Li Zhenfei/Wu Denglong/Huang Shengsong's team identified a new target for advanced prostate cancer treatment Cell Press Dialogue with Scientists

Medical MedicineIn April 2022, Li Zhenfei's research group from the Center for Excellence in Molecular and Cell Science of the Chinese Academy of Sciences and Wu Denglong/Huang Shengsong's research group from Tongji Hospital Affiliated to Tongji University jointly published a research paper "Inhibiting 3βHSD1 to eliminate the oncogenic" in Cell Reports Medicine, Cell Press.
effects of progesterone in prostate cancer” and “Management of prostate cancer by targeting 3βHSD1 after enzalutamide and abiraterone treatment”, revealing multiple mechanisms mediated by metabolic enzyme 3βHSD1 in the process of drug resistance in advanced prostate cancer, making it clear that 3βHSD1 is a highly clinical Using potential prostate cancer therapeutic targets, it was found that the small molecule compound biochanin-A is a potent inhibitor of 3βHSD1, which can be used for the treatment of advanced prostate cancer
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▲Long press the picture to identify the QR code to read the original text Prostate cancer is a high incidence of male cancer
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About 15% of prostate cancers will progress to malignant prostate cancer, threatening the patient's life
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Androgens promote prostate cancer progression by activating the androgen receptor (AR) signaling pathway
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Second-generation AR pathway inhibitors (ARPIs), such as the drugs abiraterone and enzalutamide, are the last line of defense in the treatment of advanced prostate cancer
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ARPI-resistant prostate cancer has increased heterogeneity and lacks effective treatments
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In order to solve this clinical pain point, the researchers tracked the patients receiving abiraterone, and found that the activity of the metabolic enzyme 3βHSD1 in the patients gradually increased by analyzing the changes of the drug and different metabolites in their blood during the treatment process
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The metabolic enzyme 3βHSD1 is involved in various physiological processes such as abiraterone drug metabolism and steroid metabolism
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Therefore, the increase in 3βHSD1 activity in the patient's body leads to a decrease in the plasma concentration of abiraterone and an increase in the steroid hormone progesterone
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Through a variety of systematic studies, the researchers found that different concentrations of progesterone can promote prostate cancer progression through multiple mechanisms
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Similarly, long-term treatment with the drug enzalutamide can also induce an increase in the activity of 3βHSD1, which in turn leads to the accumulation of intracellular androgen and weakens the efficacy of the drug enzalutamide
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The researchers further screened 3βHSD1 inhibitors and found that the small molecule compound BCA can effectively inhibit the activity of 3βHSD1
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BCA has demonstrated its ability to regulate steroid metabolism and drug metabolism in a variety of cell models and mouse models, and demonstrated a good effect of inhibiting prostate cancer progression
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Finally, the researchers demonstrated through different clinical trials that the metabolic enzyme 3βHSD1 is a more suitable therapeutic target for advanced prostate cancer in the Chinese population; its inhibitors can prevent disease progression in abiraterone-resistant patients
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This series of work was led by the team of Li Zhenfei from the Center for Excellence in Molecular and Cell Science of the Chinese Academy of Sciences, and the teams of Wu Denglong and Huang Shengsong from Tongji Hospital Affiliated to Tongji University, with the help and support of Tang Huiru's team from Fudan University
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Hou Zemin, Mei Zejie, Yang Tao and Chen Longlong are the co-first authors of the article
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The author's exclusive interview with the official account of Cell Press Cell Press specially invited researcher Li Zhenfei to accept the interview on behalf of the research team, and asked him to interpret it in detail for everyone
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CellPress: Can you talk about the origin of this work? Researcher Zhenfei Li: Research models do not always perfectly reproduce the heterogeneity of patients in the real world, so there are certain barriers between basic research and clinical translation
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Our previous study found a new metabolic pathway of the drug abiraterone in patients, and based on this metabolic pathway, we proposed a new mechanism of drug tolerance and potential treatment strategies (Nature 2015 & 2016)
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We believe that scientific hypotheses based on cells and animal models should not be the end point of scientific research; clinical application is the ultimate goal of tumor research
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In order to further confirm the authenticity and importance of this scientific hypothesis in patients, we began to carry out a series of studies using the abundant patient samples in our country, and in the process continued to revise our previous scientific hypothesis
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CellPress: Androgen-independent neuroendocrine prostate cancer (NEPC) is a current research hotspot
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Why do you think prostate cancer remains androgen-dependent after abiraterone or enzalutamide tolerance? Researcher Zhenfei Li: If we review the research history of prostate cancer, we find that after each treatment tolerance, the role of the androgen-AR signaling axis is questioned
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In patients resistant to abiraterone and enzalutamide, the proportion of NEPCs increased significantly (~30%); however, the predominant resistant cells remained androgen-dependent adenocarcinomas (~70%)
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At the same time, the increase of PSA (AR target gene) is a common and important clinical indication of drug tolerance
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Therefore, we believe that the androgen-AR signaling axis is still the main contradiction in the progression of prostate cancer at this stage
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CellPress: As an important rate-limiting metabolic enzyme in steroid metabolism, what are the roles of 3βHSD1 in the progression of prostate cancer? Researcher Li Zhenfei: The process of synthesizing steroid hormones such as androgens, estrogens, and glucocorticoids with cholesterol as a precursor is called the steroid metabolism pathway
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The biochemical details of this metabolic pathway have been well described in the 20th century
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However, in the field of prostate cancer, there are few studies on the structural information, regulatory mechanisms and clinical relevance of metabolic enzymes
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This is mainly because the importance of the androgen-AR signaling axis in post-resistance prostate cancer is called into question every time treatment tolerance occurs
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In 2013, researchers found that this metabolic enzyme has genetic polymorphisms in the population.
3βHSD1 (367T) is more stable than wild-type 3βHSD1 (367N) and can better promote the progression of CRPC
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Subsequent clinical studies have confirmed that this genotype can be used as a biomarker to predict disease progression; however, whether 3βHSD1 can be a therapeutic target for prostate cancer has not been confirmed
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Compared with sugar metabolism, the field of steroid metabolism is still fertile soil that has not been deeply cultivated
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CellPress: Can 3βHSD1 serve as a biomarker for predicting disease progression in prostate cancer? Researcher Li Zhenfei: As mentioned above, the genotype of HSD3B1, the gene encoding 3βHSD1, has been shown to be correlated with disease progression in different Western patient populations and disease stages
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The logic behind this is that the higher the activity of 3βHSD1, the stronger the ability of cancer cells to synthesize androgen, and the easier it is to develop treatment resistance
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However, the genotype HSD3B1 (1245C) corresponding to 3βHSD1 (367T) is very low in East Asian populations, so this genotype has no practical value in East Asian populations
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This also reflects the racial heterogeneity of prostate cancer
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In the study, we also found that the detection technology of the mRNA abundance and protein abundance of this metabolic enzyme is not perfect, and it cannot faithfully reflect the activity of 3βHSD1 in cells
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We are also developing corresponding means to assess the activity of 3βHSD1 in patient tissues, providing a new tool for clinical diagnosis and treatment of prostate cancer
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CellPress: How do you evaluate your newly discovered 3βHSD1 inhibitor? Researcher Li Zhenfei: In the laboratory, other researchers and we have found a number of small molecule compounds that can inhibit the activity of the metabolic enzyme 3βHSD1.
However, when these compounds inhibit the activity of 3βHSD1, they can directly or indirectly activate AR, so they do not have clinical applications.
application value
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The BCA we found was able to effectively inhibit 3βHSD1 at low doses (~1 M), while not exhibiting the effects of AR agonists
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Despite the low absorption of flavonoids, drug concentrations of 1 M are achievable
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The author introduces Li Zhenfei, a researcher at the Center for Excellence and Innovation in Molecular and Cell Science, Chinese Academy of Sciences
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Mainly engaged in tumor metabolism and precision treatment of prostate cancer
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The research results have been published in journals such as Nature, Nature communications, Cell Reports Medicine, Cell Chemical Biology, Clinical Cancer Research and other journals as the first author or corresponding author
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Related paper information The original paper was published in Cell Reports Medicine, a journal of CellPress Cell Press.