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

**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.