Rapid translation of small molecule GPR65 inhibitors for cancer immunotherapy

**Pathios Therapeutics** 是一家专门开发分子的公司，这些分子可以改变免疫系统中细胞表面受体的信号，从而检测pH值的变化。该公司在理解一种名为GPR65的受体方面具有特殊的专业知识，目前正在寻求制造阻断或“关闭”这种受体信号的药物，以治疗多发性硬化症和强直性脊柱炎等疾病。最近的科学证据表明，阻断GPR65的药物也可以使免疫系统攻击某些类型的癌症。Pathios现在计划与牛津大学的癌症研究人员合作，进一步利用其在GPR65方面的专业知识，并利用这一重要的额外治疗机会。近年来，针对所谓的T细胞检查点的免疫治疗药物已经为一些癌症患者带来了巨大的生存益处。然而，大多数患者仍然对这些新疗法没有充分的反应。这是因为肿瘤能够建立多种屏障来防止免疫系统攻击，其中许多是目前批准的治疗方法无法解决的。近年来，免疫系统攻击的一个关键的额外障碍是肿瘤能够通过创造低pH值（即酸性）的局部微环境来解除先天免疫系统中称为肿瘤相关巨噬细胞（TAM）的特化细胞的武装。众所周知，肿瘤可能比正常组织更酸性，因为它们依赖于不同形式的新陈代谢来生长和生存，从而产生乳酸作为副产品。人们也早就知道，这种改变的代谢，可以很容易地通过专门的血液测试检测到，强烈预测患者将对目前的免疫治疗反应不良。这在晚期黑色素瘤（一种严重的皮肤癌）中尤为明显。最近的突破性数据现在已经为这种联系提供了解释，表明肿瘤酸度通过激活GPR65受体及其信号通路来禁用TAM，导致黑色素瘤结局显著恶化。因此，阻断GPR65的药物可以在黑色素瘤中实现潜在的改变游戏规则的结果。Pathios和牛津大学之间的合作是将这种药物推向临床开发的理想选择，因为它将GPR65受体的前沿知识与对耐药黑色素瘤患者的无与伦比的临床理解结合在一起。

**Pathios Therapeutics** is a company that specialises in developing molecules that alter the signalling of cell-surface receptors in the immune system that detect changes in pH. The company has particular expertise in the understanding of a receptor called GPR65 and is currently seeking to make drugs that block or 'switch off' the signalling of this receptor to treat diseases like multiple sclerosis and ankylosing spondylitis. Recent scientific evidence suggests that drugs that block GPR65 could also enable the immune system to attack certain types of cancers. Pathios now plans to team up with cancer researchers at the University of Oxford to further capitalise on its expertise around GPR65 and exploit this important additional therapeutic opportunity.In recent years, immunotherapy agents that target so-called T-cell checkpoints have led to dramatic survival benefits in some cancer patients. However, the majority of patients still do not respond adequately to these new treatments. This is because tumours are able to put up multiple barriers to prevent immune system attack and many of these are not addressed by currently approved therapies. Therefore, new forms of treatment are needed that target these additional immune evasion mechanisms.One of the key additional barriers to immune system attack that has come to light in recent years is the ability of tumours to disarm specialized cells in the innate immune system called tumour associated macrophages (TAMs), via the creation of a low pH (i.e. acidic) local microenvironment. It is well known that tumours can be more acidic than normal tissues because they rely on a different form of metabolism for growth and survival that creates lactic acid as a by-product. It has also long been known that this altered metabolism, which can be readily detected by a specialized blood test, strongly predicts that patients will respond poorly to current immunotherapy. This is particularly marked in advanced melanoma, a serious form of skin cancer. Recent ground-breaking data has now provided an explanation for this link by showing that tumour acidity disables TAMs by activating the GPR65 receptor and its signalling pathway, leading to significantly worse melanoma outcomes. Therefore, a drug that blocks GPR65 could achieve potentially game-changing results in melanoma. A collaboration between Pathios and the University of Oxford is ideally placed to progress such a drug into clinical development as it brings together cutting-edge knowledge of the GPR65 receptor with an unparalleled clinical understanding of treatment-resistant melanoma patients.