Development and technical evaluation of first in class small molecule inhibitors for the treatment of brain tumours

**Pathios Treateutics**专门识别和开发分子，改变免疫系统中一种特殊的细胞表面受体的信号，该受体检测局部PH值的变化，称为GPR65\。Pathios对GPR65有深刻的理解，并开发出阻止或“关闭”这种受体的信号来治疗癌症的药物。Pathios与诺丁汉大学合作，希望利用其在GPR65方面的专业知识来开发可以治疗恶性脑瘤的药物。英国纳税人每年花费在脑瘤上的费用接近6亿英磅。目前的治疗方法严重不足，并伴随着令人衰弱的副作用。在英国，每年约有12000人被诊断出患有恶性脑瘤，这种类型的癌症每年导致约5000人死亡。患有最严重类型的脑瘤-多形性胶质母细胞瘤(GBM)的人通常只能存活15-16个月。大多数脑癌患者将接受手术结合放射治疗和/或化疗(c.GB 180,000/患者)。然而，治疗很少是有针对性的。巴蒂奥斯治疗癌症的方法是基于最近的突破性研究，该研究表明，许多肿瘤典型的酸性微环境激活GPR65受体，导致天然免疫系统中称为肿瘤相关巨噬细胞(TAMs)的特殊细胞解除武装。这阻止了这些细胞攻击癌症，并刺激其他类型的免疫细胞称为T细胞。通过关闭GPR65，Pathios的药物将能够恢复TAMs摧毁癌细胞和刺激有效免疫反应的能力。在所有人类肿瘤类型中，恶性脑瘤的GPR65受体水平高于任何其他类型的癌症。脑肿瘤也被TAMs高度浸透，其特点是局部微环境高度酸性。因此，脑瘤似乎特别容易接受一种试图抑制GPR65信号的方法。与巴蒂奥斯对其他形式癌症的治疗不同，脑瘤的治疗需要具有特殊的特性，使其能够进入中枢神经系统(CNS)。巴蒂奥斯已经确定了一系列具有这种性质的分子，现在正在寻求进一步优化这些分子。此外，Pathios还将与诺丁汉大学的世界级癌症科学中心(CCS)合作，创建所需的最先进的工具，以证明这些分子将对人类脑瘤有效。

**Pathios Therapeutics** specialise in identifying and developing molecules that alter the signalling of a specialised cell-surface receptor in the immune system that detects changes in the local pH called GPR65\. Pathios has a deep understanding of GPR65 and develop drugs that block or 'switch off' the signalling of this receptor to treat cancers.Pathios in collaboration with the University of Nottingham wish to capitalise on its expertise around GPR65 to develop drugs that can treat malignant brain tumours. The annual cost to the UK taxpayer of brain tumours is almost £0.6Bn. Current treatments are woefully inadequate and accompanied by debilitating side effects. Around 12,000 people a year are diagnosed with a malignant brain tumour in the UK, with this type of cancer causing ~5,000 annual deaths. People with the most severe type of brain tumour, glioblastoma-multiforme (GBM), typically only survive 15-16 months. Most brain cancer patients will receive surgery combined with radiotherapy and/or chemotherapy (c.£180,000/patient). However, treatment is rarely curative.Pathios' approach to treating cancer is based on recent ground-breaking research showing that activation of the GPR65 receptor by the acidic microenvironment that is typical of many tumours leads to the disarming of specialized cells in the innate immune system called tumour associated macrophages (TAMs). This prevents these cells from being able to attack the cancer and stimulate other types of immune cells called T-cells. By 'switching off' GPR65, Pathios' drugs will be able to restore the ability of TAMs to destroy cancer cells and stimulate an effective immune response.Across all human tumour types, the levels of the GPR65 receptor are higher in malignant brain tumours than in any other type of cancer. Brain tumours are also highly infiltrated by TAMs and are characterized by a highly acidic local microenvironment. Brain tumours would therefore appear to be especially amenable to an approach that seeks to suppress GPR65 signalling. In contrast to Pathios's therapies for other forms of cancer, a treatment for brain tumours would need to have special properties that enable it to enter the central nervous system (CNS). Pathios has identified a series of molecules with such properties and now seeks to optimise these further. Alongside this, Pathios will work with the world class Centre for Cancer Sciences (CCS) at the University of Nottingham to create the state-of-the-art tools required to demonstrate that these molecules will be effective against human brain tumours.