PERK

*仅供医学专业人士阅读参考“老而不死是为贼”，大伙都听过吧？那有多少朋友知道，这句攻击性拉满的话，出自孔子他老人家之口呢？当然攻击性高也没毛病，有些人有些事就该猛猛抨击，比如人体内一些不好好接受衰老命运，反而要转变成衰老相关分泌表型（SASPs），通过分泌各种东西促进衰老和癌症等疾病发展的细胞。而进入衰老状态的癌细胞，现在也模仿这一招来搞鬼了。近日，瑞士肿瘤研究所（IOR）团队在Immunity期刊发表的研究成果[1]就显示，被抗癌治疗诱导衰老的癌细胞，可将自身的线粒体DNA（mtDNA）装进囊泡释放到细胞外，随后这些囊泡会被肿瘤微环境中的多形核髓系来源免疫抑制细胞（PMN-MDSCs）摄取，使mtDNA激活cGAS-STING-NF-κB信号，增强PMN-MDSCs的免疫抑制性。只能说，老而不死的癌细胞也太阴险了，针对性阻断mtDNA释放的关键通道，才有望逆转免疫抑制。一图总结论文主要发现其实从分类来说，mtDNA此前更多是被划分到细胞释放的损伤相关分子模式（DAMPs）之中，全身各处的免疫细胞可通过cGAS等感受器感知到游离mtDNA，进而激活与创伤、炎症性疾病乃至癌症对应的免疫应答[2]；2023年登上《自然》的一项研究[3]还显示，凋亡应激可促使衰老细胞将mtDNA释放到细胞外驱动SASP进程，算是“机制共享”了。而化疗、靶向治疗等常用抗癌治疗手段，也经常会诱导癌细胞进入衰老状态，这些衰老癌细胞会不会也通过释放mtDNA造成负面影响呢？本次瑞士研究者们的探索就基于上述猜想展开，研究者们首先在多个不同细胞衰老模型中证实，衰老细胞释放mtDNA是普遍现象，且被多西他赛化疗或CDK4/6抑制剂治疗诱导衰老的癌细胞（前列腺癌细胞）也是如此。在相应的前列腺癌肿瘤模型中，示踪实验也表明主要负责摄取mtDNA的正是PMN-MDSCs，且mtDNA是被装在胞外囊泡（EVs）内被衰老癌细胞释放出去，再被PMN-MDSCs吞噬进胞内的；随后，PMN-MDSCs的多个免疫抑制功能相关基因（如编码PD-L1的Cd274）表达就开始显著上调，NF-κB、IL-6-STAT3等促癌信号通路也被激活，直接用mtDNA处理PMN-MDSCs也有相同效果，实锤了mtDNA可诱导免疫抑制。衰老癌细胞可将mtDNA包在EVs内释放，诱导PMN-MDSCs增强免疫抑制作用而细胞内能够感知mtDNA等核酸的，就是cGAS及Toll样受体9（TLR9）等经典感受器，实验显示敲除PMN-MDSCs的cGAS，才能使mtDNA无法诱导免疫抑制增强；而cGAS感受到mtDNA后，主要会激活STING而非I型干扰素信号（IRF3-IFN轴），再由STING介导PKR样内质网激酶（PERK）来放大NF-κB通路信号（PERK-eIF2α通路可抑制NF-κB p65抑制蛋白IκBα的翻译），完成对免疫抑制性增强的调控。回过头来说上游mtDNA的来路，导致它们被释放出来的直接原因，是癌细胞进入衰老状态时线粒体功能异常，生成了更多线粒体活性氧（mtROS），它们一方面会使mtDNA被释放到胞浆，再经由电压依赖性阴离子通道（VDACs）排到细胞以外，另一方面还会使核酸内切酶G（EndoG）发生核转位，避免它们去降解mtDNA；而要逆转mtDNA诱导的免疫抑制，最好的干预目标就是现阶段恰好有药物可用的VDAC（在研抑制剂VBIT-4），实验也证实抑制VDAC可通过增强抗肿瘤免疫应答，改善CDK4/6抑制剂的疗效。衰老癌细胞经由VDAC将线粒体释放到细胞外参考文献：[1]Lai P, Liu L, Bancaro N, et al. Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway[J]. Immunity, 2025, 58(4): 811-25.e7.[2]Lin M, Liu N, Qin Z, et al. Mitochondrial-derived damage-associated molecular patterns amplify neuroinflammation in neurodegenerative diseases[J]. Acta Pharmacologica Sinica, 2022, 43(10): 2439-2447.[3]Victorelli S, Salmonowicz H, Chapman J, et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP[J]. Nature, 2023, 622(7983): 627-636.本文作者丨谭硕

– SRC recommended that the trial escalate to the next dose level of 30mg capsule – – No dose-limiting toxicities (DLT’s) or rash observed to date – MIAMI, April 10, 2025 (GLOBE NEWSWIRE) -- Pasithea Therapeutics Corp. (NASDAQ: KTTA) (“Pasithea” or the “Company”), a clinical-stage biotechnology company developing PAS-004, a next-generation macrocyclic MEK inhibitor, for the treatment of neurofibromatosis type 1 (NF1) and other cancer indications, today announced that the external Safety Review Committee recommended that the Company’s Phase 1 clinical trial of PAS-004 in advanced cancer should proceed to Cohort 6, 30mg capsule, without modification. This recommendation was based on the review of the safety data from three patients from Cohort 5 and the absence of any dose limiting toxicities (DLT’s). In addition, no rash has been observed to date during the DLT period in any of the first 19 patients in either capsule (15 patients) or tablet (four patients) formulation of PAS-004. Rash is a common adverse event (AE) that is observed at low doses with competitor MEK inhibitors and may lead to the discontinuation rate in real world practice. “We are seeing substantial enrollment demand and have already identified Cohort 6 patients. In addition, we continue to observe substantial exposure levels of PAS-004, and remain excited about the possibility of delivering relevant pERK inhibition below the no observed adverse effect levels (NOAEL) as we modeled and observed during our previously conducted nine-month chronic toxicity studies. The on label rash rate for both approved MEKi for NF1 exceeds 80% which leads to patients discontinuing who otherwise should remain on treatment for longer periods of time”, stated Dr. Tiago Reis Marques, Chief Executive Officer of Pasithea. “We will provide additional safety, pharmacokinetic (PK) and pharmacodynamic (PD) data over the next several weeks.” The ongoing Phase 1 clinical trial is a multi-center, open-label, dose escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of PAS-004 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 or RAF mutation or patients who have failed BRAF/MEK inhibition (NCT06299839). About Pasithea Therapeutics Corp. Pasithea is a biotechnology company focused on the discovery, research and development of innovative treatments for central nervous system (CNS) disorders and RASopathies. With an experienced team of experts in the fields of neuroscience, translational medicine, and drug development, Pasithea is developing new molecular entities for the treatment of neurological disorders, including Neurofibromatosis type 1 (NF1), Solid Tumors, and Amyotrophic Lateral Sclerosis (ALS). Forward Looking Statements This press release contains statements that constitute “forward-looking statements” made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include statements regarding the Company’s ongoing Phase 1 clinical trial and the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD) and preliminary efficacy of PAS-004, as well as all other statements, other than statements of historical fact, regarding the Company’s current views and assumptions with respect to future events regarding its business, as well as other statements with respect to the Company’s plans, assumptions, expectations, beliefs and objectives, the success of the Company’s current and future business strategies, product development, preclinical studies, clinical studies, clinical and regulatory timelines, market opportunity, competitive position, business strategies, potential growth opportunities and other statements that are predictive in nature. Forward-looking statements are subject to numerous conditions, many of which are beyond the control of the Company. While the Company believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements, which are based on information available to the Company on the date of this release. These forward-looking statements are based upon current estimates and assumptions and are subject to various risks and uncertainties, including risks that future clinical trial results may not match results observed to date, may be negative or ambiguous, or may not reach the level of statistical significance required for regulatory approval, as well as other factors set forth in the Company’s most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q and other filings made with the U.S. Securities and Exchange Commission (SEC). Thus, actual results could be materially different. The Company undertakes no obligation to update these statements whether as a result of new information, future events or otherwise, after the date of this release, except as required by law. Pasithea Therapeutics Contact Patrick Gaynes Corporate Communications pgaynes@pasithea.com Released April 10, 2025

SOUTH SAN FRANCISCO, CA, USA I April 01, 2025 I TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (“BBOT” or the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, today announced that the first patient has been dosed with BBO-11818 in the Phase 1 KONQUER-101 trial for advanced solid tumors. BBO-11818 is an orally bioavailable small molecule dual inhibitor that directly binds to both the “ON” and “OFF” states of KRAS. KONQUER-101 will enroll patients globally with certain KRAS mutations. “The dosing of the first patient is a major milestone in assessing BBO-11818’s potential benefit for patients with tumors driven by mutant KRAS,” said Dr. Ignacio Garrido-Laguna, MD, PhD, Principal Investigator at Huntsman Cancer Institute at the University of Utah. “We are committed to bringing cutting-edge therapies to patients with advanced cancer in the Mountain Region. BBO-11818 has the potential to safely achieve optimal target inhibition and combine with other targeted therapies. We look forward to evaluating it in the KONQUER-101 trial.” BBO-11818 was designed to non-covalently bind both the inactive GDP-bound “OFF” and active GTP-bound “ON” forms of KRAS G12D and KRAS G12V . In cellular assays, EC 50 values for pERK inhibition in selected KRAS G12D and G12V-mutant cell lines range from sub-nanomolar to single-digit nanomolar potency. BBO-11818 is similarly effective in reducing cell viability in KRAS G12D , KRAS G12V , and KRAS G12C -mutant cell lines. Further, NRAS and BRAF mutant cell lines show insensitivity to BBO-11818, and the molecule exhibits more than 500-fold selectivity for KRAS over H- and NRAS. “There is a great need for new therapies that can safely treat patients with tumors driven by KRAS mutations, as the current standard of care lacks satisfactory options as monotherapy or to enable combinations of KRAS targeted therapies with other targeted agents,” said Yong (Ben) Ben, MD, Chief Medical and Development Officer of BBOT. “BBO-11818 marks the third molecule entering the clinic for BBOT, further proving our capability to advance novel programs into the clinic. Of note, our portfolio is uniquely positioned to deliver the combination of MAPK (BBO-8520 and BBO-11818) and PI3Kα/AKT (BBO-10203) co-inhibition, with a therapeutic index. We hope this will bring unprecedented benefit to patients with RAS-driven cancers.” The discovery of BBO-11818 was the result of a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT. About BBOT BBOT is a clinical-stage biopharmaceutical company advancing a next-generation pipeline of novel small molecule therapeutics targeting RAS and PI3Kα malignancies. Initially formed as a subsidiary of BridgeBio Pharma, Inc. (Nasdaq: BBIO), BBOT has the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information, visit bridgebiooncology.com . SOURCE: BridgeBio Oncology Therapeutics