SBIR-STTR Award

Evidence in pre-clinical and clinical settings suggests the involvement of chemokines in metastatic tumor cell disease spreading. We have recently provided data validating the involvement of the CX3CR1/Fractalkine axis in breast and prostate cancer metastasis. We have discovered a potent in vivo efficacious drug-like small molecule using in vitro chemotaxis and functional assays to provide pharmacological proof of concept that modulation of the CX3CR1/ Fractalkine axis with a small molecule CX3CR1 antagonist may have therapeutic benefit in the treatment of advanced breast and prostate cancer. Specific aims of this proposal are: Aim 1: To provide an improved drug-like CX3CR1 antagonist. The lead compound, JMS-17-2, will be optimized using medicinal chemistry approaches; maintaining potency, improving selectivity, and optimizing in vitro pharmacokinetic properties and the resulting optimized lead from this aim will be evaluated for in vivo pharmacokinetics in mice and used to determine the therapeutic potential of a CX3CR1 antagonist in a pre- clinical animal model of metastasis. Aim 2: To establish a role for CX3CR1 in supporting the bone tissue colonization of cancer cells after their homing to the skeleton. We will transduce MDA-MB-436 breast cancer cells with doxycycline inducible CX3CR1-expression lentiviral particles, sort by FACS to enrich for high-expressing cells, confirm CX3CR1 conditional expression in vivo, and use these cells to determine the importance of CX3CR1 on metastatic progression in vivo. Expression of CX3CR1 will be controlled during progression by doxycycline treatment. The ability of our lead compound to inhibit metastatic progression in this model will also be evaluated. An inhibitor of metastatic dissemination will advance clinical practice and improve therapy by directly addressing tumor spreading, the direct cause of mortality in patients with advanced disease. Synergy of a CX3CR1 antagonist and a chemotherapeutic is expected due to preventing CTCs from entering the sanctuary of the bone marrow. Evidence shows that CX3CR1 antagonism extends to oncology indications such as breast adenocarcinoma, prostate, epithelial ovarian carcinoma, pancreatic cancer, and glioma. Thus, it is envisioned that an efficacious drug to treat metastatic progression would be widely applicable and have a significant impact on the morbidity and mortality associated with metastatic disease.

Thesaurus Terms:
Address;Advanced Disease;Alzheimer's Disease;Animal Model;Anticancer Research;Area;Attenuated;Biological Assay;Bone Marrow;Bone Tissue;Breast Adenocarcinoma;Breast Cancer Cell;Cancer Cell;Cancer Etiology;Cancer Pain;Cancer Patient;Cells;Chemokine;Chemokine Receptor;Chemotaxis;Chronic;Clinical;Clinical Practice;Communities;Complex;Cx3cl1 Gene;Data;Design;Disease;Dose;Doxycycline;Drug Kinetics;Epithelial;Fractalkine;Glioma;Goals;Homing;Improved;In Vitro;In Vivo;In Vivo Model;Incidence;Inflammatory;Inhibitor/Antagonist;Inhibitory Concentration 50;Killings;Lead;Leukocyte Trafficking;Ligands;Malignant Bone Neoplasm;Malignant Breast Neoplasm;Malignant Neoplasm Of Pancreas;Malignant Neoplasm Of Prostate;Malignant Neoplasms;Mediating;Meetings;Metastatic Neoplasm To The Bone;Metastatic Process;Migration Assay;Modeling;Morbidity - Disease Rate;Mortality Vital Statistics;Mus;Neoplasm Metastasis;Neoplastic Cell;Neuropathy;New Therapeutic Target;Novel;Novel Strategies;Novel Therapeutics;Oncology;Ovarian;Ovarian Carcinoma;Painful Neuropathy;Parkinson Disease;Particle;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Play;Pre-Clinical;Prevent;Process;Property;Prostate;Public Health Relevance;Receptor;Reporting;Research;Role;Series;Signal Transduction;Skeleton;Small Molecule;Sorting - Cell Movement;Structure-Activity Relationship;Therapeutic;Therapeutic Agents;Therapy Development;Tool;Tumor;Work;

Evidence in pre-clinical and clinical settings suggests the involvement of chemokines in metastatic tumor cell disease spreading. We have designed and synthesized the first novel, potent, small molecule CX3CR1 antagonist probe, JMS-17-2. JMS-17-2 is a potent selective CX3CR1 functional antagonist (pERK IC50 = 0.32 nM; Chemotaxis IC50 ? 10 nM). JMS-17-2 is effective in vivo, as it potently blocks tumor cell seeding to the skeleton and slows metastatic progression in a mouse model of established metastasis. The improved advanced lead, JMS-FX-68 (pERK IC50 ? 1 nM) shows impressive survival data in a preliminary 16 week in vivo efficacy study, and importantly appears to demonstrate an effective and safe survival outcome. Specific aims of this proposal are: Specific Aim 1: Specific Aim 1: Identify a compound with improved liver microsome stability while maintaining good drug-like properties. Goal: To clearly provide Drug-like property and selectivity assessment for the top analogs. Specific Aim 2: Complete full characterization of JMS-FX-68 to provide Development Candidate Assessment. Goal: To clearly assess Development candidate criteria for this advanced pre-clinical lead compound. Specific Aim 3: Identification and characterization of a fast follow-up to JMS-FX-68. Goal: To clearly assess Development candidate criteria for an advanced pre-clinical follow-up lead compound. An inhibitor of metastatic dissemination will advance clinical practice and improve therapy by directly addressing tumor spreading, the direct cause of mortality in patients with advanced disease. Synergy of a CX3CR1 antagonist and a chemotherapeutic is expected due to preventing CTCs from entering the sanctuary of the bone marrow. Evidence shows that CX3CR1 antagonism extends to oncology indications such as breast adenocarcinoma, prostate, epithelial ovarian carcinoma, pancreatic cancer, and glioma. Thus, it is envisioned that an efficacious drug to treat metastatic progression would be widely applicable and have a significant impact on the morbidity and mortality associated with metastatic disease.

Public Health Relevance Statement:


Project narrative:
A NOVEL SMALL MOLECULE CX3CR1 ANTAGONIST HALTS METASTASIS This proposal will provide an advanced pre-clinical CX3CR1 antagonist as a potential new therapeutic agent for the benefit of advanced breast cancer patients, as well as patients with other cancers driven by CX3CR1 and pave the way for the development of novel and more effective therapies. After completion of the studies outlined in this proposal, we will have selected a drug candidate to enter enabling-toxicology studies with the ultimate goal of filing an IND and begin human clinical trials for the development of a novel effective treatment for advanced breast adenocarcinoma.

Project Terms:
Address; advanced disease; analog; base; Bioavailable; Bone Marrow; Bone Tissue; Breast Adenocarcinoma; Breast Cancer Patient; cancer cell; Cancer Patient; Cause of Death; chemokine; chemokine receptor; Chemotaxis; Chronic; Clinical; clinical practice; Clinical Trials; CRISPR interference; Data; design; Development; Disease; DNA Double Strand Break; Dose; drug candidate; Drug Kinetics; effective therapy; efficacy study; Epithelial; follow-up; Formulation; Fractalkine; Future; Genes; Genetic Transcription; Glioma; Goals; Hand; Homing; Human; Impairment; improved; in vivo; Industry Standard; inhibitor/antagonist; knock-down; Lead; Left; Liver Microsomes; malignant breast neoplasm; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Malignant Neoplasms; Metabolic; Morbidity - disease rate; mortality; mouse model; Mus; Neoplasm Metastasis; neoplastic cell; novel; novel strategies; novel therapeutics; oncology; Oral; Ovarian Carcinoma; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; pre-clinical; prevent; Property; Prostate; Pyrroles; Repression; research clinical testing; Role; Skeleton; small molecule; Solid Neoplasm; survival outcome; synergism; Therapeutic Agents; Toxicology; tumor; Tumor Burden; Validation