3β-HSD1

*仅供医学专业人士阅读参考 多囊卵巢综合症（PCOS）是一种复杂的生殖代谢疾病，影响约10-13%的育龄期女性，也是育龄期女性最常见的内分泌疾病之一。雄激素过多是PCOS的多种表现的主要驱动因素，也是PCOS干预的关键。目前，PCOS的药物干预主要为联合口服避孕药（COC），可改善高雄激素血症和/或月经周期不规律，但无法改善PCOS相关不孕症和多囊卵巢形态。 女性的雄激素主要由肾上腺和卵巢合成，由胆固醇经过一系列酶促反应催化而成，包括细胞色素P450（CYP）和羟基类固醇脱氢酶（HSD）中的CYP11A1、CYP17A1、HSD3B2和HSD17B。 PCOS的卵泡膜细胞中CYP11A1和CYP17A1的表达增加，CYP17A1、HSD3B和HSD17B的酶活性升高，导致孕酮、17α-羟基孕酮（17α-OHP）和睾酮的过量产生。因此，抑制这些酶的过表达可能有助于控制高雄激素血症和PCOS。 在今天的《科学》杂志上，复旦大学基础医学院汤其群教授带领团队发表了最新研究成果。他们发现，青蒿素可以与线粒体离子肽酶1（LONP1）结合，通过LONP1与CYP11A1的相互作用促进CYP11A1降解，从而抑制卵巢雄激素合成。试点临床试验显示，双氢青蒿素可以改善PCOS患者的高雄激素血症，降低抗苗勒管激素水平，改善多囊卵巢形态，以及帮助月经正常化。 在脱氢异雄酮（DHEA）诱导的PCOS小鼠和大鼠模型中，青蒿素衍生物蒿甲醚（ATM）抑制了睾酮水平的增加，使得PCOS鼠的发情周期和卵巢形态恢复正常，逆转了寡排卵表型，这一结果在胰岛素和人绒毛膜促性腺激素（hCG）诱导的高雄激素血症PCOS鼠模型中得到了验证。生育力实验显示，PCOS鼠的胚胎着床率和产仔数量显著提高。 ATM治疗引起的睾酮水平降低促使研究人员开始探索青蒿素在调节雄激素合成中的作用。他们对PCOS的卵巢卵泡膜间质细胞上清液的类固醇激素进行了分析，ATM能够以剂量依赖的方式抑制睾酮产生，另一种青蒿素衍生物SM934也具有同样的抑制作用。这种抑制作用与细胞毒性无关，没有损害卵泡膜间质细胞的活力。 ATM和SM934以剂量依赖的方式抑制了睾酮和其他中间体、前体物质的产生 通过对卵泡膜间质细胞的蛋白质组学分析，研究人员发现，ATM诱导的表达下降的蛋白中，CYP11A1是最为显著的，CYP11A1催化胆固醇向孕烯醇酮转化，这是类固醇激素生物合成的第一步。当补充孕烯醇酮时，青蒿素诱导的睾酮降低被逆转，过表达CYP11A1也有同样的效果。这些结果表明，青蒿素能够通过减少CYP11A1影响睾酮的产生。 青蒿素是内过氧化物，能够产生活性氧，从而具有抗疟疾活性，但活性氧并没有参与CYP11A1的减少。在检测CYP11A1的稳定性时，研究人员发现，ATM和SM934明显缩短了CYP11A1的半衰期。 循着这一变化，他们鉴定出了8个在ATM处理后与CYP11A1有显著相互作用的蛋白和23个在SM934处理后有相互作用的蛋白。两个蛋白组的交集是LONP1和转运调节因子（TFG）。LONP1是一种AAA+线粒体蛋白酶，利用ATP水解降解错误折叠的或氧化的蛋白，是线粒体蛋白质质控的关键一环，TFG是COPII囊泡相关蛋白，调节从内质网到高尔基体的物质转运。 免疫共沉淀实验显示，在ATM和SM934处理后，LONP1和CYP11A1的相互作用显著增强，而TFG和CYP11A1的相互作用仅在ATM处理后轻微增强，SM934则没有效果。随后的实验显示，LONP1过表达显著减少了CYP11A1。 和野生型LONP1相比，破坏了蛋白质降解功能的S844A替代突变型LONP1无法减少CYP11A1，这意味着，ATM促进LONP1催化的CYP11A1的降解。直接过表达LONP1显著降低了卵泡膜间质细胞的睾酮水平。基因表达综合数据库（GEO）的数据表明，PCOS患者卵泡膜细胞中的LONP1表达水平确实显著低于正常卵泡膜细胞，与本研究的发现相一致。 不但如此，研究人员还通过基于蛋白结构的对接计算，发现青蒿素衍生物是与LONP1蛋白水解域内已知的硼替佐米结合口袋结合，硼替佐米是已知的LONP1抑制剂。因此，LONP1是青蒿素的直接靶点，结合后通过降解CYP11A1，降低睾酮水平，发挥抗PCOS作用。 最后，研究人员开展了一项试点临床试验，以验证青蒿素治疗PCOS患者的疗效。他们招募了19例PCOS患者，接受口服双氢青蒿素治疗12周。所有参与者在治疗前均存在高雄激素血症、月经过少或闭经，以及多囊卵巢表现。 双氢青蒿素耐受性良好，未报告不良反应。经治疗，参与者的血清睾酮、抗苗勒管激素水平显著降低，血清抗苗勒管激素水平与生长中的卵泡数量密切相关，在PCOS患者中通常偏高。另外，有63.16%（12/19）的参与者恢复了正常月经周期。 综上，青蒿素具有治疗PCOS的潜力，可能会改变PCOS治疗的景观，改善数百万女性患者的生活质量，这代表着生殖医学方面的一个重要进展。未来，需要进一步的研究来充分了解治疗的长期影响和优化剂量策略，以最大化治疗结果。 参考文献： [1] Yang Liu et al, Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction. Science 384, eadk5382(2024). DOI:10.1126/science.adk5382 本文作者丨应雨妍

In collaboration with leading cancer centers, research results to be presented from eight studies across four tumor types, demonstrating Caris' impact on precision medicine IRVING, Texas, Jan. 23, 2024 /PRNewswire/ -- Caris Life Sciences®(Caris), the leading next-generation AI TechBio company and precision medicine pioneer that is actively developing and delivering innovative solutions to revolutionize healthcare and improve the human condition using molecular science and AI, today announced that the company and collaborators within the Caris Precision Oncology Alliance™ (POA) will collectively present eight studies across four tumor types at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, January 25-27, 2024 in San Francisco. The findings demonstrate the continued and expanded capabilities of Caris' comprehensive multi-modal database to enable novel insights into cancer that could have profound effects on a patient's diagnosis, prognosis, care plan and response to treatment. Continue Reading "These presentations illustrate how our physicians, scientists and collaborators in the POA are leveraging real-world clinical evidence from over 593,000 lifetime clinical cases, including over 482,000 with matched molecular data and outcomes, in Caris' unique AI-driven platform to deepen our understanding of cancer and to develop the next breakthrough medicines," said Chadi Nabhan, MD, MBA, FACP, Chairman of the Caris Precision Oncology Alliance. "Caris molecular profiling enables deep exploration of the genetic and immune landscapes of cancer, providing insights into which signaling pathways explain the pathobiology of disease and leading to more precise targeted therapy. That's a major focus of the wide array of research Caris and our POA collaborators will proudly present at this year's ASCO GU." The findings demonstrate the continued and expanded capabilities of Caris' comprehensive multi-modal database Post this Oral Abstract: A Caris study entitled "Differences in genomic, transcriptomic, and immune landscape of prostate cancer (PCa) based on site of metastasis (mets)" will be presented by Dr. Umang Swami from the Huntsman Cancer Institute on Thursday, January 25 at 4:20 p.m. PST during Rapid Oral Abstract Session A on Prostate Cancer in the Level 3 Ballroom. The research is a collaboration with the Huntsman Cancer Institute at the University of Utah and other POA members. Compared to primary PCa, both visceral (liver and lung) and non-visceral (lymph node and bone) metastases had higher Androgen Receptor (AR) and interferon g signaling, upregulation of the E2F, G2M checkpoints and MYC target pathways, and were significantly less enriched in macrophage M2, NK, and regulatory T cells. Visceral metastases also had higher neuroendocrine (NEPC) scores and were less enriched for B cells and neutrophils. These data on the molecular and immunologic mechanisms of metastatic tropism in advanced PCa may facilitate future drug development. Additional Presentations Reveal Potential Impact of Comprehensive Molecular Profiling Caris will present additional data from studies demonstrating the critical role of comprehensive molecular profiling in the treatment of genitourinary cancers. Poster and abstract summaries highlighting this research will be available onsite at Caris' booth (#8). The full abstracts will be available through Caris' website beginning on January 23. Survival outcomes in patients (pts) with prostatic cancer (PCa) based on pathologically confirmed sites of metastasis (January 25; Poster C7, Abstract 72) Examination of 6,069 PCa specimens in Caris' CODEai multi-modal database showed that metastasis to the liver was associated with overall survival significantly shorter than metastasis to the lung, arguing against combining them into the single category of visceral metastases as a stratification factor in randomized clinical trials. Correlation of PIM kinases with tumor immune microenvironment and clinical presentation of metastatic hormone-sensitive prostate cancer January 25; Poster J19, Abstract 211) In a study of 44 patients with treatment-naive metastatic hormone-sensitive prostate cancer (mHSPC), there was a strong association of high expression of PIM kinases with increased MAPK activation score, T cell inflamed score, inflammatory, PSA, AR, MHC class I and MHC class II gene expression, and differential immune cell infiltration. However, this did not significantly translate to a worse clinical presentation of mHSPC. A better understanding of these differences with additional research may provide a rationale for tailored therapeutic approaches for PIM-expressing mHSPC. The influence of the germline HSD3B1 adrenal-permissive variant (c.1100 C) on somatic alteration landscape, transcriptome, and immune-cell infiltration in prostate cancer ( January 25; Poster K3, Abstract 215) In a study of 5,421 prostate cancer biopsies from the Caris Life Sciences database, the homozygous adrenal-permissive HSD3B1 variant (c.1100 CC) was characterized by elevated AR signaling and MAPK activation and a unique immune-cell regulatory landscape, with higher B7-H3 expression, increased intratumoral dendritic cells and decreased immunosuppressive neutrophils, suggesting that B7-H3–targeted therapies might be effective against this class of cancer. The opposing effects of Class 1B and Class 2 FOXA1 mutations in prostate cancer (January 25; Poster K4, Abstract 216) Alterations in the FOXA1 transcription factor are present in 16% of prostate cancers (PCa), but different alterations exhibit divergent molecular and clinical profiles. In a study of more than 4,000 primary and metastatic PCa samples, missense mutations in the Wing2 region of FOXA1 (a.a. 248-269) had better response to androgen deprivation therapy (ADT), whereas mutations in a.a. R219, a highly conserved DNA contact residue, were associated with a neuroendocrine phenotype and showed poor survival with ADT. Canonical Wnt signaling pathway (WSP) alterations in metastatic prostate cancer (January 25; Poster K9, Abstract 221) In a study of 4,150 total PCa samples, 722 with aberrant canonical Wnt signaling (WSP-act), WSP-act tumors had pronounced upregulation of ROR1 gene expression and augmented levels of M2 macrophages, suggesting that ROR1 may contribute to immune evasion in WSP-act mPCa. Comprehensive analysis of targetable alterations in urachal cancer by NGS ( January 26; Poster K7, Abstract 663) In a comprehensive characterization the molecular and immune landscape of urachal cancer (UrC), UrC tumors rarely harbored predictive markers of response to immunotherapy, suggesting limited efficacy in this patient population. However, the recurrence of MAPK alterations and associated pathway activation in UrC warrants further investigation of MAPK-targeted therapies in prospective clinical trials. IL-6 and PIM1 expression in renal cell carcinoma ( January 27; Poster K11, Abstract 470) Based on the hypothesis that an IL-6/JAK/STAT pathway regulates the expression of PIM1 in renal cell carcinoma (RCC) as in pancreatic and breast cancer, the transcriptomes of RCC samples in the Caris multi-modal database were analyzed, showing that PIM1 expression was significantly increased in metastatic relative to primary RCC. IL-6 expression was up to 6.5-fold higher in RCC patients with PIM1 overexpression. Outcomes data showed that PIM1 overexpression was associated with decreased overall survival for RCC patients independent of treatment received. Since multiple FDA-approved agents are available that target this pathway, further investigation is warranted to determine the efficacy of these agents in pre-clinical models and clinical trials of RCC. The POA includes 90 cancer centers, academic institutions, research consortia and healthcare systems, including 42 NCI-designated cancer centers, collaborating to advance precision oncology and biomarker-driven research. POA members work together to establish and optimize standards of care for molecular testing through innovative research focused on predictive and prognostic markers that improve the clinical outcomes for cancer patients. About Caris Life Sciences Caris Life Sciences® (Caris) is the leading next-generation AI TechBio company and precision medicine pioneer that is actively developing and delivering innovative solutions to revolutionize healthcare and improve the human condition using molecular science and AI. Through comprehensive molecular profiling (Whole Exome and Whole Transcriptome Sequencing) and the application of advanced AI and machine learning algorithms, Caris has created the large-scale, multi-modal database and computing capability needed to analyze and unravel the molecular complexity of disease. This convergence of sequencing power, big data and AI technologies provides an unmatched platform to deliver the next-generation of precision medicine tools for early detection, diagnosis, monitoring, therapy selection and drug development. Headquartered in Irving, Texas, Caris has offices in Phoenix, New York, Cambridge (MA), Tokyo, Japan and Basel, Switzerland. Caris or its distributor partners provide services in the U.S., Europe, Asia and other international markets. To learn more, please visit CarisLifeSciences.com. Caris Life Sciences Media Contact: Lisa Burgner [email protected] 214.294.5606 SOURCE Caris Life Sciences

The HSD3B1 gene could hold clues for predicting and treating endometrial cancer, according to a novel finding. Researchers found a certain HSD3B1 genotype was more common in women with type 2 endometrial cancer. Those patients show lower survival rates than those diagnosed with type 1 endometrial cancer, likely driven by the fact that type 2 patient cells are less hormone-dependent. The HSD3B1 gene could hold clues for predicting and treating endometrial cancer, according to a novel finding from the Cleveland Clinic's Lerner Research Institute. Researchers found a certain HSD3B1 genotype was more common in women with type 2 endometrial cancer, according to the results published in JNCI Cancer Spectrum. Those patients show lower survival rates than those diagnosed with type 1 endometrial cancer, likely driven by the fact that type 2 patient cells are less hormone-dependent. The results are the latest step in untangling the role HSD3B1's genotype plays in hormone-driven cancers, with previous research revealing associations with breast and prostate cancer. This body of work was in part led by Cleveland Clinic researchers and physician-scientists, and continues today with translational research and clinical trials. HSD3B1 researchers are building a foundation for future options to treat and prevent cancer subtypes with a lower survival rate, says Nima Sharifi, MD, senior author of the paper and Director of the Lerner Research Institute's Genitourinary Malignancies Research Center. Despite being one of the most common cancers among women, there is no test or exam to screen for endometrial cancer. Incidence rates for this "underfunded and understudied" disease are rising in the United States, says Roberto Vargas, MD, co-author and assistant staff at the Cleveland Clinic's Division of Gynecologic Oncology. "Over the past three decades, we haven't moved the bar on outcomes," Dr. Vargas says. "Figuring out the interplay between this gene and endometrial cancer can pave a way to screen and treat it more effectively." HSD3B1 is a gene that regulates androgens and estrogens by producing the enzyme that converts adrenal steroid-precursors to androgens and estrogens. HSD3B1's genotype is either adrenal-permissive, which amplifies the process, or adrenal-restrictive, which limits it. Dr. Sharifi likens HSD3B1's role in the adrenal pathway to how a dam controls water. Opening the gates releases a rush of water, but when the dam is closed, that flow is held back. Previous research established how HSD3B1 genetics works and associates with hormone-associated cancers, starting with castration-resistant prostate cancer. When a patient undergoes chemical or surgical castration to treat prostate cancer, the procedure halts one of the body's paths to producing androgens. When the body stops producing androgens or estrogens through sex organs, the body can still produce these hormones through the adrenal pathway, Dr. Sharifi says. Castration is intended to stop androgen production when tumors grow in response to the hormone. When the adrenal pathway starts producing androgens, that can lead to recurrence. Previous research associates adrenal-permissive HSD3B1 with poorer outcomes in castration-resistant prostate cancer across multiple cohorts. Dr. Sharifi says HSD3B1 could serve as a biomarker for breast and endometrial cancer subtypes because the ovaries stop producing estrogen after menopause. The adrenal pathway could then kick in to start producing those hormones. The median endometrial cancer patient age is 60 years old, with the main symptom being irregular bleeding after menopause. Recent research investigated potential association between HSD3B1's genotype and postmenopausal breast and endometrial cancer subtypes, where the cancer grows in response to estrogen. Previous research associated ER+ cancer in postmenopausal women with HSD3B1 adrenal-permissive genotype. Dr. Sharifi's research team, through analyzing TCGA data, added to this finding by showing an association between the opposite HSD3B1 genotype, adrenal-restrictive, and a certain subtype of ER- breast cancer. In endometrial cancer, the serous subtype has less ER expression and is associated with a worse prognosis. The adrenal-restrictive HSD3B1 genotype was more commonly associated with serous-type endometrial cancer, according to the study. Additionally, in an analysis of UK Biobank data, adrenal-restrictive genotype was shown to be associated with worse outcomes among endometrial cancer patients. Jeff McManus, PhD, first author and a research associate in the Cancer Biology Department, says researchers will now need to validate the results with much larger cohorts. That will include examining HSD3B1 associations with survival rates within different cancer subtypes. Ongoing HSD3B1 collaborations include further research on HSD3B1's relationship with breast and endometrial cancer, as well as investigation into how HSD3B1 is associated with response to radiotherapy. Clinical trials for prostate cancer held at the Cleveland Clinic will test how people with specific HSD3B1 genotypes respond to therapeutics. Authors noted that Black women are more likely inherit adrenal-restrictive HSD3B1 and that certain breast and endometrial cancer subtypes that have worse outcomes -- and both are more common in Black women. Black women also were twice as likely to die from uterine cancer compared to other ethnic groups in a study released in May from the National Cancer Institute. "Chipping away at this difference in outcomes and trying to understand a genetic basis will be crucial in reducing (or eliminating) existing disparities," Vargas says.