Up until recently (2018), prostate cancer was the most commonly diagnosed cancer in Australian men. An estimated 24,000 men will be diagnosed with prostate cancer in 2022, and among these, around 3,500 will die from it. We lose 10 men to prostate cancer in Australia each day.
While this is a staggering statistic, it is important to note that anyone with a prostate can get prostate cancer, including transgender women, nonbinary and intersex people. Screening for it can be especially challenging, as the prostate-specific antigen (PSA) blood test, which is typically used to aid early detection, can only indicate changes in the prostate. Symptoms are not easily visible, even in advanced stages.
These factors that contribute to the complexity of this health problem and its significant impact on the Australian population make awareness of prostate cancer all the more crucial.
Currently, the five-year survival rate for prostate cancer is 95% compared to 59% in 1989. Cancer research has gone a long way in contributing towards improving patient outcomes for prostate cancer. For its part, Cure Cancer has funded a number of novel projects on prostate cancer from early-career researchers. Among them is Dr Zeyad Nassar, who was co-funded by The Can Too Foundation in 2019 to evaluate the targeting of lipid metabolism pathways in prostate cancer. He hopes his research contributes to discovering new treatments and decreasing patient mortality.
We caught up with Dr Zeyad to learn more about the importance of prostate cancer awareness and how his research has progressed since 2019.
CURE CANCER: WHY DO YOU THINK PROSTATE CANCER AWARENESS MONTH IS IMPORTANT?
Zeyad: Another important issue is the common belief that prostate cancer only affects old men. While 60% of men diagnosed with cancer are older than 65 years, the disease can affect men in their 40s and the diagnosis rate increases prominently at the age of 50. Hence, young men should learn about cancer and its symptoms and consult their physicians about when they have to start to test for it.
CC: ARE THERE ANY EXCITING DEVELOPMENTS OR TRENDS IN PROSTATE CANCER RESEARCH LATELY?
Z: Over the last decades, the major focus was to develop new potent therapeutics that can inhibit the androgen receptors, which are the main drivers for prostate cancer growth. These drugs were tested in a clinic in combination with other drugs in use in the clinic. The idea was to intensify the therapy by using 3 drugs at the same time. Fortunately, this strategy was successful in patients with metastatic hormone-sensitive prostate cancer (mHSPC), where the triplet therapy improved patients’ outcomes.
Researchers working on working on prostate cancer and lipid metabolism. L-R: Ms Julia Scott (PhD Student), Dr Shanice Mah (a lab alum and currently a postdoc in the lab), Ms Deanna Miller (PhD student).
CC: WHAT ARE THE MAJOR MILESTONES IN YOUR PROSTATE CANCER RESEARCH THAT YOU WOULD LIKE TO SHARE AND HAS THIS LED YOU TO OTHER PIVOTAL PROJECTS?
Z: In 2019, I was awarded a Cure Cancer early-career grant co-funded by the Can Too Foundation. In this project, I characterised the role of the fatty acid oxidation enzyme DECR1 in prostate cancer. Fatty acid oxidation is the process of breaking down fat to generate energy required for cancer cells to proliferate faster, migrate and invade other tissues and most importantly resist the treatment. DECR1 is responsible for oxidation of specific types of fatty acids called PUFA. We found that prostate cancer cells demonstrate higher abundance of DECR1 compared with normal cells, and its abundance increases with the disease stage and in drug-resistant cells.
I have established a strong national and international collaborative network that involves bioinformaticians, basic scientists, and clinical oncologists, and proudly includes international leaders in the field. The list includes the lipid expert Prof Johan Swinnen (University of Leuven). I collaborated on a number of projects with Dr Andrew Hoy and A/Prof Anthony Don (University of Sydney) to measure metabolomics and acylcarnitines; the most accurate tool to measure fatty acid oxidation. I have also collaborated with A/P Luke Selth (Flinders University) to investigate the androgenic signalling of metabolism in prostate cancer. My bioinformatic analysis is undertaken with collaboration with Prof David Lynn, the European Molecular Biology Laboratory (EMBL) Australia Group Leader and director of the South Australian Genomics Centre. I established a collaboration with prostate cancer oncologist Prof Lisa Horvath from the Garvan Institute of Medical Research to ensure my research focus is clinically-relevant and to facilitate running future clinical trials.
Dr Zeyad Nassar hopes his research contributes to discovering new treatments and decreasing patient mortality.
CC: Can you tell us more about your recent papers?
Z: I was co-first author and performed data-curation and formal analysis for the article Extracellular fatty acids are the major contributor to lipid synthesis in prostate cancer, published in Molecular Cancer Research (2019).
This article provided strong evidence that prostate cancer cells exhibit increased fatty acid β-oxidation compared to non-malignant cells, and that extracellular fatty acids are the major source of carbons to the total lipid pool compared to the amino acids or carbohydrates. The article highlights for the first time the heterogeneity of lipid metabolism in prostate cancer cells and the potential influence that obesity-associated dyslipidemia or host circulating has on prostate cancer progression. My role here was first co-author, data-curation, and formal analysis.
I took the lead role as first author for Fatty acid oxidation is an adaptive survival pathway induced in prostate tumors by heat shock protein 90 inhibition that was published in Molecular Cancer Research (2020). This article demonstrated for the first time that activated fatty acid oxidation pathways mediate drug resistance in prostate cancer and showed that targeting fatty acid oxidation sensitises prostate cancer to novel drug treatments. The article provides a proof of concept that employing a patient-derived explant model is a powerful and fast model to discover drug resistance pathways.
Another article in which I was co-first author and took on writing the original draft, methodology, and investigation, was DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumour cells from ferroptosis published in eLife (2020). Using patient-derived prostate tumour explants, I provided the first clinically relevant evidence, that targeting fatty acid oxidation in prostate cancer is efficacious. I identified DECR1, which catalyses the rate-limiting step in an auxiliary pathway for poly unsaturated fatty acid (PUFA) β-oxidation, as a previously unrecognised androgen-repressed enzyme in prostate cancer cells and found its expression to be correlated with disease progression. The article identified DECR1 roles in PUFA metabolism in prostate cancer, and its function as anti-ferroptosis enzyme. It also showed that DECR1 is a very promising new therapeutic candidate. This article led to formation of an interdisciplinary team aiming to screen and synthesise specific DECR1 inhibitors.
“Using patient-derived prostate tumour explants, I provided the first clinically relevant evidence, that targeting fatty acid oxidation in prostate cancer is efficacious. I identified DECR1, which catalyses the rate-limiting step in an auxiliary pathway for poly unsaturated fatty acid (PUFA) β-oxidation, as a previously unrecognised androgen-repressed enzyme in prostate cancer cells and found its expression to be correlated with disease progression.”
Ensuring the pipeline of future cancer research success
At Cure Cancer, we believe that brilliant emerging researchers like Dr Zeyad Nassar are the future of cancer research. Early-career researchers have the skills and abilities to explore life-changing novel projects, yet they are rarely afforded the chance to do so. Without funding, research simply doesn’t happen. This causes many promising scientists to move from Australia or leave the field altogether, putting the future of cancer research in Australia at risk.
The seed funding for his project in 2019 provided by Cure Cancer and the Can Too Foundation enabled Dr Zeyad to pursue his novel research. His exciting research findings formed the basis for other successful grant applications, including international ones. Most recently, he was awarded a US$1,557,000 grant from the United States Department of Defense-Idea Development Award as well as a grant from Cancer Australia and Can Too to further investigate the role of fatty acid oxidation process in advanced stages of prostate cancer.
We are incredibly proud of Dr Zeyad and his continued success and applaud his collaborations with other industry experts to advance cancer research. To learn more about prostate cancer or Dr Zeyad Nassar’s research, please refer to the links below:
References
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Balaban S*, NASSAR ZD*, Zhang AY*, Beheshti EH, Centenera MM, Schreuder M, Lin H-M, Aishah A, Varney B, Liu-Fu F, Lee LS, Nagarajan SR, Shearer RF, Hardie R-A, Raftopulos NL, Kakani MS, Saunders DN, Holst J, Horvath LG, Butler LM, Hoy AJ. Extracellular fatty acids are the major contributor to lipid synthesis in prostate cancer. Molecular Cancer Research. 2019.
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NASSAR ZD, Mah CY, Centenera MM, Irani S, Sadowski MC, Scott JS, Nguyen EV, Nagarajan SR, Moldovan M, Lynn DJ, Daly RJ, Hoy AJ, Butler L. Fatty acid oxidation is an adaptive survival pathway induced in prostate tumors by heat shock protein 90 inhibition. Molecular Cancer Research. 2020.
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NASSAR ZD*, Mah CY*, Dehairs J, Burvenich I, Irani S, Centenera MM, Shrestha RK, Moldovan M, Don AS, Scott AM, Horvath LG, Lynn DJ, Selth LA, Hoy AJ, Swinnen JV, Butler LM. DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumour cells from ferroptosis. eLife. 2020. *Equal contributions.
