2. Academic Validation
  3. Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy

Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy

  • Sci Adv. 2020 May 22;6(21):eaaz8521. doi: 10.1126/sciadv.aaz8521.
Stephanie J Wang 1 2,  Ran Li 2,  Thomas S C Ng 2,  Gaurav Luthria 2 3,  Madeleine J Oudin 4,  Mark Prytyskach 2,  Rainer H Kohler 2,  Ralph Weissleder 2 5 6,  Douglas A Lauffenburger 1,  Miles A Miller 2 5
Affiliations

Affiliations

  • 1 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 2 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • 3 Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
  • 5 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 6 Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
PMID: 32494745 DOI: 10.1126/sciadv.aaz8521
Abstract

Interpreting how multicellular interactions in the tumor affect resistance pathways to BRaf and MEK1/2 MAPK inhibitors (MAPKi) remains a challenge. To investigate this, we profiled global ligand-receptor interactions among tumor and stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) in some patients, which correlated with poor clinical response, and MAPKi coamplified bidirectional tumor-TAM signaling via Receptor Tyrosine Kinases (RTKs) including AXL, MERTK, and their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of RTKs, revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells. As a proof-of-principle strategy to block this signaling, we developed a multi-RTK kinase inhibitor nanoformulation that accumulated in TAMs and delayed disease progression. Thus, bypass signaling can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design.

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Products
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    Product Name
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  • HY-15617
    98.92%, JNK Inhibitor
    JNK