PXS-5505

Early laboratory results in mice show the drug PXS-5505 increases survival when combined with chemotherapy in the treatment of pancreatic ductal adenocarcinomas. Findings from the Garvan Institute of Medical Research reveal a new Australian drug that targets scar-like 'fibrotic' tissue within tumours shows promise for treating pancreatic ductal adenocarcinoma, one of the most aggressive forms of pancreatic cancer with a five-year survival rate of less than 10%. The research in mouse models showed that when given in combination with chemotherapy, the drug PXS-5505 increased survival time by more than 35%, compared to chemotherapy treatment alone. "The preclinical validation of this first-in-class anti-fibrotic drug marks a major milestone in our quest to overcome the significant challenges in treating pancreatic cancer and brings hope to patients and their families," says Associate Professor Thomas Cox, head of the Matrix & Metastasis Lab at Garvan and senior author of the study, published in the journal Nature Cancer. Potential to increase cancer survival Pancreatic cancer is often diagnosed at an advanced stage, which means that chemotherapy is often the only treatment option available. Many pancreatic cancers develop chemotherapy resistance soon after treatment starts, which contributes to the poor survival of patients. Part of this resistance is driven by tumour fibrosis -- the formation of a mesh of scar tissue-like collagen -- within and around pancreatic tumours that in turn reduces the effectiveness of chemotherapy drugs. The new drug PXS-5505, developed by Sydney-based pharmaceutical research company Pharmaxis (ASX: PXS) and currently in Phase II clinical trials for the treatment of bone marrow cancer, works by blocking a family of enzymes that are critical for the deposition of collagen into the fibrotic tissue around tumours. In collaboration with Pharmaxis, Garvan researchers found that the drug significantly reduced fibrosis in pancreatic tumours in mouse models. The combination therapy also substantially reduced the spread of the cancer to other organs, such as the liver, by 45%. "PXS-5505 returns the tumour microenvironment to a more 'normal' state by reducing fibrosis and decreasing tumour stiffness," explains Dr Jessica Chitty, Senior Research Officer at Garvan and first author of the study. "This allows chemotherapy drugs to penetrate the tumours more easily, work more effectively, and destroy more cancer cells." "PXS-5505 shows real potential to improve chemotherapy for patients," says Associate Professor Cox. "We are now in the process of progressing this work toward clinical trials that will evaluate this promising drug combination approach for pancreatic cancer patients." "Pharmaxis has already seen very promising early results in a Phase II trial with patients that have the bone marrow cancer myelofibrosis," commented Gary Phillips, CEO of Pharmaxis. "This groundbreaking research stems from a long collaboration with the team of high calibre researchers at the Garvan Institute and provides exciting new evidence that PXS-5505 may also have a role as a therapy to improve the effect of current chemotherapy drugs in solid tumours like pancreatic cancer and extending the life of patients."

来自伦敦大学学院等机构的科学家们通过研究首次描述了癌细胞是如何从血液中逃出并侵入到其它器官的生物力学机制。 癌细胞的溢出是转移过程的一个关键步骤，其主要包括癌细胞在内皮组织上的停滞、跨内皮的迁移（TEM），随后就是侵入远端的内皮下细胞外基质（ECM）中，尽管癌症研究大多数集中在肿瘤细胞和细胞外基质之间的生物力学相互作用中，尤其是原发性肿瘤位点，但研究人员对内皮细胞和内皮下ECM的机械特性以及其如何促进癌细胞的溢出过程却知之甚少。近日，一篇发表在国际杂志Advanced Science上题为“Endothelium and Subendothelial Matrix Mechanics Modulate Cancer Cell Transendothelial Migration”的研究报告中，来自伦敦大学学院等机构的科学家们通过研究首次描述了癌细胞是如何从血液中逃出并侵入到其它器官的生物力学机制。 文章中，研究者发现，组织的多孔性越强，越柔软，癌细胞就越有可能快速侵入其它器官，且能更加快速地做到这一点，这就为科学家们寻找预防或遏制癌症转移的方法提供了宝贵的数据，而癌症转移是引发癌症死亡的主要原因。影响肿瘤周围环境硬度的药物，比如PAT-1251和PXS-5505，目前都正在临床试验中进行测试来研究尚未发生扩散的癌症，研究人员希望类似的方法能被用来治疗人类转移性的癌症。 实体肿瘤会在机体的一个地方出现，其被称之为原发性肿瘤位点，而当癌细胞从原发性肿瘤位点脱落后就会发生转移并通过血液或淋巴系统扩散到机体的其它部位，这可能就会导致其它器官发生继发性肿瘤，癌细胞冲出循环系统进入其它组织的过程被称之为癌细胞溢出（extravasation）。大多数癌症研究的重点都是尽可能早地发现癌症并在其扩散之前对其进行治疗，这往往会明显改善患者的治疗结局，但一旦癌症发生转移往往就难以治疗了，癌症转移是绝大多数癌症死亡的一个因素，而这一事实或许就强调了这一点，尽管转移的癌症能被治疗，但其往往不能被治愈。 揭示癌细胞在机体中发生强行转移背后的分子机制。 图片来源：Advanced Science (2023). DOI:10.1002/advs.202206554 这项研究中，研究人员通过研究更好地理解了能决定癌细胞从血液中入侵其它机体组织的生物力学机制。他们创建了内皮组织的体外模型，内皮组织是将血液与其它组织分开的单细胞层，随后研究者将该模型置于不同的胶原蛋白凝胶上，从而模拟较硬或更多孔的组织，研究者将肿瘤细胞引入到模型中来观察是否其能渗透到内皮组织中，以及这一过程需要多长时间，其又在机械方面是如何做到这一点的。Yousef Javanmardi博士说道，我们观察到，癌细胞需要抓到内皮组织上来建立一个固定点，从而利用这个固定点来将自身推拉通过紧密编织的细胞层，从而进入到机体其它组织中，这有点像你被困在泥浆中，你需要利用像岩石一样坚硬的东西来将身体推拉到安全的地方，而泥浆越厚往往就越困难，越难以脱身。 这些研究发现或许就提出了这样一个问题，即是否机体特定组织的生物力学特性能确定继发性肿瘤的形成过程。鉴于以这种方式在人类组织中研究癌细胞的转移极为困难，下一步研究人员将会开发出一种更先进的血管系统三维模型，在更好地模仿人类生物学的条件下更详细地观察癌症的生物力学特征，这或许就能帮助他们进行药物测试，并识别出能进行人类临床试验的候选药物。 研究者表示，看到这项跨学科的研究在5年后取得了巨大成果，我们非常高兴，研究癌细胞转移所面临的挑战是非常巨大的，忘完更需要包括物理学、生物学等多个领域的科学家付出大量的努力，而本文中，科学家们的联合研究成果或许也能帮助进一步理解癌症的转移以及开发治疗癌症的新型药物。综上，本文研究结果表明，远端组织的机械特性（包括内皮和内皮下细胞外基质的相互作用）或许是癌细胞转移性亲器官特性的关键因素。（生物谷Bioon.com） 原始出处： Yousef Javanmardi,Ayushi Agrawal,Andrea Malandrino, et al. Endothelium and Subendothelial Matrix Mechanics Modulate Cancer Cell Transendothelial Migration, Advanced Science (2023). DOI:10.1002/advs.202206554