MerTK, a preclinical project (unleashing innate responses).......
ir.celldex.com
>> Two lead candidate human anti-MerTK antibodies were then selected based on their potent induction of cytokines from human macrophages, dendritic cells, and monocytes. Treatment of dendritic cells with the MerTK antibodies led to production of a broad array of pro-inflammatory cytokines and chemokines. Isolated peripheral blood monocytes were found to express high levels of MerTK and were similarly activated by the MerTK antibodies. <<
Fascinating poster presentation, project has lots of moving parts (Antibody H04 potently blocks Gas6:MerTK interaction, but weakly elicits cytokines compared to the antibodies selected for preclinical evaluation. Hope baby wasn't thrown out with bath water.).......
celldex.com
Background........
ncbi.nlm.nih.gov
Just a random, recent study with a small molecule inhibitor.....
Mol Cancer Ther. 2018 Nov 27. pii: molcanther.0456.2018. doi: 10.1158/1535-7163.MCT-18-0456. [Epub ahead of print]
Inhibition of MERTK promotes suppression of tumor growth in BRAF mutant and BRAF wild-type melanoma.
Sinik L1, Minson KA2, Tentler JJ3, Carrico J1, Bagby SM3, Robinson WA3, Karni R4, Burstyn-Cohen T5, Eckhardt SG6, Wang X7, Frye SV7, Earp HS8, DeRyckere D2, Graham DK9.
1
School of Medicine, University of Colorado Anschutz Medical Campus.
2
Pediatrics, Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Emory University.
3
Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center.
4
Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School.
5
Institute for Dental Sciences, Faculty of Dental Medicine, Hebrew University - Hadassah Medical School.
6
Medical Oncology,, University of Texas at Austin Dell Medical School.
7
Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill.
8
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill.
9
Pediatrics, Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Emory University douglas.graham@choa.org.
Molecularly-targeted agents have improved outcomes for a subset of patients with BRAF-mutated melanoma, but treatment of resistant and BRAF wild-type tumors remains a challenge. The MERTK receptor tyrosine kinase is aberrantly expressed in melanoma and can contribute to oncogenic phenotypes. Here we report the effect of treatment with a MERTK-selective small molecule inhibitor, UNC2025, in preclinical models of melanoma. In melanoma cell lines, treatment with UNC2025 potently inhibited phosphorylation of MERTK and downstream signaling, induced cell death, and decreased colony formation. In patient-derived melanoma xenograft models, treatment with UNC2025 blocked or significantly reduced tumor growth. Importantly, UNC2025 had similar biochemical and functional effects in both BRAF-mutated and BRAF wild-type models and irrespective of NRAS mutational status, implicating MERTK inhibition as a potential therapeutic strategy in tumors that are not amenable to BRAF-targeting and for which there are limited treatment options. In BRAF-mutated cell lines, combined treatment with UNC2025 and the BRAF inhibitor vemurafenib provided effective inhibition of oncogenic signaling through ERK, AKT, and STAT6, increased induction of cell death, and decreased colony forming potential. Similarly, in NRAS-mutated cell lines, addition of UNC2025 to cobimetinib therapy increased cell death and decreased colony-forming potential. In a BRAF-mutated patient-derived xenograft, treatment with combined UNC2025 and vemurafenib was well-tolerated and significantly decreased tumor growth compared to vemurafenib alone. These data support the use of UNC2025 for treatment of melanoma, irrespective of BRAF or NRAS mutational status, and suggest a role for MERTK and targeted combination therapy in BRAF and NRAS-mutated melanoma.
First blush, I like this project. Sounds like 3F4 or 97-A7 may be ready for clinic within a year?? |
