2. Academic Validation
  3. Combination mTOR and SHP2 inhibitor treatment of lymphatic malformation endothelial cells

Combination mTOR and SHP2 inhibitor treatment of lymphatic malformation endothelial cells

  • Microvasc Res. 2022 Sep;143:104397. doi: 10.1016/j.mvr.2022.104397.
Jennifer K Wolter 1,  Ivette Valencia-Sama 2,  Alex J Osborn 1,  Evan J Propst 1,  Meredith S Irwin 3,  Blake Papsin 1,  Nikolaus E Wolter 4
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Head & Neck Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • 2 Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.
  • 3 Cell Biology Program, The Hospital for Sick Children, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada.
  • 4 Department of Otolaryngology, Head & Neck Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Electronic address: nikolaus.wolter@sickkids.ca.
PMID: 35671835 DOI: 10.1016/j.mvr.2022.104397
Abstract

Mammalian target of rapamycin (mTOR) inhibitors are clinically effective at treating some complex lymphatic malformations (LM). The mTOR Inhibitor rapamycin blocks the phosphoinositide 3-kinase (PI3K) pathway, which is commonly mutated in this condition. Although rapamycin is effective at controlling symptoms of LM, treatment courses are long, not all LMs respond to treatment, and many patients relapse after treatment has stopped. Concurrent rat sarcoma virus (Ras) pathway abnormalities have been identified in LM, which may limit the effectiveness of rapamycin. Protein tyrosine phosphatase-2 (SHP2) controls the Ras pathway upstream, and SHP2 inhibitors are being investigated for treatment of various tumors. The objective of this study was to determine the impact of SHP2 inhibition in combination with rapamycin on LM growth in vitro. Using primary patient cells isolated from a surgically resected LM, we found that combination treatment with rapamycin and the SHP2 Inhibitor SHP099 caused a synergistic reduction in cell growth, migration and lymphangiogenesis. These results suggest that combination treatment targeting the PI3K and Ras signaling pathways may result in effective treatment of LMs of the head and neck.

Keywords

Lymphangiogenesis; Lymphatic malformation; PI3K; Rapamycin; SHP2.

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