Study Solves Testosterone’s Paradoxical Effects in Prostate Cancer

The AHA! Team — Mon, 30 Sep 2024 08:33:27 +0000

Duke Health – A treatment paradox has recently come to light in prostate cancer: Blocking testosterone production halts tumor growth in early disease, while elevating the hormone can delay disease progression in patients whose disease has advanced. The inability to understand how different levels of the same hormone can drive different effects in prostate tumors has been an impediment to the development of new therapeutics that exploit this biology. Now, a Duke Cancer Institute-led study, performed in the laboratory of Donald McDonnell, Ph.D. and appearing this week in Nature Communications, provides the needed answers to this puzzle. The researchers found that prostate cancer cells are hardwired with a system that allows them to proliferate when the levels of testosterone are very low. But when hormone levels are elevated to resemble those present in the normal prostate, the cancer cells differentiate. “For decades, the goal of endocrine therapy in prostate cancer has been to achieve absolute inhibition of androgen receptor function, the protein that senses testosterone levels,” said lead investigator Rachid Safi, Ph.D., research assistant professor in the Department of Pharmacology and Cancer Biology, at Duke University School of Medicine. “It’s been a highly effective strategy, leading to substantial improvements in overall survival,” he said. “Unfortunately, most patients with advanced, metastatic disease who are treated with drugs to inhibit androgen signaling will progress to an aggressive form of the disease for which there are limited therapeutic options.” Using a combination of genetic, biochemical, and chemical approaches, the research team defined the mechanisms that enable prostate cancer cells to recognize and respond differently to varying levels of testosterone, the most common androgenic hormone. It turned out to be rather simple. When androgen levels are low, the androgen receptor is encouraged to “go solo” in the cell. In doing so, it activates the pathways that cause cancer cells to grow and spread. However, as androgens rise, the androgen receptors are forced to “hang out as a couple,” creating a form of the receptor that halts tumor growth. “Nature has designed a system where low doses of hormones stimulate cancer cell proliferation and high doses cause differentiation and suppress growth, enabling the same hormone to perform diverse functions,” McDonnell said. In recent years, clinicians have begun treating patients with late-stage, therapy resistant prostate cancers using a monthly, high-dose injection of testosterone in a technique called bi-polar androgen therapy, or BAT. The inability to understand how this intervention works has hindered its widespread adoption as a mainstream therapeutic approach for prostate cancer patients. “Our study describes how BAT and like approaches work and could help physicians select patients who are most likely to respond to this intervention,” McDonnell said. “We have already developed new drugs that exploit this new mechanism and are bringing these to the clinic for evaluation as prostate cancer therapeutics.” In addition to McDonnell and Safi, study authors include Suzanne E. Wardell, Paige Watkinson, Xiaodi Qin, Marissa Lee, Sunghee Park, Taylor Krebs, Emma L. Dolan, Adam Blattler, Toshiya Tsuji, Surendra Nayak, Marwa Khater, Celia Fontanillo, Madeline A. Newlin, Megan L. Kirkland, Yingtian Xie, Henry Long, Emma Fink, Sean W. Fanning, Scott Runyon, Myles Brown, Shuichan Xu, Kouros Owzar, and John D. Norris. The study received funding support from the National Cancer Institute (R01-CA271168, P30CA014236) and the North Carolina Biotechnology Center. To read the original article click here.

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Researchers Developing New Cancer Treatments With High-Intensity Focused Ultrasound

AHA Publisher — Fri, 27 Aug 2021 07:00:27 +0000

University of Waterloo via Newswise – Researchers are bringing the use of acoustic waves to target and destroy cancerous tumours closer to reality. While doctors have used low-intensity ultrasound as a medical imaging tool since the 1950s, experts at the University of Waterloo are using and extending models that help capture how high-intensity focused ultrasound (HIFU) can work on a cellular level. Led by Siv Sivaloganathan, an applied mathematician and researcher with the Centre for Math Medicine at the Fields Institute, the study found by running mathematical models in computer simulations that fundamental problems in the technology can be solved without any risk to actual patients. Sivaloganathan, together with his graduate students June Murley, Kevin Jiang and postdoctoral fellow Maryam Ghasemi, creates the mathematical models used by engineers and doctors to put HIFU into practice. He said his colleagues in other fields are interested in the same problems, “but we’re coming at this from different directions”. “My side of it is to use mathematics and computer simulations to develop a solid model that others can take and use in labs or clinical settings. And although the models are not nearly as complex as human organs and tissue, the simulations give a huge head start for clinical trials.” One of the obstacles that Sivaloganathan is currently working to overcome is that in targeting cancers, HIFU also poses risks to healthy tissue. When HIFU is being used to destroy tumours or cancerous lesions, the hope is that good tissue won’t be destroyed. The same applies when focusing the intense acoustic waves on a tumour on the bone where lots of heat energy gets released. Sivaloganathan and his colleagues are working to understand how the heat dissipates and if it damages the bone marrow. Other researchers working with Sivaloganathan include engineers, who are building the physical technology, and medical doctors, in particular, James Drake, chief surgeon at Hospital for Sick Children, looking at the practical application of HIFU in clinical settings. Sivaloganathan believes HIFU will make significant changes in cancer treatments and other medical procedures and treatments. HIFU is already finding practical application in the treatment of some prostate cancers. “It’s an area that I think is going to take center stage in clinical medicine,” he said. “It doesn’t have the negative side effects of radiation therapy or chemotherapy. There are no side effects other than the effect of heat, which we are working on right now. It also has applications as a new way to break up blood clots and even to administer drugs.” To read the original article click here.

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Study Solves Testosterone’s Paradoxical Effects in Prostate Cancer

Researchers Developing New Cancer Treatments With High-Intensity Focused Ultrasound