Acitretin

*仅供医学专业人士阅读参考阿达帕林，抗痘战士的必修之课。阿达帕林凝胶是一种局部使用的类视黄醇化合物，广泛用于治疗轻至中度痤疮。它通过调节细胞分化和角化过程，减少皮脂堵塞，抑制炎症，从而减少粉刺和痤疮的形成。 今天要说的，是阿达帕林在抗肿瘤领域与化疗的特殊合作。 近日，瑞士肿瘤研究所Andrea Alimonti团队的最新研究成果发表在《癌细胞》期刊上[1]。他们发现，视黄酸受体（RAR）的激活能够触发前列腺癌细胞强烈的衰老反应，使其表现为肿瘤抑制性衰老相关分泌表型（SASP）。作为视黄酸受体激动剂，阿达帕林是前列腺癌细胞的一种有效的促衰老化合物，与化疗联合治疗前列腺癌小鼠时，能够在诱导肿瘤细胞衰老的同时，增加自然杀伤细胞的肿瘤浸润和活性，从两方面着手来实现强大的抗肿瘤效应。 论文首页截图 细胞随时间推移失去其分裂和增殖的能力，最终进入一种静止状态，即细胞衰老。 肿瘤细胞衰老后，表现为衰老相关分泌表型（SASP），在肿瘤微环境中保持代谢活跃并分泌多种细胞因子和炎症因子。合理利用SASP，能够促使免疫系统强力清除衰老细胞，已经有证据表明化疗和靶向治疗可以通过诱导肿瘤细胞衰老以发挥抗肿瘤效果。相反，如果没能及时清除衰老肿瘤细胞，SASP则会持续诱导炎症反应，刺激肿瘤细胞生长、血管生成、转移和治疗抵抗。 现在存在的几种促衰老化合物，由于抗肿瘤效果不足以及潜在的副作用，严重限制了它们的临床应用，目前仍然缺乏一种能够提供持久益处的有效促衰老疗法。 在这项研究中，Andrea Alimonti团队利用其实验室先前开发的化学基因组筛选平台，识别能够促进前列腺肿瘤细胞衰老的化合物。在筛选超过90000种化合物时，研究团队优先考虑了当前处于更高阶段临床试验或已在临床中使用的化合物。 筛选结果得到三种类视黄醇化合物，为阿达帕林、贝沙罗汀和acitretin，在促进小鼠和人类前列腺癌细胞衰老方面最为有效。此外，这些化合物显著减少肿瘤细胞的生长，并激活强烈的衰老反应。 筛选和鉴定通过对机制的进一步研究，研究团队发现，这三种类视黄醇化合物作为视黄酸受体（RAR）的激动剂，通过作用于前列腺癌细胞表达的视黄酸受体，上调p21表达，从而导致细胞周期停滞和持续衰老状态。换句话说，依赖于p21，激活视黄酸受体便可以驱动前列腺癌细胞衰老。 与机制相符，利用RNA-seq技术对前列腺癌患者的样本组织进行分析，提示视黄酸信号的减弱可能与癌症的恶化相关联，在癌症进展过程中，肿瘤组织中与视黄酸信号相关的多条途径以及视黄酸代谢都相对于正常组织大幅下调；阿达帕林便是通过激活视黄酸受体，增强了前列腺癌细胞中的视黄酸下游信号。 将阿达帕林与已有的促衰老化合物联手时，弥补了后者的“毒点”。 正如前文所述，化疗药物多西他赛虽然起初可以通过诱导衰老来阻止一小部分细胞的增殖，但在培养十天之后，SASP反倒“助纣为虐”，促进肿瘤生长和迁移，属于促肿瘤型SASP。 但是当阿达帕林或贝沙罗汀与多西他赛联合使用时，与多西他赛单一治疗相比，能够造成持久的衰老诱导效应，使衰老前列腺癌细胞的占比从30%增加到60%，长期诱导细胞生长停滞，更加有效抑制肿瘤细胞生长。 多西他赛单独治疗诱导促肿瘤型SASP，联合治疗可产生持续有效的促衰老效果和肿瘤抑制效果相比于多西他赛，阿达帕林、贝沙罗汀作为促衰老化合物的优势究竟何在？ 研究团队验证表明，多西他赛诱导衰老细胞表现为促肿瘤型SASP，是因为会促使前列腺癌细胞中转录因子AP-1活性显著提升。如果在使用多西他赛诱导肿瘤细胞衰老的时候抑制AP-1的活性，便可以在其发挥促衰老效应时避免出现促肿瘤型SASP。而阿达帕林能够正是抑制AP-1的激活，重新修正多西他赛的失误，对前列腺癌细胞的SASP进行重编程。 前列腺癌小鼠实验结果显示，不同于多西他赛诱导的SASP中存在AP-1这个“二五仔”，阿达帕林和多西他赛联合治疗时诱导肿瘤细胞分泌的SASP，富含可以吸引和激活自然杀伤细胞的细胞因子。 简单而言，阿达帕林+多西他赛联合治疗的抗肿瘤作用通过两种方式来实现：一方面凭借强烈的促衰老效应，诱导前列腺癌细胞衰老；另一方面，借由衰老肿瘤细胞分泌的SASP招募和激活自然杀伤细胞，激发强大的免疫效应，进一步抑制肿瘤的发展。 多西他赛单独治疗或多西他赛+类视黄醇化合物诱导的肿瘤细胞衰老效应不同这些结论意味着，阿达帕林+多西他赛的组合可以更有效地利用自然杀伤细胞来对抗肿瘤，支持了一种全新的前列腺癌疗法。参考文献：[1]https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00048-5本文作者丨张艾迪

DUBLIN, March 14, 2024 /PRNewswire/ -- The "Psoriasis in America 2023: Understanding the Psoriasis Patient Experience" report has been added to ResearchAndMarkets.com's offering. Approximately 7.5 million people in the United States have psoriasis. This Psoriasis in America report provides a comprehensive look at life for those living with psoriasis. Using detailed quantitative data, it gives a full picture of the psoriasis patient experience - from symptoms to treatment to HCP relationships to quality of life - so you can make informed, strategic decisions, identify opportunities, and understand potential challenges. The report offers an in-depth look at the psoriasis patient experience. This large-scale, patient-reported data leverages vital quantitative insights essential to understanding key touchpoints in the psoriasis patient journey, including condition management, HCP engagement, quality of life, treatment experience and satisfaction, and much more. This report lifts the curtain on life with psoriasis, giving stakeholders an actionable look at the behaviors, attitudes, perceptions, needs, and experiences of people living with the condition. Data can be used to inform strategic decisions, including product communications, competitive assessments, concept development, landscape analyses, patient journey overlays, and forecasting inputs. This report also addresses important questions that stakeholders may not even know to ask while offering valuable insights into must-have patient-reported data points not available anywhere else. Add-on custom data analysis opportunities are also available for an additional cost - please see the report following purchase for more information. The analyst reaches millions of people through its portfolio of 45+ condition-specific online health communities - including PlaquePsoriasis.com - to provide information, connection, and support to patients and caregivers in the U.S. This report includes a deep-dive into: Psoriasis patient demographics Age, gender, ethnicity, marital status, children, employment status, income, location, insurance, and other health conditions Impact of psoriasis on quality of life Severity, impact on quality of life, symptoms experienced, and what patients wish others better understood Information-seeking behaviors Information sources used, plus topics of interest HCP engagement Primary HCP seen for condition, satisfaction with HCP, and discussion about brands aware of/not used Psoriasis treatment awareness and experiences Aided awareness of specific treatments, treatment experience, satisfaction with current treatments, perceived control with current treatment plan, and interest/participation in clinical trials Key questions answered in this report: To what extent do people say psoriasis impacts their overall quality of life? What's the average number of flares in the past year? What do patients wish others understood about psoriasis? What percentage of patients see a specialist for psoriasis treatment? What treatments have the highest aided brand awareness among patients? What percentage of patients use a biologic? How many patients feel their psoriasis is well-controlled on their current treatment plan? What percentage of patients are likely to switch or add new treatments in the next six months? What medications have patients discussed with their HCP? What are the top online resources people with psoriasis use to find information? What kinds of content and information do patients search for? What percentage of patients search for information on treatment options? Methodology Psoriasis in America consists of: A 20-minute online quantitative survey, covering demographics, comorbidities, quality of life/impact, HCP interactions, as well as treatment awareness, experiences, and discussions Qualitative patient insights from open-ended responses Additional details: Fielded: January 16, 2023 to April 14, 2023 Convenience sample of 490 respondents diagnosed with psoriasis Respondents are age 18+, living in the U.S., and are recruited from proprietary online health communities and recruiting partners Key Topics Covered: Respondent Demographics Research Highlights Condition Status and Quality of Life Severity and Exacerbations Symptoms Experienced Impact on Quality of Life Qualitative Patient Insights Information-Seeking Behaviors Resources Used to Manage Health Types of Content/Information Sought Treatment Awareness and Experiences Primary HCP Seen for Psoriasis Care Aided Brand Awareness of Treatments Treatment Usage Condition Control on Current Treatment and Clinical Trial Interest Treatment Discussions with HCP Appendix with All Data Charts and Distributions Brands and treatments mentioned in this report include: Topical corticosteroid (such as hydrocortisone) BRYHALIT (halobetasol propionate) lotion DesOwen (desonide) SERNIVOT (betamethasone dipropionate) SORILUXT Foam (calcipotriene) TACLONEX (calcipotriene and betamethasone) TAZORAC (tazarotene) VECTICAL (calcitriol) VTAMA (tapinarof) ZITHRANOLT-RR (anthralin) ZORYVET (roflumilast) Acitretin (SORIATANE) ARAVA (leflunomide) Azathioprine (such as IMURAN, AZASAN) Cyclosporine (such as Sandimmune, NEORAL, RESTASIS) Methotrexate (eg, Rheumatrex), also sometimes given as an injection OTEZLA (apremilast) PLAQUENIL (hydroxychloroquine) RINVOQ (upadacitinib) SOTYKTUT (deucravacitinib) Sulfasalazine (Azulfidine) XELJANZ/XELJANZ XR (tofacitinib citrate) AMJEVITAT (adalimumab-atto) Hide until launched in US AVSOLA (infliximab-axxq) CIMZIA (certolizumab) COSENTYX (secukinumab) CYLTEZO (adalimumab-adbm) Hide until launched in US ENBREL (etanercept) ERELZIT (etanercept-szzs) Hide until launched in US HULIO (adalimumab-fkjp) Hide until launched in US HUMIRA (adalimumab) HYRIMOZ (adalimumab-adaz) Hide until launched in US ILUMYAT (tildrakizumab-asmn) INFLECTRA (infliximab-dyyb) IXIFIT (infliximab-qbtx) Hide until launched in US ORENCIA (abatacept) REMICADE (infliximab) RENFLEXIST (infliximab-abda) SIMPONI (golimumab) SIMPONI ARIA (golimumab for infusion) SILIQT (brodalumab) SKYRIZI (risankizumab-rzaa) STELARA (ustekinumab) TALTZ (ixekizumab) TREMFYA (guselkumab) For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. 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