PKCβ

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 细胞不断感知和响应微环境中的生化和生物力学变化，需要动态代谢适应。ECM硬化是癌症侵袭性的标志，而底物剥离下的生存也与不良预后相关。 近日，北京大学研究人员在权威期刊《Advanced Science》上发表了题为“mTORC1 Mediates Biphasic Mechano-Response to Orchestrate Adhesion-Dependent Cell Growth and Anoikis Resistance”的研究论文，本文中，研究人员报道了一种整合素- gsk3 β- fto - mtor轴，它可以整合刚度感知，以确保刚性底物赋予的生长优势和基质剥离下细胞的抗死亡能力。研究表明，底物硬化可以通过整合素和GSK3β-FTO介导的mRNA m6A修饰激活mTORC1，提高mTOR水平，促进合成代谢。在ECM脱离时抑制这条轴增强了自噬，这反过来又传递了肿瘤细胞对肿瘤的弹性，正如在人乳腺导管原位癌(DCIS)和小鼠恶性腹水中所证明的那样。 总的来说，这些结果强调了细胞代谢的双相机制调节，在诸如纤维化等硬化条件下的肿瘤生长以及癌症转移期间的抗氧化性中具有重要意义。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202307206 研究背景 01 细胞通过整合素结合的黏着斑(FAs)来感知ECM的物理特性，从而影响细胞的迁移、分化和存活。由于组织纤维化和细胞外基质硬化与肿瘤的不良预后相关，因此通过胶原消耗或赖氨酰氧化酶(LOX)抑制来改变细胞外基质刚度，或通过药物改变细胞力学转导已成为有前景的癌症治疗选择。然而，肿瘤细胞也表现出对失巢凋亡(ECM脱离诱导的细胞死亡)的抵抗。 肿瘤细胞如何在坚硬的基质上获得生长优势，同时在基质脱离后抵抗细胞死亡仍然是一个谜。 细胞生长和增殖与细胞合成代谢密切相关。耐氧性也与代谢适应同时发生，可被自噬所阻碍。雷帕霉素复合体1 (mTORC1)的机制靶点是响应细胞内和细胞外信号的代谢调节的中心支柱。它的激活与增强蛋白质翻译和减少自噬有关。mTORC1被招募到溶酶体表面释放其抑制作用。最近的研究表明，溶酶体mTORC1可以被运输到FAs周围并被激活，FAs是连接ECM与细胞内部的基于整合素的机械转导中心。然而，仍然缺乏证据表明基质的物理性质是否可以信号传导到mTORC1通路。 研究进展 02 机械力广泛参与各种生物过程，包括细胞增殖、分化和迁移需要代谢重组。作为合成代谢的主要调节因子，mTORC1一直是细胞生长和肿瘤生存研究的重点，然而，其与机械微环境的关联在很大程度上缺失。 基于整合素的FAs是一种动态蛋白复合物，介导肌动蛋白细胞骨架与ECM的结合，并通过经典的机械转导途径在功能上参与细胞极化、扩散和迁移。最近的证据表明生长因子受体和氨基酸转运蛋白在FA位点的分布。此外，在FA富集的细胞区域也发现了本地化的蛋白质翻译。在机械传感方面，FAs的新作用将被揭示。在这里，研究人员发现mTOR和phos-S6可以通过整合素- fa位点的局部激活来促进细胞增殖和抑制自噬。这种激活依赖于底物感知、细胞收缩以及整合素β1。这些观察一致表明了整合素共轭FAs在调节细胞代谢中的作用。 研究人员鉴定了fto - m6A去甲基化酶之一，它对mTOR mRNA和随后的蛋白丰度的机械调节至关重要。近年来，FTO的翻译后修饰(PTMs)受到越来越多的关注。据报道，150个磷酸化位点显著改变了FTO的亚细胞定位和底物特异性。此外，蛋白激酶Cβ (PKCβ)的磷酸化引导FTO参与泛素介导的蛋白降解。在本研究中，研究人员发现丝氨酸256位点的磷酸化阻碍了FTO的催化活性，但不影响其亚细胞定位或蛋白丰度，表明PTMs通过多种方式影响FTO。不同硬度下FTO活性改变的一种可能性是，磷酸化通过先前报道的Ca2+结合增强来修饰FTO活性。另一种可能是磷酸化状态通过影响FTO的寡聚化来改变其活性，然而，由于FTO结构的复杂性和技术的局限性，确定二聚化对FTO催化活性的确切影响并不容易。 本研究揭示了mTORC1通路的机械激活可能在硬度促进细胞生长和抗失巢凋亡方面发挥双重作用。增加的基底刚度或细胞张力增强了mTORC1的激活，维持细胞增殖和合成代谢。而ECM脱离则使mTORC1信号失活，并通过提高自噬促进细胞存活。 肿瘤细胞如何利用这一机制在力学-微环境的变化中前行，以及这一通路如何有助于靶向治疗，有待未来的研究。 底物刚性通过mTORC1途径调节自噬 研究结论 03 综上，研究人员发现了mTORC1途径在坚硬基质或底物脱离时的机械调节现象和潜在机制。研究结果表明，肿瘤细胞利用细胞代谢的双相机械调节来协调细胞在坚硬基质上的生长和在底物脱离时的抵抗。靶向整合素- gsk3 β- fto - mtor轴可能揭示癌症的双重打击策略。 参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202307206 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布） 点击对应文字 查看详情

40-site U.S. trial enrolling more than 300 patients could significantly change the way DCIS is treated and reduce possibly unnecessary surgery SAN FRANCISCO, Oct. 30, 2023 /PRNewswire/ -- Quantum Leap Healthcare Collaborative (QLHC) announces the enrollment launch for the Re-Evaluating Conditions for Active Surveillance Suitability as Treatment: Ductal Carcinoma In Situ (RECAST DCIS), a Phase 2 platform study aimed at preventing the progression of DCIS to breast cancer. The study is evaluating three investigational endocrine therapy arms: (Z)-endoxifen, a selective estrogen receptor modulator (SERM) in development by Atossa Therapeutics (Nasdaq: ATOS); HAVAH T+Ai™, a proprietary combination of testosterone (T) and anastrozole (Ai) that targets the androgen and estrogen receptor pathways in development by Havah Therapeutics; and ORSERDU® (elacestrant), the only FDA approved oral selective estrogen receptor degrader (oSERD) in development by Stemline Therapeutics Inc. (Stemline), a wholly-owned subsidiary of the Menarini Group. "DCIS indicates the very earliest, noninvasive stage of the disease, that's why it is important for us to seek out alternative therapies for DCIS patients and find ways to reduce toxicity and unnecessary surgeries. We are excited to partner with three innovative companies to explore new treatments for this large and often over-treated patient population," said Laura Esserman, MD, a lead investigator for the study and founder of QLHC. Surgery is the current standard treatment for DCIS even though many patients never progress to breast cancer, which means that patients are often over-treated with invasive procedures. This new trial, sponsored and operated by QLHC, offers DCIS patients up to six months of endocrine therapy with the intent to forego surgery and instead be monitored via long-term active surveillance, if appropriate. A key element in reducing overtreatment of DCIS is identifying biomarkers that reflect the risk of progression so that those with low-risk lesions are spared surgery. RECAST DCIS features the assessment of imaging and molecular-based biomarkers in addition to evaluating new investigational agents in this setting. The study is open to enrollment with each investigational agent arm expected to enroll up to 110 patients. The three collaborators for this trial, Atossa Therapeutics, Havah Therapeutics, and Stemline, all aim to find alternative solutions for DCIS patients and are providing different agents for assessment. Atossa's (Z)-endoxifen has the potential to mitigate breast cancer risk (by reducing the density of breast tissue); to reduce cancer cell activity before surgery; and to reduce the risk of recurrent or new breast cancer after the initial treatment. According to published studies, (Z)-endoxifen is a competitive inhibitor of ERα and represses ERα transcriptional activity (Z)-endoxifen is 100-fold more potent in anti-estrogen activity compared to other SERMs. (Z)-endoxifen also binds to and disrupts protein kinase C beta one function (PKCb1, a known oncogenic protein). The National Cancer Institute (NCI) and others have studied (Z)-endoxifen and have demonstrated promising results in the treatment of breast cancer as well as for the treatment of other solid tumors. Treatment with (Z)-endoxifen may avoid off target effects of tamoxifen and remaining metabolites potentially increasing adherence by improving the safety profile. Havah Therapeutics' HAVAH T+Ai™ combines T, the natural ligand for the androgen receptior and Ai, an inhibitor of T conversion to estradiol, to modulate the growth of abnormal breast tissues. HAVAH T+Ai™ is a proprietary combination subcutaneously delivered system to overcome hormonal symptoms by balancing hormonal irregularities in the breast, developed from more than 10 years of clinical research into hormonal regulation in women. Havah has extensive clinical experience using HAVAH T+Ai™ to address pre- and postmenopausal prevention of breast disease, and the company generated data from more than 1,000 Australian women with breast disease through an ongoing open label cohort study (more than 6,200 implants), with critical safety pharmacokinetic and early efficacy data already demonstrated. Stemline's Elacestrant (ORSERDU), was approved by the U.S. Food & Drug Administration in January 2023 for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR-1 mutated advanced or metastatic breast cancer, following at least one line of endocrine therapy. For more information including full prescribing information and important safety information, please visit . About Quantum Leap Healthcare Collaborative Quantum Leap Healthcare Collaborative is a 501c(3) charitable organization established in 2005 as a collaboration between medical researchers at University of California, San Francisco and Silicon Valley entrepreneurs. Our mission is to integrate high-impact research with clinical processes and systems technology, resulting in improved data management and information systems, greater access to clinical trial matching and sponsorship, and greater benefit to providers, patients and researchers. Our goal is to improve and save lives. For more information, visit . About Atossa Atossa Therapeutics is a clinical stage biopharmaceutical company developing innovative medicines in areas of significant unmet medical need in oncology. Atossa's current focus is on breast cancer. More information is available at atossatherapeutics.com. About Havah Therapeutics Havah Therapeutics is a biopharmaceutical company developing innovative, proprietary hormonal therapies that aim to improve quality of life for women. Havah brings together a world-class team passionate about helping women live lives free from the suffering caused by breast pain, debilitating menopausal symptoms and breast cancer. More information is available at . About The Menarini Group The Menarini Group is a leading international pharmaceutical and diagnostics company, with a turnover of over $4.4 billion and over 17,000 employees. Menarini is focused on therapeutic areas with high unmet needs with products for cardiology, oncology, pneumology, gastroenterology, infectious diseases, diabetology, inflammation, and analgesia. With 18 production sites and 9 Research and Development centers, Menarini's products are available in 140 countries worldwide. For further information, please visit . About Stemline Therapeutics Inc. Stemline Therapeutics, Inc. ("Stemline") a wholly-owned subsidiary of the Menarini Group, is a commercial-stage biopharmaceutical company focused on the development and commercialization of novel oncology therapeutics. Stemline commercializes ORSERDU® (elacestrant) in the United States, an oral endocrine therapy indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Stemline also commercializes ELZONRIS® (tagraxofusp-erzs), a novel targeted treatment directed to CD123 for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic cancer, in the United States and Europe, which is the only approved treatment for BPDCN in the US and EU to date. Stemline also commercializes NEXPOVIO® in Europe, an XPO1 inhibitor for multiple myeloma. Stemline also has an extensive clinical pipeline of small molecules and biologics in various stages of development for a host of solid and hematologic cancers. SOURCE Quantum Leap Healthcare Collaborative

- Series B led by Double Point Ventures with major support from Viking Global Investors as well as other new and existing investors - - A combined $27.1 million Series B first close and $8.1 million in converting outstanding notes funds the company’s two assets in development, SM-020 for the treatment of seborrheic keratoses and SM-030 for the treatment of melasma, through end of Phase 2 meetings with FDA and commencement of Phase 3 trials - BOSTON--(BUSINESS WIRE)-- DermBiont, Inc., a clinical-stage biotechnology company that is advancing targeted topical therapeutics for the treatment of dermatological indications, today announced a $35.2 million Series B financing, including a $27.1 million Series B first close and $8.1 million in converting outstanding notes. Proceeds will be used to advance two drugs in development, SM-020, a topical novel AKT kinase inhibitor for the treatment of seborrheic keratoses (SKs), and SM-030, a topical novel PKC-beta inhibitor for the treatment of melasma and other hyperpigmentation disorders of the skin. The Series B was led by new institutional investor, Double Point Ventures, and includes continued support from Viking Global Investors, Civilization Ventures, Olive Tree Capital, and others. Concurrent with the financing, Daniel Yadegar, M.D., Managing Partner at Double Point Ventures, joined DermBiont’s board of directors, adding, “I am excited to be working closely with DermBiont’s team to advance two products, one for the treatment of seborrheic keratoses and the other for the treatment of melasma, two of the most frequently diagnosed skin diseases by dermatologists. These products prioritize the patient experience by addressing the root cause of both diseases with excellent efficacy, safety, and tolerability. Physicians understand that patients with SKs and hyperpigmentation disorders of the skin are seeking effective, safe, and well-tolerated topical treatment options compared with existing ablative surgical procedures for treating SKs or ineffective lasers with frequent recurrence or unsafe toxic chemicals with very low efficacy like hydroquinone for treating melasma.” The proceeds from the Series B financing will be used to advance the clinical development of SM-020 and SM-030. They are expected to fund the company through end of its Phase 2 meetings with the U.S. Food and Drug Administration (FDA), which are expected in the second half of 2024 for both programs. In the next twelve months, DermBiont will commence enrollment for three planned seborrheic keratoses clinical trials and one melasma trial as follows: Phase 2b randomized, double-blind, vehicle-controlled clinical trial in 60 subjects with seborrheic keratoses treated with SM-020 gel 1% or vehicle twice daily for 28 days. Phase 2b open label clinical trial in 10 subjects with DPN (Dermatosis Papulosa Nigra) treated with SM-020 gel 1% twice daily for 28 days. Phase 2 open label clinical trial extension in 25 additional subjects with seborrheic keratoses treated with SM-020 gel 0.1% or SM-020 gel 1% daily or twice daily for 28 to 56 days. Phase 2b randomized, observer-blinded, placebo-controlled clinical trial in 138 subjects with melasma treated with SM-030 gel 0.64%, SM-030 gel 0.08%, or placebo gel twice daily for 12 weeks “The addition of Double Point Ventures as a major backer alongside continued financial and strategic support from Viking Global Investors and other investors allows us to accelerate the development of our pipeline of novel topical therapeutics for the treatment of the number one and number three most frequently diagnosed disorders of the skin by dermatologists in the US, seborrheic keratoses and hyperpigmentation, respectively,” stated Karl Beutner, M.D., Ph.D., Chief Executive Officer and Co-Founder of DermBiont. “This funding comes on the heels of our successful Phase 2 proof of concept trials, where SM-030 gel 0.64% achieved greater efficacy than 4% hydroquinone, and where over 80% of SKs responded to treatment with SM-020 gel 1.0% twice daily for 14 to 28 days and over 50% of SK lesions completely cleared in the most effective dosing regimen.” About DermBiont DermBiont’s mission is to become the world’s leading precision dermatology company developing and commercializing targeted topical therapeutics that treat, cure, and prevent skin diseases. The company aims to impact the root causes of skin diseases through the development of first-in-class targeted therapeutics with well-defined mechanisms of action. The company’s targeted topical therapeutics pipeline includes two lead assets: SM-020 for the treatment of seborrheic keratoses and SM-030 for the treatment of melasma and other hyperpigmentation disorders of the skin. For more information, please visit . About Double Point Ventures At Double Point Ventures, we see beyond today's treatments to envision tomorrow's cures. Our fund invests in revolutionary companies developing cutting-edge therapeutics, from gene therapies to precision medicines. While novel drugs are our focus, we also target innovative early revenue-stage diagnostic companies, medical device startups, digital health startups, and healthcare services providers catalyzing the future of healthcare. Backed by visionary investors, our mission is clear - fund the science superstars solving the medical mysteries of our time. By powering pioneering companies, we strive to bring groundbreaking treatments from bench to bedside. Double Point Ventures is led by Managing Partner, Daniel Yadegar, M.D. For more information, please visit .