Scientific Rationale and Approach
There is significant evidence for the involvement of chemokines in cancer, both in tumor progression and metastatic dissemination of the disease. The chemokine receptor CX3CR1 (a GPCR) and its ligand fractalkine (CX3CL1) define a compelling new therapeutic axis for the treatment of cancer and metastatic disease.
The CX3CR1 / fractalkine axis has been strongly implicated in the progression and dissemination of a number of solid tumors, including breast and prostate cancers. Unlike all other chemokines, fractalkine binds to a single receptor, CX3CR1 and it exists in both a membrane bound form (found predominantly in bone stroma) and a soluble form. The soluble form of the molecule is a strong chemo-attractant, recruiting circulating cells into the local stroma.
Kerberos is at the forefront in the research and development of highly potent small molecule antagonists of CX3CR1. Kerberos has shown the critical role CX3CR1 / fractalkine plays in the recruitment of breast circulating tumor cells (CTCs) from the systemic blood circulation into the bone stroma.
Pre-Clinical Proof of Concept
Kerberos has completed target validation of CX3CR1 using transgenic knockout mice, silencing using CRISPRi, neutralizing antibodies and its own proprietary small molecules.
Kerberos has treated rodents harboring small metastatic tumors in the skeleton and soft-tissue organs such as liver and lungs with our lead CX3CR1 antagonist, KB-03. We have shown that KB-03 dramatically impairs metastatic dissemination and prevents the seeding of further lesions by existing metastases. Furthermore, systemic administration of this compound dramatically extends overall survival as compared to untreated animals. Taken together, we have generated compelling evidence that CX3CR1 antagonists could dramatically reduce seeding and progression of metastatic tumors in patients.
Kerberos is developing a series of CX3CR1 antagonists initially for inflammatory breast cancer (IBC), one of the most aggressive forms of breast cancer. A significant percentage of IBC patients already have bone metastases at presentation. Patients progress rapidly in weeks rather than months or years, and many succumb to the disease within a year of presenting with metastasis. IBC is an indication with a high unmet need as there are no specifically approved therapies for this disease. Additionally, the indication is considered an orphan drug patient population.