On September 27, 2023 Pathios Therapeutics Limited ("Pathios"), a biotech company focused on the development of first-in-class therapies for cancer, reported that the company has been awarded a £567K (~US$727K) grant from Innovate UK, the UK government’s innovation agency (Press release, Pathios Therapeutics, SEP 27, 2023, View Source [SID1234635457]). The grant funding will enable the company to expand its development of novel small molecule GPR65 inhibitors into the area of a possible treatment of malignant brain tumors. The project is being conducted in collaboration with researchers from the University of Nottingham and is focused on optimizing small molecule GPR65 inhibitors to penetrate the central nervous system (CNS) and evaluate those optimized compounds in preclinical models of brain cancer.
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The treatment of patients with malignant brain tumors remains a high unmet medical need. While chemotherapy has modestly improved survival rates among these patients, the need for truly impactful treatments remains. Immunotherapy has demonstrated some promise in this area, though overcoming the immunosuppressive tumor microenvironment (TME) remains a key challenge.
Pathios is pursuing a novel immuno-oncology approach to the treatment of cancer focused on counteracting the immunosuppressive polarization of immune cells, including tumor associated macrophages (TAMs), that is triggered by an acidic TME. This is achieved by the design and development of inhibitors of GPR65, an acid sensing G protein-coupled receptor that is exclusively expressed on immune cells and is associated with driving the immunosuppressive immune cell phenotype in the TME that prevents immune-mediated killing of cancer cells. Pathios’ internal human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumor types, positioning it as a unique immuno-oncology target for therapeutic intervention.
With this grant, Pathios is utilizing an extensively developed proprietary assay platform to optimize CNS penetration of small molecule GPR65 inhibitors for the treatment of human malignant gliomas. Optimized GPR65 inhibitors are being tested in a human ex vivo co-culture system model of human glioblastoma in collaboration with University of Nottingham researchers, followed by in vivo efficacy evaluation in mouse models.
"Recent research suggests that a portion of glioblastoma patients do not respond to approved immuno-oncology drugs due to the immunosuppression of immune cells in the TME by the acidic microenvironment inherent to all solid tumors, including brain cancers." said Stuart Hughes, Ph.D., chief executive officer of Pathios. "We believe there is promise in applying our novel immuno-oncology approach to cancers of the brain with a CNS-penetrating small molecule GPR65 inhibitor. We are excited to be working alongside the talented team at the University of Nottingham on this important preclinical research, which we hope will pave the way for future clinical studies."
"We are excited to be supporting the research and development of this novel therapy for malignant brain tumours. By working with Pathios we aim to support their preclinical development and
expedite the progress of their inhibitors into the clinic," said Alan McIntyre, Associate Professor of Faculty of Medicine & Health Sciences, at the University of Nottingham. "This is important as malignant brain tumours are difficult to treat. In addition, this approach offers a new avenue to overcome the therapy resistance caused by the acidic microenvironment, frequently found in malignant brain tumours."
About Acidity in the Tumor Microenvironment
The acidic tumor microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumor associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes.