GAPDH

Misetionamide demonstrated significant single agent activity and synergy with either PARP inhibitors (PARPi) or bevacizumab in ovarian cancer preclinical studiesProfound effects on tumor metabolism, anti-angiogenic activity, protein synthesis, and DNA transcription BERWYN, PA, Aug. 14, 2024 (GLOBE NEWSWIRE) -- Panavance Therapeutics Inc. (“Panavance” or the “Company”), a clinical-stage pharmaceutical company advancing the development of a novel oncology therapeutic intended to improve the outcomes and quality of life for patients, today announced publication of positive data in the peer-reviewed journal, Cancer Medicine, in a manuscript titled “Mechanism and Rational Combinations with GP-2250, a Novel Oxathiazine Derivative, in Ovarian Cancer.”1 The publication by Kim, et al. (2024) at MD Anderson Cancer Center reports the research on misetionamide which demonstrated excellent monotherapy results as well as synergistic activity with PARPi’s and bevacizumab antineoplastic in ovarian cancer. Misetionamide is a tumor cell selective small molecule drug that is broadly active in multiple cancer models. Misetionamide’s inhibition of hexokinase-2 (HK-2), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and pyruvate dehydrogenase (PVD) in aerobic glycolysis greatly inhibits ATP production for cancer cells, setting up oxidative, metabolic and hypoxic stresses within the cancer cell. Additionally, misetionamide’s inhibition of key transcription factors such as NFkB further impairs the ability of the cancer cell to express genes and thus sustain viability and proliferation.2 “The key findings in our research are that misetionamide exerts a profound antitumor effect when used as monotherapy as well as synergistically when used either in combination with PARP inhibitors or bevacizumab. Misetionamide also has anti-angiogenic activity that interacts synergistically with bevacizumab. Both findings, and others, strongly suggest that misetionamide in combination with PARPi or bevacizumab should be studied further as a new antitumor drug in ovarian cancers,” said Anil Sood, MD, Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. “This research demonstrates that misetionamide exerts major anti-cancer effects through new metabolic and transcription inhibition mechanisms. As such, misetionamide may be a promising new therapeutic approach for ovarian cancer patients, which is the fifth leading cause of female cancer death,” commented study author, Robert L. Coleman, MD, Gynecologic Oncologist, Texas Oncology. “The results of this study support our strategy to initiate a clinical trial in ovarian cancer. The Company had a pre-IND meeting with the FDA to discuss our ovarian cancer clinical and regulatory plan in May, and we plan to pursue a Phase 1/2 proof of concept study in platinum-resistant ovarian cancer. Given the high unmet need with approximately 20,000 new cases of ovarian cancer diagnosed each year in the US alone, we are dedicated to bringing new treatment options to these patients,” said Greg Bosch, Chairman and CEO. About Panavance Therapeutics Panavance Therapeutics Inc. is a privately held, clinical-stage pharmaceutical company developing a novel oncology asset, misetionamide (GP-2250). Panavance was formed in 2021 as a US-based, wholly-owned carve out of Geistlich group, a family owned Swiss company, to focus on GP-2250 and the oncology business. Misetionamide is a tumor cell selective and broadly active small molecule with a unique dual mechanism of action of selectively disrupting the energy metabolism of cancer cells leading to cancer cell death as well as impacting nuclear factor-κB (“NFκB”) which affects cancer cells’ ability for protein synthesis and DNA transcription thereby restricting cancer cell growth and proliferation. The Company plans to initiate two clinical studies: a Phase 1/2 study of misetionamide for the treatment of platinum-resistant ovarian cancer and a clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients. Extensive preclinical studies have demonstrated that misetionamide’s broadly anti-neoplastic MOA has the potential to be effective in additional tumor types, including melanoma, squamous cell, breast, and colorectal cancers. For more information, please visit panavance.com and connect with the Company on Twitter, LinkedIn, and Facebook. Corporate and Investor Relations Contact Lisa DeScenzaLaVoieHealthScience(978) 395-5970ldescenza@lavoiehealthsceince.com Media ContactEla WangLaVoieHealthScience(617)-582-3091 ewang@lavoiehealthscience.com________________________________________ 1Kim MS, Glassman D, Handley KF, Lankenau Ahumada A, Jennings NB, Bayraktar E, Foster K, Joseph R, Lee S, Coleman RL, Sood AK. Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer. Cancer Med. 2024 Aug;13(15):e70031. doi: 10.1002/cam4.70031. PMID: 39114948; PMCID: PMC11306972. 2Majchrzak-Stiller, B.; Buchholz, M.; Peters, I.; Waschestjuk, D.; Strotmann, J.; Höhn, P.; Hahn, S.; Braumann, C.; Uhl, W.; Müller, T.; et al. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J. Cell. Mol. Med. 2023, 27, 2082–2092.

引言微血管网络在为受伤组织提供营养和交换各种代谢物方面发挥着重要作用。然而，如何有效渗透损伤组织是制约微血管网络重建的重要难题。2024年4月10日，同济大学左克强、谢晓云及上海交通大学崔文国共同通讯在Advanced Science 在线发表题为“Tissue-Penetrating Ultrasound-Triggered Hydrogel for Promoting Microvascular Network Reconstruction”的研究论文，该研究制备的水凝胶前体溶液可以有效穿透受损组织区域，超声触发溶液中脂质体释放凝血酶，水解纤维蛋白原，以钙离子和谷氨酰胺转印酶为催化剂，原位形成纤维蛋白固体水凝胶网络，有效解决受损组织的穿透受阻问题，显著促进组织内微血管网络的形成。首先，纤维蛋白原复合物溶液有效地渗透到受伤组织中。其次，超声触发钙离子和凝血酶的释放，激活谷氨酰胺转酶并水解纤维蛋白原。最后，催化纤维蛋白单体在受损组织区域原位形成纤维蛋白水凝胶。体外研究表明，纤维蛋白原复合物溶液在超声触发后15 s内有效穿透人工骨组织，连续触发30 s后形成水凝胶。总体而言，该研究有效地解决了超声触发水凝胶在损伤组织中的渗透阻力问题，最终激活原位微血管网络再生。微血管网络是一个复杂的循环系统，可有效地将气体、营养物质和代谢物输送到细胞并从细胞中运输出来，在受伤组织中起着关键作用。不完整的血管内皮生长因子（VEGF）信号传导可能会导致器官组织老化和损伤。相反，增强VEGF信号传导可以预防与年龄相关的毛细血管损伤，改善各种损伤组织的灌注和功能，最终延长寿命。此外，有学者发现损伤组织中锌指E-box结合同源盒蛋白1（ZEB1）缺失减少了启动子上的组蛋白乙酰化，从而抑制血管生成信号通路，减少损伤组织中微血管形成。该研究进一步揭示了微血管网络的产生与损伤组织发育之间的密切关系。研究表明，骨质疏松症会导致严重的骨损伤，包括外观结构破坏、微观结构改变和微血管网络活性降低。微血管网络与损伤组织骨细胞代谢失衡和骨发育异常密切相关。此外，微血管网络重建对于修复各种损伤组织至关重要，能够确保再生和扩张过程中充足的血液供应，但仍难以实现微血管网络的有效重建。因此，为有效解决受损组织微血管网络重建的技术难题，临床治疗中常用血管蒂组织移植来修复受损组织。健康的微血管组织移植可以使毛细血管穿透受损组织，从而提高原位修复的成功率。部分供体组织难以移植，或移植后微血管网络不发达、组织通透性差，使临床技术受到极大限制。此外，还有许多分子生物学研究致力于重建受伤组织中的微血管网络。微血管网络系统重建的关键要素在于内皮细胞的活化，研究发现，血管内皮生长因子、血小板衍生生长因子-AA、血小板衍生生长因子-BB等血管生成因子可激活内皮细胞，进一步促进血管重建。然而，这些血管活性因子的活性难以维持，更难以有效穿透损伤组织，持续促进微血管网络的原位重建。机制研究表明，ZEB1基因过表达可以激活ZEB1/Notch信号通路，促进血管再生，但基因治疗需要频繁的全身注射，难以缓慢释放并有效穿透局部损伤组织以实现微血管网络重建。因此，现有的临床损伤组织微血管网络重建仍存在组织通透性差的问题，尚未取得有效突破。AS 超声触发的组织渗透性水凝胶示意图（Credit: Advanced Science）近年来，组织工程技术已应用于微血管网络重建，主要目标是构建一个再生微血管网络，能够有效穿透受伤组织，促进微血管原位再生并与天然血管契合。近年来，能够利用生物材料模仿血管的细胞外基质，通过血管细胞与细胞外基质之间的相互作用重塑血管网络的结构和功能。尽管生物材料对大血管的再生有很强的促进作用，但在微观层面的组织渗透和血管网络重建方面仍面临许多挑战。此外，3D打印支架或水凝胶结合血管细胞、生长因子和基因药物，能够为血管生长提供适当的生物、物理和结构基础，确保药物缓慢、稳定释放，促进微血管重建。但该方法也存在生物材料组织通透性差的局限性，只能植入损伤组织区域。近年来，超声技术与功能生物材料的融合在剂量、空间和时间等方面有望实现精确治疗。超声波技术的应用可以促进液体在组织中的有效渗透，触发固态水凝胶的原位形成，有效递送药物。截至目前，利用超声触发组织内生物材料形成和促进微血管网络原位再生的研究尚需进一步发展，以实现受损组织中微血管网络的有效重建。局部组织基因工程技术为探索基因功能和微血管网络再生的潜力提供了有效方法。然而，有效触发技术和递送载体的缺乏阻碍了组织内微血管网络的重建。该研究中，水凝胶前体溶液可以有效地穿透受损组织区域，超声触发脂质体释放凝血酶以水解纤维蛋白原。随后，以钙离子和谷氨酰胺转氨酶为催化剂，原位触发固体纤维蛋白水凝胶网络形成，突破受损组织的穿透阻抗瓶颈，显著促进组织内微血管网络的形成。首先，将纤维蛋白原溶液的混合物注射到受伤的组织区域，使其完全穿透受伤组织及其周围的微血管网络。随后，超声触发脂质体释放钙离子和凝血酶，钙离子改变了转谷氨酰胺酶的能量配位，导致其构象发生变化，激活转谷氨酰胺酶。凝血酶催化纤维蛋白原水解为纤维蛋白单体，纤维蛋白单体通过转酰胺反应被活化的谷氨酰胺转氨酶催化交联，使得纤维蛋白分子的赖氨酸和谷氨酰胺侧链残基共价交联，同时与携带甘油醛-3-磷酸脱氢酶（PI3K）基因的脂质体结合，在受损组织区域原位形成纤维蛋白网络。最终，构建了一种超声触发的原位交联水凝胶渗透受损组织，通过基因工程局部激活PI3K-AKT通路，促进受损组织区域微血管网络的重建。体外研究中，将水凝胶前体溶液加入人工骨中，超声连续触发15 s内骨组织的有效穿透，30 s内快速形成水凝胶。值得注意的是，该水凝胶在体外也显示出良好的促血管形成功能。体内研究表明，该系统可有效穿透胫骨，连续8周促进胫骨内微血管网络。因此，该团队构建的组织渗透超声触发水凝胶可以有效解决损伤组织穿透阻抗问题，在微血管网络的重建中潜力巨大。原文链接https://onlinelibrary.wiley.com/doi/10.1002/advs.202401368责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

Misetionamide showed broad antineoplastic activity in 15 different cancer types including multiple human cancer cell lines with no detrimental effect on normal cells Misetionamide reduces energy metabolism by inhibiting aerobic glycolysis BERWYN, PA, Feb. 01, 2024 (GLOBE NEWSWIRE) -- Panavance Therapeutics Inc. (“Panavance” or the “Company”), a clinical-stage pharmaceutical company advancing the development of a novel oncology therapeutic intended to improve the outcomes and quality of life for patients, today announced publication of positive data in the peer-reviewed Anti-Cancer Drugs in an article titled, “Antineoplastic Activity of GP-2250 In Vitro and in Mouse Xenograft Models.”1 The publication by Sofia et al. (2024) provided early research evidence that misetionamide exhibits a dose-dependent antineoplastic effect on both established cancer cell lines and xenograft models from patient tissues.2 Antineoplastic activity was tested in over 300 cancer cell lines using the OncoPanel® cytotoxicity assay and was further tested in eight human cancer xenograft models. Results included a reduction of 30-40% of tumor volume in xenograft mouse models treated with misetionamide and demonstrated a reduction in the progression of tumor cell volume in multiple cancer cell lines including pancreatic and ovarian cancer suggesting a strong antineoplastic effect. Most notably in the ovarian tumor xenograft model, misetionamide produced a regression in the original tumor volume. Concentrations for IC50 and EC50 were determined as was the concentration at which a 10-fold increase in apoptosis was induced. All these concentrations have subsequently been shown to be clinically achievable in an on-going Phase 1 clinical trial. In addition, misetionamide was also shown to induce a cancer cell cycle block that would inhibit tumor cells from replicating and thus inhibiting tumor growth. The results of these studies also reinforce the results of other studies demonstrating strong synergism with other anticancer agents, including gemcitabine, bevacizumab, and PARP inhibitors. To that end, the results support the development of misetionamide as a promising new therapeutic agent with a unique mechanism of action for human cancers. “While this paper details the early screening work in 300 human cancer lines using in vitro studies as well as 8 in vivo studies to determine if misetionamide showed any antineoplastic activity, and, if so, in which cancer cells, we were pleased that the results showed both the very broad activity in many cancer cell lines and that normal cells were not detrimentally affected, said R. Duane Sofia, PhD, Head Nonclinical Research, Panavance Therapeutics. “The results from these studies demonstrate that misetionamide has a broad mechanism of action which could be impactful in treating most cancers. While our initial focus is on pancreatic and ovarian cancers, these studies further support the potential to pursue other cancer indications with misetionamide in the future,” said Greg Bosch, Chairman and CEO. About Misetionamide (GP-2250) Misetionamide is a tumor cell selective drug that is broadly active in multiple cancer models with a unique mechanism of action that suppresses cancer by disrupting its energy metabolism, leading to cancer cell death while not affecting normal cells. This activity occurs due to misetionamide’s targeting at least 3 key enzymes in the aerobic glycolysis pathway as well as downstream effects on other enzymes, transcription factors and tumor suppressor genes. Misetionamide’s inhibition of hexokinases, GAPDH (glyceraldehyde 3-phosphate dehydrogenase), and PVD (pyruvate dehydrogenase) during aerobic glycolysis greatly inhibits ATP production for cancer cells, setting up oxidative, metabolic, and hypoxic stresses within the cancer cell. Additionally, misetionamide’s inhibition of key transcription factors such as NFkB and enzymes further impair the ability for the cancer cell to provide sufficient energy for cellular reproduction for proliferation and survival. It also induces tissue hypoxia by inhibiting new blood vessel development in tumors.3 About Panavance Therapeutics Panavance Therapeutics Inc. is a privately held, clinical-stage pharmaceutical company developing a novel oncology asset, GP-2250 (also known as misetionamide). Panavance was formed in 2021 as a US-based, wholly owned carve out of Geistlich group, a family-owned Swiss company, to focus on GP-2250 and the oncology business. GP-2250 is a tumor cell selective and broadly active small molecule with a unique dual mechanism of action of selectively disrupting the energy metabolism of cancer cells leading to cancer cell death as well as impacting nuclear factor-κB (“NFκB”) which effects cancer cells’ ability for protein synthesis and DNA transcription thereby restricting cancer cell growth and proliferation. The Company is advancing towards the initiation of two registration directed clinical studies expected: a Phase 2/3 study of GP-2250 for the treatment of platinum resistant ovarian cancer and a pivotal Phase 3 clinical trial as a first-line maintenance therapy for non-BRCA mutated pancreatic cancer patients. Extensive preclinical studies have demonstrated that GP-2250’s broadly anti-neoplastic MOA has the potential to be effective in additional indications, including for example melanoma, squamous cell, breast, and colorectal cancers. For more information, please visit panavance.com and connect with the Company on Twitter, LinkedIn, and Facebook. ________________________________________ 1Sofia, R. Duane; Martin, Kathryn M.b; Costin, James C.c. Antineoplastic activity of GP-2250 in-vitro and in mouse xenograft models. Anti-Cancer Drugs 35(2):p 183-189, February 2024. | DOI: 10.1097/CAD.0000000000001550 2Buchholz, M; Majchrzak-Stiller, B; Hahn, S.; Vangala, D; Pfirrmann, RW; Uhi, W; et al. Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma – in vitro and in vivo. MGC Cancer 2017; 17:216. 3Majchrzak-Stiller, B.; Buchholz, M.; Peters, I.; Waschestjuk, D.; Strotmann, J.; Höhn, P.; Hahn, S.; Braumann, C.; Uhl, W.; Müller, T.; et al. GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells. J. Cell. Mol. Med. 2023, 27, 2082–2092. Corporate and Investor Relations Contact Lisa DeScenza LaVoieHealthScience (978) 395-5970 ldescenza@lavoiehealthsceince.com Media Contact Sara Krane LaVoieHealthScience (617) 865-2197 skrane@lavoiehealthscience.com