Open Label, Multicenter, Phase 1 Study to Evaluate the Maximum Tolerated Dose of Orally Administered CB-03-10 With Dose Expansion Phase, in Subjects With Advanced Solid Tumors

Subjects will undergo baseline evaluation and an assessment of extent of disease.
Subjects in Part 1 (Dose Escalation) will receive escalating doses of CB-03-10 based on a modified Fibonacci schema using a standard oncology 3+3 study design to define an MTD and a RP2D. Plasma PK samples will be collected at predetermined timepoints for all subjects.
Subjects in Part 2 (Dose Expansion) of the study will receive CB-03-10 at the RP2D determined in the Part 1 of the study. The indications included in each group will be determined at the completion of Part 1 of the study by Safety Review Committee (SRC).
Subjects will be evaluated weekly initially (for 2 cycles in Part 1 and for 1 cycle in Part 2) and every 2 weeks thereafter. Reassessment of disease will be conducted at Week 8 and every 8 weeks thereafter. Subjects with evidence of response (partial or complete) will be re-evaluated at least 4 weeks later for confirmation.

开始日期2022-06-14

申办/合作机构

Cosmo Technologies Ltd.

100 项与 AR x GR 相关的临床结果

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100 项与 AR x GR 相关的转化医学

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0 项与 AR x GR 相关的专利（医药）

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项与 AR x GR 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

EP300/CREBBP acetyltransferase inhibition limits steroid receptor and FOXA1 signaling in prostate cancer cells

Article

作者: Huttunen, Jasmin ; Aaltonen, Niina ; Paakinaho, Ville ; Rilla, Kirsi ; Helminen, Laura

AbstractThe androgen receptor (AR) is a primary target for treating prostate cancer (PCa), forming the bedrock of its clinical management. Despite their efficacy, resistance often hampers AR-targeted therapies, necessitating new strategies against therapy-resistant PCa. These resistances involve various mechanisms, including AR splice variant overexpression and altered activities of transcription factors like the glucocorticoid receptor (GR) and FOXA1. These factors rely on common coregulators, such as EP300/CREBBP, suggesting a rationale for coregulator-targeted therapies. Our study explores EP300/CREBBP acetyltransferase inhibition’s impact on steroid receptor and FOXA1 signaling in PCa cells using genome-wide techniques. Results reveal that EP300/CREBBP inhibition significantly disrupts the AR-regulated transcriptome and receptor chromatin binding by reducing the AR-gene expression. Similarly, GR’s regulated transcriptome and receptor binding were hindered, not linked to reduced GR expression but to diminished FOXA1 chromatin binding, restricting GR signaling. Overall, our findings highlight how EP300/CREBBP inhibition distinctively curtails oncogenic transcription factors’ signaling, suggesting the potential of coregulatory-targeted therapies in PCa.

2024-10-18·RSC medicinal chemistry

Synthesis and biological evaluation of novel D-ring fused steroidal N(2)-substituted-1,2,3-triazoles.

Article

作者: Kopp, Florian ; Sakač, Marija ; Tenjović, Branislava ; Scholda, Julia ; Petri, Edward ; Nikolić, Andrea ; Ćelić, Andjelka ; Bekić, Sofija

In this study, a series of 13 new D-ring fused steroidal N(2)-substituted-1,2,3-triazoles were synthesized, characterized and evaluated for their biological activities. The relative binding affinities of the synthesized compounds for the ligand-binding domains of estrogen receptors α and β, androgen receptor and glucocorticoid receptor demonstrated that androstane derivatives 3a and 3h and estratriene derivative 4e showed highly specific and strong binding affinity for estrogen receptor β, while 3b, 3e, 4a and 4b displayed high binding affinity for the glucocorticoid receptor. The synthesized compounds were tested for their ability to inhibit aldo-keto reductases 1C3 and 1C4 in vitro by monitoring NADPH consumption using fluorescence spectroscopy. The most potent aldo-keto reductase 1C3 inhibitors were compounds 3h (71.17%) and 3f (69.9%). Moreover, a molecular docking study was carried out for compounds 3f and 3h against aldo-keto reductase 1C3 and results showed that compounds 3h and 3f could bind in the same site and orientation as EM1404. However, polar atoms in the triazole group enable additional hydrogen bonding deeper in SP1 with Tyr319, Tyr216 and the NADP⁺ cofactor, which are not visible in the AKR1C3-EM1404 crystal structure. The synthesized compounds were screened for their anticancer activity against four cancer cell lines. Compound 3f demonstrated moderate toxic effects across various cancer types, while displaying lower toxicity towards the healthy cell line. In summary, our findings indicate that N(2)-substituted-1,2,3-triazoles are high-affinity ligands for estrogen receptor β and glucocorticoid receptor, inhibitors of aldo-keto reductase 1C3 enzyme, and exhibit antiproliferative effects against cancer cells, suggesting that they could serve as scaffolds for anticancer drug development.

2024-10-12·Journal of Biomolecular Structure and Dynamics

Multitargeted pharmacokinetics, molecular docking and network pharmacology-based identification of effective phytocompounds from Sauropus androgynus (L.) Merr for inflammation and cancer treatment

Article

作者: Gayathiri, Ekambaram ; Dayalan, Haripriya ; Prakash, Palanisamy ; Thangaraj, Pratheep ; Venkidasamy, Baskar ; Pandiaraj, Saravanan ; Chaudhari, Somdatta Y. ; Ahamed, Maqusood ; Thiruvengadam, Muthu ; Selvam, Kuppusamy ; Govindasamy, Rajakumar

According to worldwide health data, cancer, and inflammatory illnesses are on the rise and are among the most common causes of death. Across the world, these types of health problems are now considered top priorities for government health organizations. Hence, this study aimed to investigate medicinal plants' potential for treating cancer and inflammatory disorders. This network pharmacology analysis aims to learn more about the potential targets and mechanisms of action for the bioactive ingredients in Sauropus androgynus (L.) Merr L. The compound-target network and protein-protein interaction analysis were built using the STRING database. Using Network Analyst, Gene Ontology, and Kyoto Encyclopaedia of Genes and Genomes, pathway enrichment was performed on the hub genes. 1-hexadecanol was shown to inhibit drug-metabolizing enzymes in a pharmacokinetic investigation. Those samples of 1-hexadecanol were found to be 1-hexadecanol (BBB 0.783), GI High, Pgp Substrate Yes, CYP2C19 Inhibitor Yes, CYP2D6 Yes, and HI -89.803. The intermolecular binding energies for 1-hexadecanol (4-DRI, -8.2 kcal/mol) are evaluated. These results from a study on S. androgynus used molecular docking and network pharmacology to gain insight into the prime target genes and potential mechanisms identified for AKT1, mTOR, AR, PPID, FKBP5, and NR3C1. The PI3K-Akt signalling pathway has become an important regulatory node in various pathological processes requiring coordinated actions. Stability and favourable conformations have been resolved by considering nonbonding interactions such as electrostatic and hydrogen bonds in MD simulations of the perfect molecules using the Desmond package. Thus, using an appropriate platform of network pharmacology, molecular docking, and in vitro experiments, this study provides for the first time a clearer knowledge of the anti-cancer and anti-inflammatory molecular bioactivities of S. androgynus. Further in vitro and in vivo confirmations are strongly needed to determine the efficacy and therapeutic effects of 1-hexadecanol in the biological process.Communicated by Ramaswamy H. Sarma.

项与 AR x GR 相关的新闻（医药）

2024-07-08

·Insight数据库

年中盘点｜国内 40 款化药新药进入 III 期临床

岁月不居，时节如流。2024 年，新药研发稳中求进。在这半年间，各大药企争分夺秒，力求尽早推出具有竞争力的创新药品，从而在市场上占据一席之地。那么，有哪些值得期待的新药呢？在这里我们基于 Insight 数据库，整理了 2024 上半年各个药企在国内新进入 III 期临床试验阶段（包括 2/3 期临床）的化药小分子新药。这些项目或将成为最接近申报上市的新药，代表着化药领域的最新突破和蓬勃发展。研发热度不减，抗肿瘤新药仍占大头作为全球最大的细分赛道，肿瘤领域一直都是各大药企的「兵家必争之地」，今年也是如此。从目前来看，肿瘤领域共有 11 款新产品，其适应症涵盖了肺癌等癌症类型，同时为了避免「同质化」，靶点也更为多样化。在这里我们选取几款具有代表性的新药进行分析。在肺癌领域，既有拜耳这样的国际药企加入赛道，也有首要控股、加科思等国内药企积极发力。其中，BAY 2927088 是拜耳开发的酪氨酸激酶抑制剂（TKI），主要针对携带 HER2 激活突变的非小细胞肺癌（NSCLC）患者。今年 2 月和 6 月，该药物先后获得 FDA 和 CDE 的「突破性疗法」认定，并于 6 月启动针对这一患者群体的一线治疗 III 期临床试验。首药控股的 CT-3505 属于国产第三代 ALK 抑制剂。它在靶向 ALK 的同时还靶向 FAK、LTK 和 PTK2B 等关键蛋白，旨在克服单一靶点药物容易产生的耐药性问题。今年 1 月，首药控股启动 CT-3505 在 ALK 阳性 NSCLC 患者中的 III 期临床试验，并在 3 月 25 日完成首例受试者的入组工作。 CTR20240005 试验历史时光轴截图来自：Insight 数据库官网 JAB-3312 是加科思自主研发的高选择性 SHP2 变构抑制剂，也是全球第二个获得 FDA 批准进入临床的同类产品。2020 年 9 月，FDA 授予该新药治疗食道癌（包括食管鳞癌）的孤儿药资格认定。今年 5 月，JAB-3312 与戈来雷塞联合用于晚期非鳞状 NSCLC 患者的临床试验正式启动。在血液肿瘤方面，Golcadomide 是 BMS 子公司新基医药开发的新型 E3 泛素连接酶 Cereblon 调节剂（CELMoD）分子。该药物针对非霍奇金淋巴瘤（NHL）的特性进行了优化，显著增强其在淋巴器官中的分布。目前，Golcadomide 正在开展针对多种类型 B 细胞淋巴瘤的 III 期临床研究。此外，BCL2 作为调节细胞凋亡的关键蛋白，在慢性淋巴细胞白血病（CLL）和小淋巴细胞淋巴瘤（SLL）等血液系统恶性肿瘤中呈现高表达。针对这一靶点，亚盛医药和诺诚健华均进行了战略布局。亚盛医药的 Lisaftoclax 是首个在国内进入临床阶段、本土研发的 BCL2 抑制剂，它在上半年连续启动了 2 项中国内地 III 期临床试验。目前唯一获批上市的 BCL2 抑制剂是艾伯维的维奈托克（Venetoclax）。 Lisaftoclax 国内 III 期临床试验截图来自：Insight 数据库官网除肺癌及血液肿瘤外，来凯医药的 AKT 抑制剂 Afuresertib 也在今年 5 月展开了针对局部晚期或转移性 HR+/HER2- 乳腺癌患者的 III 期临床研究。聚焦内分泌与代谢疾病，六款新药实现突破在内分泌与代谢领域，靶向新药的开发正日益受到重视。接下来，我们将聚焦于表格中提到的几款新药，来探讨其临床潜力。首先，糖尿病作为该领域的热门话题，其庞大的患者基数促使多个药企纷纷抢占市场。此次在国内新进入 III 期临床的新药包括诺和诺德的 Cagrilintide 和中国科学院上海药物研究所研发的 LH-1801。 Cagrilintide 是一种基于胰淀素模板的衍生多肽，目前正在进行 2 型糖尿病的 III 期临床研究。除此之外，Cagrilintide 与「减肥神药」司美格鲁肽的组合疗法也在 2023 年进入了肥胖治疗的 III 期临床研究。 Cagrilintide III 期临床研究截图来自：Insight 数据库官网其次，痛风领域长期缺乏疗效显著的新药，具备了创新的土壤。URAT1 作为降尿酸的热门靶点，目前全球在研新药达 40 种，其中大多数由国内药企开发。海创药业的 HP501 以及一品红和美国 Arthrosi 公司合作研发 AR 882 都是靶向 URAT1 的创新药物，前者于今年 3 月正式启动治疗原发性痛风伴高尿酸血症的 Ⅱ/Ⅲ 期临床试验，后者则在 4 月展开适应症为痛风的 Ⅱ/Ⅲ 期临床研究。最后，恒瑞医药自主研发的 HRS9531 和 SHR-6508 也备受关注。HRS9531 是靶向 GIPR 和 GLP1R 的双重受体激动剂，通过增加胰岛素分泌、抑制食欲和促进体重减轻来治疗肥胖。SHR-6508 则是用于治疗继发性甲状旁腺功能亢进症的新分子药物，尽管其具体靶点尚未公开，但其创新的作用机制有望为这一疾病提供新的治疗选择。打破桎梏，心血管疾病治疗又添「新将」心血管疾病涉及心脏和血管的多种病理生理机制，每种机制都可能对治疗效果产生重大影响。此外，临床试验设计的严格要求、庞大的样本量需求以及长期的随访观察，都增加了新药研发的复杂性。因此，针对这一领域的新药，我们将对其中两款展开评述。脂蛋白(a) [Lp(a)] 是心血管疾病的要遗传因素，而 LPA 基因负责编码构建 Lp(a) 的载脂蛋白(a)。Lepodisiran 是基于小干扰 RNA（siRNA）技术设计的药物，其原理是通过阻断或「沉默」LPA 基因，降解编码载脂蛋白(a) 的信使 RNA (mRNA)，从而抑制 LPA 基因的翻译，降低血液中 Lp(a) 的水平。目前尚无针对 Lp(a) 的药物获得监管部门的批准，Lepodisiran 的研发填补了这一空白。今年 3 月，在 Lp(a) 水平升高且确诊为动脉粥样硬化性心血管疾病或具有首次心血管事件高风险的成年人中进行的 III 期临床研究正式启动，旨在评估 Lepodisiran 对主要不良心血管事件的影响。 Lepodisiran 最初由 Dicerna 制药公司研发。2018 年，礼来公司与 Dicerna 达成战略合作协议，共同开发多种 siRNA 疗法，其中 Lepodisiran 是这一合作中的第二条管线产品。 Lepodisiran 医药交易截图来自：Insight 数据库官网 CYP11B2 是负责编码醛固酮合成酶的基因，参与了醛固酮的合成过程。Baxdrostat 作为醛固酮合成酶抑制剂（ASI），通过靶向 CYP11B2 以用于高血压和慢性肾病的治疗。今年 2 月和 3 月，Baxdrostat 针对这两项适应症的 III 期临床研究分别正式启动。 Baxdrostat 针对高血压和慢性肾病的 III 期临床研究截图来自：Insight 数据库官网据悉，Baxdrostat 最初由罗氏着手开发。2019 年 CinCor 收购该药物并接管其全部开发、制造和商业化工作。2023 年阿斯利康又通过收购该药物来加强其心肾疾病治疗产品线。呼吸系统、皮肤及眼科新药，同样不容错过呼吸系统、皮肤及眼科领域的新药竞争同样相当激烈。从研发机构和靶点出发，以下几款新药值得关注。在呼吸系统领域，阿斯利康的沙丁胺醇与布地奈德组合药物（PT027）是靶向 ADRB1、ADRB2、ADRB3 和 GR 的复方药物。作为首款且唯一经 FDA 批准的哮喘抗炎缓解药，它在国内已进入治疗哮喘的 III 期临床研究，有望为我国患者带来生存获益。 Camlipixant 是一种选择性口服 P2X3 受体拮抗剂，通过靶向 P2RX2 和 P2RX3 用于治疗慢性咳嗽。其作用机制是抑制嘌呤能受体，从而减少咳嗽反射的频率和强度。对于那些受到顽固性咳嗽困扰的患者来说，Camlipixant 提供了全新的治疗选择。 Camlipixant 最初由 BELLUS Health 开发。2023 年 4 月，GSK 以 20 亿美元收购了 BELLUS Health，将 Camlipixant 纳入其产品管线。在皮肤和眼科这两个小众赛道，靶向新药也在不断涌现。芦可替尼乳膏通过抑制 JAK1 和 JAK2 的活性，阻断 JAK-STAT 信号通路，用于治疗非节段型白癜风和特应性皮炎。 Incyte Corporation 是芦可替尼乳膏的开发者。2022 年 12 月，康哲药业与 Incyte 达成协议，负责芦可替尼乳膏在中国市场的开发、注册和商业化推广。此外，AR 在调节皮脂腺功能和维护皮肤健康方面也发挥着重要作用。三生制药与 Cosmo 合作开发的克拉考特通过抑制 AR，减少皮脂腺的活性，降低皮脂分泌，从而防止毛囊堵塞和炎症反应，有效控制痤疮的发展。眼科疾病方面，莱恩医药研发的洛索洛芬通过抑制 COX，减少前列腺素生成，有效缓解眼部术后炎症和疼痛。维眸生物的 VNV001 靶向整合素 ITGAL 和 ITGB2，减少炎症细胞在眼表面的积聚，减轻干眼症症状。博瑞制药的阿托品作为 CHRM 激动剂，通过调节眼球生长和发育，延缓近视进展。其他此外，上半年新进入 III 期临床的化药小分子新药还涉及精神障碍、镇静止痛和感染性疾病等多个领域，参与研发的企业包括吉贝尔药业、Zevra Therapeutics、立品药业和恩华药业等。封面来源：站酷海洛 Plus 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。 PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验点击阅读原文，立刻解锁！

临床3期突破性疗法孤儿药

2024-07-08

·BiG生物创新社

诺和诺德高血压药物，OcedurenoneⅢ期临床失败

作者｜YY 在坐拥“法力无边”的GLP-1药物semaglutide的同时，诺和诺德也居安思危地扩展其商业领域。去年以13亿美元收购亨利医药（KBP Biosciences）的心/肾脏病控制高血压药物ocedurenone（图1），就代表着诺和诺德将业务扩展到代谢疾病以外的战略思想。 Ocedurenone的原本目标是成为同类最优的控制高血压治疗药物，然而近期风光无限的诺和诺德却在ocedurenone的Ⅲ期临床研究Clarion-CKD中遭遇失败。图1. Ocedurenone化学结构。 01 诺和诺德罕见临床失败诺和诺德日前表示，在研究了ocedurenone的临床数据之后，他们决定终止这一项目。这将造成约 57 亿丹麦克朗（8.2 亿美元）的减值损失（impairment loss）。之所以做出这一决定，是因为独立监督委员会认为ocedurenone未能达到 12 周后改变血压的主要目标。 Clarion-CKD 是一项针对 600 多名患者的临床项目，研究ocedurenone对高血压失控和晚期慢性肾病患者的作用。该试验未达到其主要终点，即从基线到第 12 周收缩压的变化。去年10 月在宣布这项购买交易时，诺和诺德高管曾表示，他们预测ocedurenone将满足心脏病和慢性肾病患者的巨大需求。诺和诺德在做出终止Clarion-CKD研究之后表示，目前他们正在重新评估ocedurenone针对其它适应症的研究计划。 02 晚期慢性肾病和难治性高血压晚期慢性肾病（CKD）患者的疾病负担很重，并伴有严重的合并症，最常见的是高血压。控制高血压对于这些患者来说至关重要，可以降低相关的发病率和死亡率，以及降低心肾风险，但由于使用现有药物存在安全问题，治疗选择有限。较轻的 CKD 可能多年都无法确诊，而治疗则集中在更明显的高血压、糖尿病和其他合并症问题上。对于那些未患晚期 CKD 的难治性高血压患者来说，螺内酯（spironolactone，商品名Aldactone）比 β 受体阻滞剂（β-blockers，例如Acebutolol，Nadolol，Propranolol等）和 α 受体阻滞剂（α-blockers，例如Cardura，Minipress等）能更有效地降低血压。然而，服用螺内酯会给患者带来安全风险。然后就是依普利酮（Eplerenone），每天服用两次，虽然安全，但降压效果比螺内酯弱得多。患者选择非常有限。高血压领域已经有 15-20 年没有新药了。醛固酮合酶抑制剂baxdrostat公布的II期数据令人鼓舞，但对象是正常肾脏人群。此外，双重内皮素受体拮抗剂aprocitentan也是一个有力竞争者。它在 3 期 PRECISION 试验中针对难治性高血压患者表现出非常好的降压效果，但有水肿副作用，这是内皮素受体拮抗剂常见的副作用。 03 OcedurenoneⅢ期临床失败是该领域的一大遗憾 Ocedurenone为一款非甾体类、第三代盐皮质激素受体拮抗剂（MRA）。醛固酮（aldosterone）激素在高血压过程中扮演着重要的角色，尤其是在肾源性高血压中特别突出。醛固酮是一种由肾上腺皮质分泌的激素，它主要作用于肾脏内的盐皮质激素受体，调节钠钾的代谢来维持体内的电解质平衡。它的主要生理作用包括促进肾小管对钠的重吸收，同时增加钾和氢离子的排泄。在肾小管的集合管和近曲小管，醛固酮促进钠的再吸收，这导致血容量增加，从而使血压升高。醛固酮可以增强肾素-血管紧张素系统（RAAS）的活性。RAAS的激活会导致血管收缩和钠水潴留，进一步提高血压。在高血压患者中，醛固酮的水平通常升高，尤其是在原发性高血压（特别是肾性高血压）和部分难治性高血压患者中。长期高血压导致肾脏血管损伤，进而刺激醛固酮的释放。同时血压升高导致RAAS系统过度活跃，促使醛固酮的合成和释放增加。醛固酮释放不当升高会导致高血压、心血管和肾脏终末器官损伤和衰竭，因此针对这种病理的药物开发主要集中在两个方向：抑制醛固酮合成，以及阻断盐皮质激素受体 (MR)，醛固酮是MR的内源性配体。常见类固醇类MRA（盐皮质激素受体拮抗剂）可以抑制醛固酮与MR受体的作用，可以降低“醛固酮逃逸”，但其应用受到高钾血症的风险而被限制。另外，由于现有类固醇MRA药物对糖皮质激素受体和雄激素受体有作用，导致多种内分泌的不良事件，同样限制了此类药物的广泛应用。以ocedurenone为代表的第三代非甾体类盐皮质激素受体拮抗剂（Non-steroidal mineralocorticoid receptor antagonists，nsMRA）被FDA认定为一种独特的新型抗高血压药物，也成为了治疗CKD和难治性高血压的新希望。Ocedurenone与甾体类MRA截然不同，特点是半衰期长（约为 60 小时），盐皮质激素受体 (MR) 亲和力高，而对糖皮质激素、孕酮和雄激素受体的结合亲和力很小或为零。它不会进入大脑，没有活性代谢物。非甾体 MRA 药物esaxerenone（图2）已在日本获批用于治疗高血压，但其对晚期 CKD 患者的疗效尚未经过测试。拜耳的nsMRA药物finerenone在2021年获得了FDA的批准，用于降低 2 型糖尿病（T2D）相关慢性肾病（CKD）成人患者持续 eGFR （估算肾小球滤过率）下降、肾衰竭、心血管死亡、非致命性心肌梗死（MI）和心力衰竭住院的风险，成为获得FDA批准的首例nsMRA类药物，可显著减缓慢性肾病进展并降低 2 型糖尿病相关慢性肾病患者的心血管风险。图2. nsMRA拮抗剂药物esaxerenone和finerenone化学结构。虽然两款nsMRA被不同的监管机构批准上市，但患有难治性高血压的晚期CKD仍然缺乏有效的治疗方法。Ocedurenone原本肩负着人们攻克这一顽症的希望，而且也收获了令人鼓舞的II期临床数据，但最终的III期临床却没有能够达到设定的血压临床终点，这不得不说是一个相当大的遗憾。参考资料： [1] Novo Nordisk stops the ocedurenone CLARION-CKD trial and recognises impairment loss. Novo Nordisk Press Release. 26. 06. 2024. [2] Kresge, N. Novo to Buy Experimental Heart Drug for Up to $1.3 Billion. Bloomberg. 16. 10. 2023. [3] FDA Approves Kerendia. Drugs.com. July. 2021. [4] Ocedurenone: A Novel Therapy for Uncontrolled Hypertension in Advanced Chronic Kidney Disease. European Medical Journal. 16. 03. 2023. 共建Biomedical创新生态圈！如何加入BiG会员？

临床3期临床终止临床2期临床失败并购

2024-04-10

·Science Daily

New insight into combating drug-resistant prostate cancer

New research sheds light on the significance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting the activity of coregulator proteins. New research from the University of Eastern Finland sheds light on the significance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting the activity of coregulator proteins. Glucocorticoids regulate vital biological processes by affecting gene encoding through a DNA-binding transcription factor, namely the glucocorticoid receptor. The activity of the glucocorticoid receptor is made extensive use of in medicine because glucocorticoids have a strong anti-inflammatory effect. For this reason, synthetic glucocorticoids are one of the most prescribed drugs in the world. They are used to treat inflammatory diseases, such as rheumatoid arthritis, and as adjuvant therapy for cancer patients to alleviate the side effects of cancer therapy. In blood cancer, glucocorticoids are important drugs that limit the growth of cancer cells. However, recent studies have shown that the glucocorticoid receptor also has an oncogenic, or cancer-promoting, effect in cancers like breast and prostate cancer. In prostate cancer, the glucocorticoid receptor can replace the activity of the androgen receptor, which is main oncogenic factor in this cancer, when its activity is inhibited by drug therapy. Thus, glucocorticoids help prostate cancer develop resistance to drug therapy. "Due to these drug resistance and cancer-promoting effects, it is important to study how the glucocorticoid receptor functions on the cellular and molecular level in cancer," Academy Research Fellow, Docent Ville Paakinaho of the University of Eastern Finland notes. The Paakinaho Lab has published two recent genome-wide deep sequencing studies on the subject. The first, published in Nucleic Acids Research, explored how the glucocorticoid receptor replaces the androgen receptor on the molecular level. "This study showed that the glucocorticoid receptor can only use regulatory regions that are already active in prostate cancer cells," says Doctoral Researcher Laura Helminen of the University of Eastern Finland. In other words, glucocorticoid receptor-mediated drug resistance emerges through these regulatory regions, and by affecting the activity of these areas, the harmful effects of glucocorticoids in prostate cancer could be prevented. Bioinformatics analyses indicated the pioneer transcription factor FOXA1 as one possible target. FOXA1 is known to have cancer-promoting properties, which is why the researchers assumed that inhibiting its activity would limit the development of glucocorticoid receptor-mediated drug-resistant prostate cancer. Surprisingly however, the effect was exactly the opposite: inhibiting the activity of FOXA1 further increased the activity of the glucocorticoid receptor -- and the development of drug resistance. This is because FOXA1 was found to be involved in the silencing of the glucocorticoid receptor gene, and this is what increased its activity when FOXA1 was inhibited. "Research often reveals the unexpected, and that's part of its charm," Paakinaho says. The activity of the glucocorticoid receptor in regulatory regions can, however, be influenced in drug-resistant prostate cancer through an alternative pathway. Coregulator proteins were identified as an alternative target through which the glucocorticoid receptor affects the regulation of gene expression. These proteins include EP300 and CREBBP. Several pharmaceutical companies are developing small-molecule inhibitors targeting these proteins, and some are already being studied in patients. In another study by the Paakinaho Lab, the researchers explored ways to inhibit glucocorticoid receptor-mediated effects by inhibiting coregulator proteins. These findings were reported in Cellular and Molecular Life Sciences. "Silencing the EP300 and CREBBP proteins with a small-molecule inhibitor clearly prevented the activity of the glucocorticoid receptor in prostate cancer cells," Project Researcher Jasmin Huttunen of the University of Eastern Finland says. This allowed the growth of drug-resistant prostate cancer cells to be inhibited. Furthermore, the researchers found that silencing EP300 and CREBBP also effectively inhibited the activity of the androgen receptor especially in prostate cancer cells that have an amplification of the androgen receptor gene. This amplification is found in up to half of patients with advanced prostate cancer. Surprisingly, the EP300 and CREBBP inhibitor also inhibited the activity of FOXA1, while still preserving its ability to silence the expression of the glucocorticoid receptor gene. By using the EP300 and CREBBP inhibitor, it was possible to block the activity of FOXA1 without the development of glucocorticoid receptor-mediated drug resistance. Ultimately, inhibiting the activity of both the androgen and the glucocorticoid receptor was found to be primarily due to the limitation of FOXA1 activity. The study suggests that treatment targeting coregulator proteins could also be effective in untreated prostate cancer. The studies were funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland.