DYRK1B

*仅供医学专业人士阅读参考 “吃饭不积极，思想有问题”，这句话奇点糕还挺认可，但如果吃吃吃变成了工作，或许就不是一回事了，这么想的话，好像癌症微环境里经常不务正业，不去吞噬掉癌细胞的巨噬细胞们也情有可原？但为了消灭掉癌症，还是得想办法让巨噬细胞们“吃”起来。 近日，德国马尔堡大学研究团队在Gut期刊发表最新研究成果，首次揭示了调动巨噬细胞有效吞噬“癌王”胰腺癌的治疗靶点——DYRK1B，采用基因敲除或药物抑制手段处理胰腺癌细胞表达的DYRK1B，可将巨噬细胞募集到胰腺癌部位，并下调吞噬检查点（Phagocytosis Checkpoint）即“别吃我”信号CD24表达，使巨噬细胞们有效抗癌[1]。 论文首页截图 众所周知，胰腺癌的免疫微环境抑制性极强，而介导抑制性的元凶之一，就是大量存在的肿瘤相关巨噬细胞（TAMs），这对免疫治疗、化疗等许多治疗手段的起效都极为不利，但如果换个角度来看，以巨噬细胞作为治疗突破口，把它们“扳回来”发挥抗癌作用的话，那其中蕴藏的抗癌潜能可实在是够丰富的。 而马尔堡大学研究团队瞄准的DYRK1B，其全称是“双特异性酪氨酸磷酸化调节激酶1B”，既往研究报告在胰腺癌中的检出率可达10-40%，且DYRK1B可能会帮助癌细胞脱离细胞周期、进入静止状态（quiescence），由此躲避许多常用化疗药物的杀伤[2]，但这次研究还真是它们和巨噬细胞头一回“同屏出现”。 研究者们首先确认，胰腺癌中表达DYRK1B的主要是导管上皮来源癌细胞，且DYRK1B表达水平与患者预后负相关，然而接下来评估敲除Dyrk1b基因的影响时，实验结果相当出人意料：在体外细胞实验中，敲除Dyrk1b使胰腺癌细胞的增殖速率像踩了油门一样快，在TGFβ信号和mTOR激酶的调控下，癌细胞能更快速地完成细胞周期，加速分裂增殖。 但是，敲除Dyrk1b的胰腺癌细胞被植入小鼠体内后，它们形成肿瘤的速度和体积反而远不及正常的胰腺癌细胞；对肿瘤的单细胞测序显示，有海量的巨噬细胞从外部涌入了肿瘤部位，而且表型基本都向着有利于抗癌的M1型TAMs极化。也就是说，敲除Dyrk1b虽然让胰腺癌细胞增殖更快，但也招来了巨噬细胞铺天盖地的追杀，导致强有力的抑癌效应。 敲除Dyrk1b使大量巨噬细胞被募集到肿瘤部位抗癌 那下一个问题就很自然了：敲除胰腺癌细胞的Dyrk1b为什么会激活巨噬细胞呢？研究者们猜测这可能与胰腺癌细胞外分泌物质的改变有关，于是用癌细胞培养上清液处理了巨噬细胞，发现巨噬细胞的基因表达会在两个层面受影响，一方面是M1型TAMs相关基因（如Cd40）的表达上调，另一方面则是炎症相关（如il1a/1b）和M2型TAMs相关基因的表达下调。 此外，敲除癌细胞Dyrk1b后被“吸引”来的巨噬细胞，迁移能力和存活能力也显著提高，这与敲除Dyrk1b改变了癌细胞的多种趋化因子分泌水平有关；而更为关键的是，巨噬细胞们在共培养实验中吞噬癌细胞的能力大幅增强，这主要是因为敲除Dyrk1b会使癌细胞表面的“别吃我”信号CD24水平直接减半，癌细胞就无法靠CD24从巨噬细胞嘴下逃命了。 敲除Dyrk1b可在多个层面影响巨噬细胞，使它们抗癌能力更强 最后研究者们在小鼠实验中证实，以针对DYRK1B的小分子抑制剂（AZ191/KU0063794，后者还可抑制mTOR激酶）配合胰腺癌化疗中常用的吉西他滨，可显著延长胰腺癌模型小鼠的生存时间，研究者们还乐观推测，DYRK1B抑制剂或许也能与现有免疫治疗实现协同增效，在胰腺癌攻坚战中发挥作用，那就看看未来会不会有临床研究的好消息吧。 参考文献： [1]Brichkina A, Ems M, Suezov R, et al. DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer [J]. Gut, 2024, gutjnl-2023-331854. [2]Ewton D Z, Hu J, Vilenchik M, et al. Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells[J]. Molecular Cancer Therapeutics, 2011, 10(11): 2104-2114. 本文作者丨谭硕

- CBL-514 is the first and only drug to receive both Orphan Drug Designation and Fast Track designation for Dercum's disease treatment. NEW TAIPEI CITY, March 3, 2024 /PRNewswire/ -- Caliway Biopharmaceuticals (Caliway) announced that the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) to CBL-514 for Dercum's disease treatment. CBL-514 is a lipolysis injection that can reduce local subcutaneous fat by inducing adipocyte apoptosis, and is the first drug to receive both ODD and Fast Track designation for Dercum's disease treatment. "Receiving Orphan Drug Designation and Fast Track designation from the U.S. FDA is a huge milestone in CBL-514 development. Moreover, of all Dercum's disease treatment studies, CBL-514 is by far the most advanced program with the clinical efficacy being proven to reduce the size of the painful lipoma by more than 50% significantly," said Vivian Ling, CEO of Caliway. "With these two designations, we look forward to accelerating CBL-514 clinical development, and becoming the first approved drug for Dercum's disease treatment with a 7-year marketing exclusivity." Caliway has completed a Phase 2 study (CBL-0201DD, NCT05387733) to evaluate CBL-514's efficacy and safety in treating Dercum's disease last year. The study results demonstrated that after treating with CBL-514, 64.5% of painful lipomas showed dimension reduction of more than 50%, 38.7% of painful lipomas showed complete clearance, with pain being reduced by 4.7 point. In January 2024, a placebo-controlled Phase 2b study (CBL-0202DD) to evaluate efficacy of CBL-514 for treating Dercum's disease has been approved by the U.S. FDA. The subject recruitment will be initiated in Q2 2024. About Orphan Drug Designation To support the development and evaluation of new treatments for rare diseases, the U.S. FDA grants orphan drug designation to a drug or biological product to prevent, diagnose, or treat a rare disease or condition that affects fewer than 200,000 people in the United States. Orphan drug designation qualifies sponsors for incentives including 7-year marketing exclusivity to sponsors of approved orphan products, federal tax credit for expenses, waiver of Prescription Drug User Fee Act (PDUFA) fees, and eligibility for regulatory assistance and guidance from the FDA in the design of a drug development plan. For more information regarding Orphan Drug Designation, please visit the U.S. FDA official website: About Dercum's Disease Dercum's disease is a rare disorder that is characterized by the development of painful lipomas primarily located on the trunk region, and the extremities close to the trunk. The pain is chronic (>3 months), symmetrical, often disabling, and resistant to traditional analgesics. The etiology of Dercum's disease remains unknown. There is no approved drug nor recommended standard treatment for Dercum's disease yet. The current treatment options, including surgical removal, liposuction, electrotherapy, and inflammation inhibitors, are symptomatic, and the efficacies are limited with numerous adverse events. The clinical need for Dercum's disease remains unmet. According to the Global Dercum's Disease Market Research Report, the global Dercum's disease treatment market size in 2021 was $11.3 billion. With a compound annual growth rate (CAGR) of 6.76%, the global market of Dercum's disease treatment in 2030 is estimated to expand to $19.95 billion. About CBL-514 CBL-514, a potentially first-in-class small-molecule drug, is an injection lipolysis drug that can induce adipocytes apoptosis and lipolysis to reduce subcutaneous adiposity in treatment areas in animal studies without causing any systematic side effects on the central nervous system, cardiovascular system, and respiratory system. Caliway's nonclinical studies showed that CBL-514 upregulates the apoptosis mediators caspase 3 and Bax/Bcl-2 ratio, and then induces dose-dependent adipocyte apoptosis in vivo and in vitro. Caliway is investigating multiple indications for CBL-514, including non-invasive subcutaneous fat reduction, Dercum's disease, cellulite, and lipoma treatment. About Caliway Biopharmaceuticals Caliway Biopharmaceuticals (Caliway) is a Taiwan-headquartered, clinical-stage biopharmaceutical company driven to breakthrough drug discovery of novel small-molecule therapeutics. Listed on the emerging stock market in Taiwan (TPEX6919), Caliway aims to become an innovative pharmaceutical leader in aesthetic medicine and other diseases. For more information, please visit: Disclaimer This article and related information on this site contain forward-looking statements. The forward-looking information requires the Company to make numerous assumptions and is subject to inherent risks, uncertainties, and other factors that are beyond the control of the Company which may cause actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by such forward-looking statements. The Company undertakes no obligation to timely inform, update, or revise the information on this site if circumstances should change. SOURCE Caliway Biopharmaceuticals

- Fast Track designation indicates CBL-514's potential in filling the unmet medical need of Dercum's disease. - CBL-514 is the first drug to receive Fast Track designation for Dercum's disease treatment. - CBL-514 Phase 2 study in Dercum's disease demonstrated its efficacy in significant painful lipomas' size reduction of more than 50%, complete clearance and pain improvement by 4.7 points. NEW TAIPEI CITY, Feb. 14, 2024 /PRNewswire/ -- Caliway Biopharmaceuticals (Caliway) announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the investigation of CBL-514 in Dercum's disease treatment. CBL-514 is a lipolysis injection that can reduce local subcutaneous fat by selectively inducing adipocyte apoptosis, and is the first drug to receive Fast Track designation for Dercum's disease treatment. "We are very pleased to see the FDA's decision on granting Fast Track designation to CBL-514," said Vivian Ling, CEO of Caliway. "Dercum's disease is a rare disease characterized by the growth of painful lipomas, the pain can often be chronic and disturbing. With the Fast Track designation, Caliway can benefit from more frequent engagement with the FDA, which will support the collection of appropriate clinical data to accelerate CBL-514 development, and provide the treatment to patients who have been suffering with this disease." Fast Track Designation Fast track designation is a process that the FDA designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need, providing a therapy where none exists, or providing a therapy which may be potentially better than available therapy. For more information on the Fast Track process, please visit the U.S. FDA official website: . The FDA's decision was based on Caliway's preclinical and CBL-0201DD Phase 2 (NCT05387733) clinical study results, showing that CBL-514 is the first and only product to demonstrate clinically meaningful and statistically significant in painful lipomas complete clearance or dimensions reduction of more than 50%, as well as significant pain improvement by 4.7 points. Therefore, the CBL-0201DD Phase 2 study demonstrated the substantial improvement over available therapies to address the unmet medical need for Dercum's disease. Expanded Access Program The Expanded Access Program is a program recognized by the FDA as a follow-on to their Fast Track Designation. An EAP provides a potential pathway for patients with a serious or life-threatening condition to gain access to an investigational drug for treatment outside of a clinical trial, particularly when no comparable or satisfactory alternative therapy options are available. For physicians that have identified a patient, or have spoken to a patient who contacted you, please contact Caliway at [email protected]. Caliway's goal is to acknowledge receipt to the requesting physician within (10-12) business days. About Dercum's Disease Dercum's disease is a rare disorder that is characterized by the development of painful lipomas primarily located on the trunk region, and the extremities close to the trunk. The pain is chronic (>3 months), symmetrical, often disabling, and resistant to traditional analgesics. The main symptoms of Dercum's disease, according to the early reports, are obesity, pain from the lipomas, and numerous psychiatric manifestations, including sleep disturbances, depression, and anxiety. The etiology of Dercum's disease remains unknown. There is no approved drug nor recommended standard treatment for Dercum's disease yet. The current treatment options, including surgical removal, liposuction, electrotherapy, and inflammation inhibitors, are symptomatic, and the efficacies are limited with numerous adverse events. The clinical need for Dercum's disease remains unmet. According to the Global Dercum's Disease Market Research Report, the global Dercum's disease treatment market size in 2021 was $11.3 billion. With a compound annual growth rate (CAGR) of 6.76%, the global market of Dercum's disease treatment in 2030 is estimated to expand to $19.95 billion. About CBL-514 CBL-514, a potentially first-in-class small-molecule drug, is an injection lipolysis drug that can induce adipocytes apoptosis and lipolysis to reduce subcutaneous adiposity in treatment areas in animal studies without causing any systematic side effects on the central nervous system, cardiovascular system, and respiratory system. Caliway's nonclinical studies showed that CBL-514 upregulates the apoptosis mediators caspase 3 and Bax/Bcl-2 ratio, and then induces dose-dependent adipocyte apoptosis in vivo and in vitro. Caliway is investigating multiple indications for CBL-514, including non-invasive subcutaneous fat reduction, Dercum's disease, cellulite, and lipoma treatment. About Caliway Biopharmaceuticals Caliway Biopharmaceuticals (Caliway) is a Taiwan-headquartered, clinical-stage biopharmaceutical company driven to breakthrough drug discovery of novel small-molecule therapeutics. Listed on the emerging stock market in Taiwan (TPEX6919), Caliway aims to become an innovative pharmaceutical leader in aesthetic medicine and other diseases. For more information, please visit: Disclaimer This article and related information on this site contain forward-looking statements. The forward-looking information requires the Company to make numerous assumptions and is subject to inherent risks, uncertainties, and other factors that are beyond the control of the Company which may cause actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by such forward-looking statements. The Company undertakes no obligation to timely inform, update, or revise the information on this site if circumstances should change. SOURCE Caliway Biopharmaceuticals