program at Cedars-Sinai.

“We can no longer treat males and females as asexual and ignore these differences.”

More common in men
Bladder cancer ranges from unaggressive and usually noninvasive tumors that recur and commit patients to long-term invasive surveillance, to aggressive and invasive tumors with high disease-specific mortality.[2]

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Even after adjusting for environmental factors such as smoking Bladder cancer is three to five times more common in men than in women.

“We chose to focus on bladder cancer because the difference in rates between men and women is so dramatic,” Li said.

Beyond bladder cancer
The difference in incidence isn’t limited to bladder cancer, however.

“Liver, skin, colon, lung, brain and pancreatic cancers are also more prevalent in men than in women, so this is only the beginning of our efforts to understand these important nuances,” Li said.

The award is a Program Project Grant, a type that is awarded to multidisciplinary teams with shared objectives. Li said it is only the second Program Project Grant for the study of sex as a biological variable that the NCI has awarded in its history.

Dan Theodorescu, MD, Ph.D.

“We have made efforts to build a world-class research and clinical program in bladder cancer,” said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “Dr. Li has made a significant contribution since joining Cedars-Sinai, and we are eager to see his research efforts continue to unfold.”

Three research teams–two at Cedars-Sinai and one at The Ohio State University Comprehensive Cancer Center–will each examine sex as a sex in bladder cancer from a unique standpoint.

Epigenetics
The X. Li Lab at Cedars-Sinai will examine epigenetic factors that might contribute to the greater prevalence of bladder cancer in men versus women. Epigenetic factors are not part of genes, but can change the way that genes work. Epigenetic factors might influence cells’ vulnerability to being transformed into cancer cells, or might influence the immune system, creating an environment that allows cancerous tumors to grow.

Genetics
The Theodorescu Lab at Cedars-Sinai will focus on the role of the Y chromosome, the male-determining sex chromosome, in bladder cancer. Loss of the Y chromosome (LOY) happens as men age and when they are exposed to carcinogens such as cigarette smoking (and other forms of tobacco use). LOY in cancer cells allows them to evade the immune system, but also makes them vulnerable to a common treatment called immune checkpoint therapy.

Immunology
The Zihai Li Lab  at the James Comprehensive Cancer Center at The Ohio State University will investigate how signaling of the sex hormone androgen may exhaust immune cells called T-cells. This exhaustion could result in more aggressive cancer, and the work could lead to improvements to immune checkpoint therapy, which helps reverse that exhaustion.

“At our cancer center, we emphasize awareness of sex and gender across the entire spectrum of cancer research and care, not just bladder cancer,” said Theodorescu. “We need to really consider this interplay between the biological sex, the epigenome and the immune system in cancers in order to make the most impactful discoveries for our patients.”

Li said that the Program Project Grant has catalyzed collaboration and synergy among the three teams, “which we hope will be a game changer in the world of bladder cancer-and beyond.”

Reference
[1] Koti M, Ingersoll MA, Gupta S, Lam CM, Li X, Kamat AM, Black PC, Siemens DR. Sex Differences in Bladder Cancer Immunobiology and Outcomes: A Collaborative Review with Implications for Treatment. Eur Urol Oncol. 2020 Oct;3(5):622-630. doi: 10.1016/j.euo.2020.08.013. Epub 2020 Sep 20. PMID: 32967818.
[2] Lenis AT, Lec PM, Chamie K, Mshs MD. Bladder Cancer: A Review. JAMA. 2020 Nov 17;324(19):1980-1991. doi: 10.1001/jama.2020.17598. PMID: 33201207.

Featured image: Blader cancer.  photo courtesy: Fotolia/Adobe. Used with permission. Photo #1: Xue Li, Ph.D., photo courtesy Cedars-Sinai and photo #2: Dan Theodorescu, MD, Ph.D., courtesy Cedars-Sinai.

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