作者: Abouayana, Aya ; Aldalqamouni, Ahmad ; Younas, Bilal ; Abouayana, Ahmed Eid Ahmed ; Qazi, Abdul Rehman ; Cheema, Zian Zafar ; Rauf, Muhammad Atif ; Adikari, Sanka ; Ayub, Haroon ; Shahzad, Maryam ; Khan, Muhammad Azhar Waheed ; Ahmed, Saeed ; Mesmar, Ahmad ; Ahmed, Raheel ; Sohail, Sameen ; Ahmed, Mushood ; Hasan, Ali ; Goh, Jia Shen ; Paray, Nitish Behary ; Atout, Mohammad

ABSTRACT:

Background:

Hypertension remains a major contributor to global cardiovascular morbidity and mortality. Aldosterone, a key hormone in blood pressure regulation, plays a significant role in hypertension pathophysiology. This has led to growing interest in aldosterone synthase inhibitors (ASIs) as a potential treatment. This meta‐analysis aims to evaluate the efficacy and safety of ASIs in managing hypertension.

Methods:

A systematic search of PubMed, Google Scholar and Cochrane Central was conducted up to 13 July 2025, to identify randomised controlled trials (RCTs) evaluating ASIs in hypertensive adults. Data were analysed using RevMan version 5.4, employing random‐effects models with significance set at p < 0.05.

Results:

A total of 8 RCTs were included, with a total of 2003 participants in the ASI group and 650 participants in the placebo group. ASIs significantly reduced systolic blood pressure (SBP) compared to placebo (MD: −6.01 mmHg; 95% confidence interval [CI]: −9.31 to −2.71; I2 = 85%; p = 0.0004); diastolic blood pressure (DBP) was found to be comparable between the two groups (MD: −2.20 mmHg; 95% CI: −4.46 to 0.06; I2 = 69%; p = 0.06). There was a significant reduction in serum aldosterone levels favouring ASI use (MD: −1.46; 95% CI: −2.76 to −0.16; I2 = 99%; p < 0.00001). The risk of serious (RD: 0.00; 95% CI: −0.01 to 0.02; I2 = 30%; p = 0.75) and non‐serious adverse events (RD: 0.05; 95% CI: −0.02 to 0.12; I2 = 64%; p = 0.20) did not differ significantly between ASI and placebo groups. However, ASI use was associated with a significantly higher risk of hyperkalemia (RD: 0.04; 95% CI: 0.02 to 0.06; I2 = 70%; p = 0.002).

Conclusion:

ASIs effectively lower SBP and serum aldosterone in adults with hypertension. They appear safe overall but may increase the risk of hyperkalemia.

2025-08-01·JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY

Incidental use of angiotensin system inhibitors during neoadjuvant therapy for esophageal adenocarcinoma: An analysis of survival

Article

作者: Tang, Hexiao ; Costantino, Christina ; Abston, Eric ; Muniappan, Ashok ; Geller, Abraham ; Lanuti, Michael

OBJECTIVE:

Renin-angiotensin-aldosterone system signaling affects tumorigenesis and treatment susceptibility of various cancers. We investigate the impact of angiotensin system inhibitors on survival in patients treated for locally advanced esophageal adenocarcinoma.

METHODS:

Patients with esophageal adenocarcinoma receiving trimodal therapy from 2002 to 2017 at a single institution were abstracted. Primary outcomes were overall survival and disease-free survival, analyzed with the Kaplan-Meier method, Cox regression, and propensity score-matched analysis. Secondary outcomes included pathologic complete response and tumor regression grade.

RESULTS:

A total of 375 patients with esophageal adenocarcinoma were included; 92 patients (25%) were angiotensin system inhibitor users, and 283 patients (75%) were angiotensin system inhibitor nonusers. Median follow-up was 32.4 months. Compared with angiotensin system inhibitor nonusers, angiotensin system inhibitor users were older (mean age, 62 vs 64 years) and had higher rates of comorbidities (P < .05 for all). Distribution of tumor stages was similar between groups (P = .3). Compared with angiotensin system inhibitor nonusers, angiotensin system inhibitor users showed improved median overall survival (30 vs 59 months, P = .025) and disease-free survival (18 vs 26 months, P = .032). After controlling for age and comorbidities, angiotensin system inhibitor users showed improved overall survival (hazard ratio, 0.633, P = .031) and disease-free survival (hazard ratio, 0.661, P = .036) compared with angiotensin system inhibitor nonusers. Among 182 propensity score-matched patients, angiotensin system inhibitor users showed greater median overall survival (59 vs 26 months, P = .025) and disease-free survival (25 vs 13 months, P = .030) than angiotensin system inhibitor nonusers. The hazard ratio was 0.623 for overall survival (95% CI, 0.410-0.946, P = .027) and 0.651 for disease-free survival (95% CI, 0.440-0.961, P = .031), both favoring angiotensin system inhibitor users. No differences between groups were identified with respect to secondary outcomes (P > .05).

CONCLUSIONS:

Angiotensin aldosterone system inhibition during esophageal cancer treatment is associated with improved outcomes. Our study suggests that angiotensin system inhibitors may provide additional survival benefits in the multi-modality treatment of esophageal adenocarcinoma.

2025-08-01·BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY

Blood Pressure–Lowering Effects of Aldosterone Synthase Inhibitors—A Systematic Review

Review

作者: Buus, Niels Henrik ; Rasmussen, Anders Almskou ; Simonsen, Ulf ; Nordestgaard, Ketil Lehm

ABSTRACT:

Excess aldosterone production contributes to the development of hypertension and results in fibrosis with dysfunction of the heart, vasculature and kidneys. Consequently, new agents have been developed to reduce endogenous aldosterone synthesis. The primary objective of this systematic review is to describe the BP‐lowering effects of aldosterone synthase inhibitors (ASIs) in hypertensive patients and, secondly, to describe their potential renal protective effects and possible influence on cortisol production and plasma potassium. We searched PubMed, Embase and ClinicalTrials.gov and included randomized controlled and clinical trials according to PICO using the review tool Covidence. Thirteen studies were included and all demonstrated BP reduction through ASI treatment. Among patients with apparent resistant hypertension, the placebo‐corrected reductions in seated systolic BP were 11.0 mmHg for baxdrostat and 9.6 mmHg for lorundrostat. A significant suppression of cortisol production was found for LCI699 (osilodrostat) but not for baxdrostat, lorundrostat, BI 690517 (vicadrostat) or dexfadrostat. Studies on BI 690517 showed a reduction in urine–albumin–creatinine ratio, indicating renal protection. ASIs may increase potassium levels. We conclude that ASIs have promising BP‐lowering effects with very limited effects on cortisol production and offer reno‐protective effects in chronic kidney disease. Studies on hypertensive target organ damage and cardiovascular outcomes are, however, lacking.

项与 Taneptacogin alfa 相关的新闻（医药）

2023-03-14

·生物谷

CCR：老牌降压药或能搞定“癌王”？科学家发现，氯沙坦可逆转胰腺癌抑制性肿瘤微环境，与患者总生存期改善有关

该研究表明氯沙坦与FFX+CRT联合应用，能降低促进侵袭和免疫抑制相关基因的表达，减少了FOXP3+Treg和FOXP3+肿瘤细胞数量，并增加CD8+T细胞浸润，通过重塑免疫微环境实现与化疗/放化疗的胰腺导管腺癌（PDAC）是“癌中之王”胰腺癌的主要类型，素来以恶性程度极高著称，特别是已无法手术的局部晚期和转移性PDAC，患者长期生存率极低，这主要与其恶性程度高、侵袭性强，以及免疫抑制性的肿瘤微环境有关，当前临床治疗选择也非常有限[1,2]。既往有临床前研究显示，作为PDAC的常用新辅助/转化治疗方案，FOLFIRINOX方案化疗（FFX）和放化疗（CRT）可调控免疫效应细胞（CD8+T细胞、CD4+T细胞）和免疫抑制性细胞（Tregs、TAMs）的平衡，但要想破解PDAC这个臭名昭著的“冷肿瘤”，临床医生们仍然需要更多的助力。血管紧张素系统抑制剂（ASIs）是临床常用的降压药，而近年来越来越多的研究发现它们还有抗肿瘤效果，其作用机制与重塑细胞外基质、调控氧化磷酸化、下调多种肿瘤进展相关通路（如细胞周期、NOTCH和WNT通路）和增强抗肿瘤免疫应答有关[3]，这类降压药能否成为改变PDAC抑制性免疫微环境的奇兵呢？近期，来自哈佛大学麻省总医院的Rakesh K.Jain团队，在Clinical Cancer Research上发表了重要的研究成果[4]。研究发现，常用ASIs类药物氯沙坦（Losartan）可下调PDAC中的免疫抑制和侵袭相关基因表达，且这种作用与患者总生存期（OS）改善有关；而在化疗后放化疗（FFX+CRT）的基础上联合使用氯沙坦，可显著减少PDAC病灶中免疫抑制性Treg和FOXP3+肿瘤细胞数量，增加抗肿瘤CD8+T细胞浸润，从而正向重塑免疫抑制微环境。文章首页截图研究团队此前在PDAC小鼠模型中发现，氯沙坦可通过调控肿瘤相关成纤维细胞和细胞外基质，改善肿瘤血管灌注和缺氧，从而增强化疗药物的疗效[5]。基于这一发现，研究团队在局部晚期PDAC患者中开展了两项II期临床试验，结果显示，氯沙坦+FFX+CRT新辅助治疗可显著提高手术切除率，其中R0切除率达到61%[6]。为分析氯沙坦对PDAC肿瘤免疫微环境的影响、确定潜在的分子机制，研究团队对患者组织切片进行基因表达差异分析。与未经治疗样本相比，FFX+CRT和氯沙坦+FFX+CRT组的血管成熟相关基因（CDH5、THBS1、THBD、PDGFRB、ENG）、白细胞经内皮迁移相关基因（PECAM1、MCAM、JAM3、ICAM2、SELL、SELPLG）、T细胞活化和细胞毒性杀伤相关基因（GZMA、GZMB、KLRB1）和树突状细胞迁移和成熟相关基因（CD1C、IL3RA、CD86）表达均上调。这些结果表明，在血管正常化、增加抗肿瘤活性T细胞的经内皮迁移和增殖杀伤能力，以及刺激特定树突状细胞亚群浸润和成熟方面，FFX+CRT和氯沙坦+FFX+CRT两种方案均有促进作用。进一步分析显示，与FFX+CRT相比，氯沙坦+FFX+CRT显著降低了促进侵袭（CEACAM6、CXCL16、CCR1、PRAME、ELK1）和免疫抑制性M2型巨噬细胞（CCR1, MARCO, APOE）相关基因，以及免疫检查点TIGIT和FOXP3基因（调节Tregs转录活性）的表达，且残留病灶也明显减少，说明在FFX+CRT基础上联合氯沙坦，可能通过降低肿瘤细胞增殖和逆转免疫抑制微环境，延缓肿瘤进展。氯沙坦+FFX+CRT显著降低了促进侵袭、免疫抑制相关基因表达，减少残留病灶按照临床研究中的OS将患者进行分层（＜36个月和＞36个月）分析时，结果显示，在氯沙坦+FFX+CRT治疗的患者中，免疫抑制和侵袭相关基因的低表达，以及树突状细胞和肿瘤抑制基因的高表达，与OS改善显著相关。在氯沙坦+FFX+CRT治疗的患者中，免疫抑制和侵袭/增殖基因的低表达与OS改善相关研究者进一步对比了氯沙坦+FFX+CRT或FFX+CRT治疗的PDAC病灶组织，并使用免疫荧光技术对病理应答者（R）与无应答者（NR）的浸润免疫细胞类型进行定量和空间分析，发现在氯沙坦+FFX+CRT治疗患者的病灶样本中，应答者病灶FOXP3+Tregs数量明显更高，且CD8+T细胞浸润更多；而在无应答病灶中，Treg细胞存在于更靠近残留癌细胞的位置。氯沙坦+FFX+CRT治疗可减少Treg细胞的数量，增加CD8+T细胞的浸润 FOXP3不仅是调控Treg细胞的关键转录因子，还在PDAC肿瘤细胞中表达，是患者预后不良的生物标志物，并与FOXP3+Treg细胞的数量高度相关[7]。在氯沙坦+FFX+CRT样本中无应答组中，表达FOXP3的肿瘤细胞（C-FOXP3+）数量显著增加，并与FOXP3+Tregs呈强正相关。这些结果提示，残余肿瘤病灶中Treg的高比例，可能反映了一种对机体抗肿瘤反应的持续抑制状态。氯沙坦+FFX+CRT治疗的无应答组中，表达FOXP3的肿瘤细胞（C-FOXP3+）数量显著增加最后，研究者比较了FFX+CRT和氯沙坦+FFX+CRT组患者血浆的细胞因子水平变化差异：随着时间的推移，联合氯沙坦治疗的患者血浆中白细胞介素-8（IL-8）和转化生长因子（TGF-β）水平显著下降，sTie2（一种与血管生成相关的受体）的水平显著降低。这些特异的分子水平改变，也一定程度可作为PDAC血管生成和肿瘤进展的生物指标。氯沙坦+FFX+CRT治疗患者血浆中IL-8，TGF-β和sTie2的改变总而言之，该研究表明氯沙坦与FFX+CRT联合应用，能降低促进侵袭和免疫抑制相关基因的表达，减少了FOXP3+Treg和FOXP3+肿瘤细胞数量，并增加CD8+T细胞浸润，通过重塑免疫微环境实现与化疗/放化疗的协同增效。虽然作为一项回顾性研究，相应临床试验样本量有限且未设置对照组，但该研究也有着较好的参考价值，期待这项氯沙坦老药新用的成果能尽快转化到PDAC治疗的临床实践中。参考文献： [1] Sideras K, Braat H, Kwekkeboom J, et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies [published correction appears in Cancer Treat Rev. 2014 Aug;40(7):892]. Cancer Treat Rev. 2014;40(4):513-522. doi:10.1016/j.ctrv.2013.11.005 [2] Bazhin AV, Shevchenko I, Umansky V, Werner J, Karakhanova S. Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy. Cancer Immunol Immunother. 2014;63(1):59-65. doi:10.1007/s00262-013-1485-8 [3] Liu H, Naxerova K, Pinter M, et al. Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2017;23(19):5959-5969. doi:10.1158/1078-0432.CCR-17-0256 [4] Boucher Y, Posada JM, Subudhi S, et al. Addition of losartan to FOLFIRINOX and chemoradiation reduces immunosuppression-associated genes, Tregs and FOXP3+ cancer cells in locally advanced pancreatic cancer [published online ahead of print, 2023 Feb 7]. Clin Cancer Res. 2023;CCR-22-1630. doi:10.1158/1078-0432.CCR-22-1630 [5] Chauhan VP, Martin JD, Liu H, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516. doi:10.1038/ncomms3516 [6] Murphy JE, Wo JY, Ryan DP, et al. Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2019;5(7):1020-1027. doi:10.1001/jamaoncol.2019.0892 [7] Wang X, Lang M, Zhao T, et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma. Oncogene. 2017;36(21):3048-3058. doi:10.1038/onc.2016.458

免疫疗法临床2期

2023-02-27

·生物谷

Cancer Res: ROR2可能为前列腺癌潜在的生物标志物

前列腺癌症（PCa）是男性癌症相关死亡的主要原因。雄激素剥夺治疗（ADT）仍然是标准的全身治疗，但患者总是进展为转移性去势耐受性前列腺癌症（mCRPC）。前列腺癌症（PCa）是男性癌症相关死亡的主要原因。雄激素剥夺治疗（ADT）仍然是标准的全身治疗，但患者总是进展为转移性去势耐受性前列腺癌症（mCRPC）。这些肿瘤大多会对雄激素信号抑制剂（ASIs）的进一步治疗产生反应，但不可避免地会产生耐药性。雄激素受体（AR）和相互作用途径的改变在许多情况下有助于AR的持续活性和肿瘤生长，而其他肿瘤则独立于AR，其中一部分肿瘤具有神经内分泌特征（神经内分泌前列腺癌，NEPC）。Wnt信号的增加是与mCRPC和ASI抵抗进展相关的机制之一。图片来源：https://pubmed.ncbi.nlm.nih.gov/36622276/ 近日，来自哈佛医学院医学与癌症中心医学部血液肿瘤科的研究者们在Cancer Res. 杂志上发表了题为“WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth”的文章，研究结果表明：通过ROR2的WNT5a信号传导激活Hippo通路，以下调YAP1/TAZ活性并抑制肿瘤生长，将ROR2确定为潜在的生物标志物，以识别可能受益于WNT5a相关药物的患者。 WNT5a的非规范Wnt信号传导具有致癌和肿瘤抑制活性，但介导这些特定效应的下游途径仍有待完全建立。在前列腺癌症器官样培养和异种移植模型的一个子集中，Wnt合成的抑制刺激生长，而WNT5a或WNT5a-模拟肽（Foxy5）显著抑制肿瘤生长。 WNT5a导致YAP1活性的ROR2依赖性降低，这与MST1/2、LATS1、MOB1和YAP1的磷酸化增加相关，表明Hippo通路激活。删除MST1/2取消了WNT5a响应。WNT5a类似地激活表达ROR2的黑色素瘤细胞中的Hippo，而在ROR2阴性细胞中的WNT5a抑制Hippo。这种抑制与在表达ROR2的细胞中未观察到的NF2/Merlin的抑制性磷酸化增加有关。 WNT5a还增加了编码Hippo通路成分（包括MST1和MST2）的mRNA，并与前列腺癌症临床数据集中的这些成分呈正相关。相反，ROR2和WNT5a的表达受到YAP1的刺激，并与临床数据集中YAP1活性的增加相关，显示WNT5a/ROR2负反馈回路调节YAP1活性。 WNT5a/FZD介导的对Hippo的抑制与WNT5a/ROR2介导的Hippo激活的模型。图片来源：https://pubmed.ncbi.nlm.nih.gov/36622276/ 综上所述，这些发现确定Hippo通路激活是介导WNT5a肿瘤抑制作用的机制，并表明ROR2的表达可能是WNT5a模拟药物反应性的预测性生物标志物。（生物谷 Bioon.com）参考文献 Keshan Wang et al. WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth. Cancer Res. 2023 Jan 9;CAN-22-3003.doi: 10.1158/0008-5472.CAN-22-3003.

临床结果信使RNA临床研究

2023-02-14

·MedCity News

Mineralys IPO Lands $192M for Blood Pressure Trials and Chance to Challenge AstraZeneca

Mineralys Therapeutics’ hypertension drug candidate could offer a new treatment option for patients who don’t adequately respond to currently available blood pressure medicines. The once-daily pill is nearing a pivotal test, and Mineralys has raised $192 million in IPO cash to finance its clinical trial plans. When Mineralys set preliminary terms for the IPO last week, it planned to sell 10 million shares in the range of $14 to $16 per share. The Radnor, Pennsylvania-based company ended up adding 2 million shares to the offering, which priced late Thursday at the top of the projected price range. Those shares began trading Friday on the Nasdaq under the stock symbol “MLYS.” Many patients who have hypertension take multiple medications to manage the condition. However, more than half of the 115 million people in the U.S. with sustained elevated blood pressure fail to meet their blood pressure reduction goals, Mineralys says in its IPO filing. That failure puts these patients at greater risk of death due to cardiovascular disease or stroke. Standard-of-care drugs include angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which work by lowering levels of aldosterone, a hormone that regulates blood pressure. Another class of drugs work by blocking aldosterone’s activity at the called mineralcorticoid receptor. Mineralys aims to address aldosterone, but in a different way than currently available medications. Its small molecule drug, lorundrostat (previously known as MLS-101), is an aldosterone synthase inhibitor (ASI). It blocks aldosterone synthase, an enzyme key to the synthesis of the hormone. The company says its molecule is highly selective, hitting its enzyme target without also hitting other targets, such as the hormone cortisol. “Several large pharmaceutical companies have tried to develop ASIs, but their efforts have been hampered due to insufficient selectivity for aldosterone, resulting in off-target toxicities associated with cortisol inhibition,” Mineralys said in the filing. “These challenges have led to the discontinuation of many ASIs in development to date.” Last November, Mineralys reported preliminary data from a placebo-controlled Phase 2 test enrolling 200 patients with uncontrolled or treatment-resistant hypertension. Those participants had been taking up to two anti-hypertensive drugs to manage their blood pressure. Results showed the study met its blood pressure reduction goals. Furthermore, the study drug was well tolerated by patients. Serious adverse events were reported in three participants. In two of them, the effects were deemed unrelated to the drug. The third patient had pre-existing below normal sodium levels in the blood, which reversed after stopping treatment with the Mineralys drug. The next step for lorundrostat is another Phase 2 study to evaluate the safety and efficacy of the molecule when used as an add-on therapy in patients who are taking two or three anti-hypertensive medications. This double blind, placebo-controlled study will enroll up to 240 adults and will start in the first half of this year. Meanwhile, Mineralys plans to start a Phase 3 study in the second half of this year. The trial design will be similar to that of the Phase 2 study except it will have more patients—up to 1,000 adults with uncontrolled or treatment-resistant hypertension. Preliminary data are expected in mid-2025. Mineralys also wants to see how its drug works addressing hypertension in patients with chronic kidney disease. A Phase 2 study is expected to start in the middle of this year. Mineralys is pursuing its clinical trial plans as rival CinCor Pharma prepares for a pivotal test of its aldosterone synthase inhibitor, baxdrostat. Despite failing in Phase 2 last November, the biotech reported encouraging results in a subgroup of patients that it said could inform the design of a Phase 3 study. AstraZeneca apparently sees potential in the CinCor drug. Last month, it agreed to pay $1.3 billion to acquire CinCor. Lorundrostat traces its origins to Mitsubishi Tanabe, which discovered the molecule and advanced it as far as Phase 1 testing. Venture capital firm Catalys Pacific founded Mineralys in 2019, according to the filing. The following year, Mineralys licensed global rights to lorundrostat, paying $1 million up front. The deal includes milestone payments of up to $9 million for development and $155 million if the drug reaches the market. Mineralys has raised $158 million since its inception, most recently a $118 million Series B financing last June led by RA Capital and Andera Partners. According to the prospectus, Catalys Pacific is Mineralys’s largest shareholder, owning a 24.1% post IPO stake, followed by Samsara Capital’s 9.7% stake. Mineralys’s CEO is Jon Congleton, a veteran of Impel NeuroPharma, Nivalis Therapeutics, and Teva Pharmaceutical Industries. The company reported its cash position was $110.4 million at the end of 2022. It estimates that this capital combined with the IPO proceeds will be sufficient to fund operations for at least the next 18 months—enough time for the two planned Phase 2 tests of lorundrostat to report preliminary data. Photo by Getty Images 内容来源于网络，如有侵权，请联系删除。