PXS-5505

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

PXS-5505 shows good tolerability and >90% inhibition of target enzymes LOX and LOXL2 in myelofibrosis phase 1c dose escalation study Safety committee approves progression to 6 month phase 2 study SYDNEY, Oct. 5, 2021 /PRNewswire/ -- Clinical stage drug development company Pharmaxis Ltd (ASX: PXS) today announced further positive results of data analysis from a phase 1c clinical trial (MF-101) studying its drug PXS-5505 in patients with the bone marrow cancer myelofibrosis for 28 days at three dosage levels. Assessment with Pharmaxis' proprietary assays of the highest dose has shown inhibition of the target enzymes, LOX and LOXL2, at greater than 90% over a 24-hour period at day 7 and day 28. The trial safety committee has reviewed the results and having identified no safety signals, has cleared the study to progress to the phase 2 dose expansion phase where 24 patients will be treated at the highest dose twice a day for 6 months. Pharmaxis CEO Gary Phillips said, "We are very pleased to have completed the dose escalation phase of this study with such clear and positive findings. We will now immediately progress to the phase 2 dose expansion study where we aim to show PXS-5505 is safe to be taken longer term with the disease modifying effects that we have seen in the pre-clinical models. The trial infrastructure and funding is in place and we are on track to complete the study by the end of 2022." Independent, peer-reviewed research has demonstrated the upregulation of several lysyl oxidase family members in myelofibrosis. The level of inhibition of LOX achieved in the current study at all three doses significantly exceeds levels that caused disease modifying effects with PXS-5505 in pre-clinical models of myelofibrosis with improvements in blood cell count, diminished spleen size and reduced bone marrow fibrosis. LOXL2 was inhibited to a similar degree and based on pre-clinical work such high inhibition is likely replicated for other LOX family members (LOXL1, 3 and 4). [1] Study data can be viewed in the full announcement. Commenting on the results of the trial, Dr Gabriela Hobbs, Assistant Professor, Medicine, Harvard Medical School & Clinical Director, Leukaemia, Massachusetts General Hospital said, "Despite improvements in the treatment of myelofibrosis, the only curative therapy remains an allogeneic stem cell transplantation, a therapy that many patients are not eligible for due to its morbidity and mortality. None of the drugs approved to date consistently or meaningfully alter the fibrosis that defines this disease. PXS-5505 has a novel mechanism of action by fully inhibiting all LOX enzymes. An attractive aspect of this drug is that so far in healthy controls and in this phase 1c study in myelofibrosis patients, the drug appears to be very well tolerated. This is meaningful as approved drugs and those that are undergoing study, are associated with abnormal low blood cell counts. Preliminary data thus far, demonstrate that PXS-5505 leads to a dramatic, >90% inhibition of LOX and LOXL2 at one week and 28 days. This confirms what's been shown in healthy controls as well as mouse models, that this drug can inhibit the LOX enzymes in patients. Inhibiting these enzymes is a novel approach to the treatment of myelofibrosis by preventing the deposition of fibrosis and ultimately reversing the fibrosis that characterizes this disease." The phase 1c/2a trial MF-101 cleared by the FDA under the Investigational New Drug (IND) scheme aims to demonstrate that PXS-5505, the lead asset in Pharmaxis' drug discovery pipeline, is safe and effective as a monotherapy in myelofibrosis patients who are intolerant, unresponsive or ineligible for treatment with approved JAK inhibitor drugs. Trial sites will now open to recruit myelofibrosis patients into the 6-month phase 2 study in Australia, South Korea, Taiwan and the USA. An effective pan-LOX inhibitor for myelofibrosis would open a market that is conservatively estimated at US$1 billion per annum. While Pharmaxis' primary focus is the development of PXS-5505 for myelofibrosis, the drug also has potential in several other cancers including liver and pancreatic cancer where it aims to breakdown the fibrotic tissue in the tumour and enhance the effect of chemotherapy treatment. AUTHORISED FOR RELEASE TO ASX BY: Pharmaxis Ltd Disclosure Committee. Contact: David McGarvey, Chief Financial Officer and Company Secretary: T +61 2 9454 7203, E david.mcgarvey@pharmaxis.com.au Join the Pharmaxis mailing list here Follow us on LinkedIn and Twitter About Pharmaxis Pharmaxis Ltd is an Australian clinical stage drug development company developing drugs for inflammatory and fibrotic diseases, with a focus on myelofibrosis. The company has a highly productive drug discovery engine built on its expertise in the chemistry of amine oxidase inhibitors, with drug candidates in clinical trials. Pharmaxis has also developed two respiratory products which are approved and supplied in global markets, generating ongoing revenue. Pharmaxis is developing its drug PXS-5505 for the bone marrow cancer myelofibrosis which causes a build up of scar tissue that leads to loss of production of red and white blood cells and platelets. The US Food and Drug Administration has granted Orphan Drug Designation to PXS-5055 for the treatment of myelofibrosis and permission under an Investigational Drug Application (IND) to progress a phase 1c/2 clinical trial that began recruitment in Q1 2021. PXS–5505 is also being investigated as a potential treatment for other cancers such as liver and pancreatic cancer. Other drug candidates being developed from Pharmaxis' amine oxidase chemistry platform are targeting fibrotic diseases such as kidney fibrosis, NASH, pulmonary fibrosis and cardiac fibrosis; fibrotic scarring from burns and other trauma; and inflammatory diseases such as Duchenne Muscular Dystrophy. Pharmaxis has developed two products from its proprietary spray drying technology that are manufactured and exported from its Sydney facility; Bronchitol® for cystic fibrosis, which is approved and marketed in the United States, Europe, Russia and Australia; and Aridol® for the assessment of asthma, which is approved and marketed in the United States, Europe, Australia and Asia. Pharmaxis is listed on the Australian Securities Exchange (PXS). Its head office, manufacturing and research facilities are in Sydney, Australia. About PXS-5505 PXS-5505 is an orally taken drug that inhibits the lysyl oxidase family of enzymes, two members LOX and LOXL2 are strongly upregulated in human myelofibrosis. In pre-clinical models of myelofibrosis PXS-5505 reversed the bone marrow fibrosis that drives morbidity and mortality in myelofibrosis and reduced many of the abnormalities associated with this disease. It has already received IND approval and Orphan Drug Designation from the FDA. About Myelofibrosis Myelofibrosis is a disorder in which normal bone marrow tissue is gradually replaced with a fibrous scar-like material. Over time, this leads to progressive bone marrow failure. Under normal conditions, the bone marrow provides a fine network of fibres on which the stem cells can divide and grow. Specialised cells in the bone marrow known as fibroblasts make these fibres. In myelofibrosis, chemicals released by high numbers of platelets and abnormal megakaryocytes (platelet forming cells) over-stimulate the fibroblasts. This results in the overgrowth of thick coarse fibres in the bone marrow, which gradually replace normal bone marrow tissue. Over time this destroys the normal bone marrow environment, preventing the production of adequate numbers of red cells, white cells and platelets. This results in anaemia, low platelet counts and the production of blood cells in areas outside the bone marrow for example in the spleen and liver, which become enlarged as a result. Myelofibrosis can occur at any age but is usually diagnosed later in life, between the ages of 60 and 70 years. The cause of myelofibrosis remains largely unknown. It can be classified as either JAK2 mutation positive (having the JAK2 mutation) or negative (not having the JAK2 mutation). Source: Australian Leukemia Foundation: Forward-looking statements Forward–looking statements in this media release include statements regarding our expectations, beliefs, hopes, goals, intentions, initiatives or strategies, including statements regarding the potential of products and drug candidates. All forward-looking statements included in this media release are based upon information available to us as of the date hereof. Actual results, performance or achievements could be significantly different from those expressed in, or implied by, these forward-looking statements. These forward-looking statements are not guarantees or predictions of future results, levels of performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this document. For example, despite our efforts there is no certainty that we will be successful in developing or partnering any of the products in our pipeline on commercially acceptable terms, in a timely fashion or at all. Except as required by law we undertake no obligation to update these forward-looking statements as a result of new information, future events or otherwise. CONTACT: Media: Felicity Moffatt: T +61 418 677 701, E felicity.moffatt@pharmaxis.com.au Investor relations: Rudi Michelson (Monsoon Communications) T +61 411 402 737, E rudim@monsoon.com.au View original content: SOURCE Pharmaxis Limited Company Codes: Australia:PXS