Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination "nanochemotherapy" for treating patients with MPNSTs.
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010, USA.
Elizabeth E
EE
Sweeney
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010, USA.|Institute for Biomedical Sciences, The George Washington University, 2330 Eye St NW, Washington, DC 20037, USA.
Rachel A
RA
Burga
Center for Cancer and Immunology Research, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010, USA.
Chaoyang
C
Li
Center for Cancer and Immunology Research, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010, USA.
Yuan
Y
Zhu
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Health System, 111 Michigan Ave NW, Washington, DC 20010, USA.|Institute for Biomedical Sciences, The George Washington University, 2330 Eye St NW, Washington, DC 20037, USA.|Department of Radiology, The George Washington University, 2330 Eye St NW, Washington, DC 20037, USA.|Department of Pediatrics, The George Washington University, 2330 Eye St NW, Washington, DC 20037, USA.
Rohan
R
Fernandes
D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005295:Ferrocyanides; D006979:Hyperthermia, Induced / Q000379:methods*; D007259:Infrared Rays / Q000627:therapeutic use*; D053685:Laser Therapy / Q000379:methods; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D053758:Nanoparticles / Q000528:radiation effects / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009442:Neurilemmoma / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D009456:Neurofibromatosis 1 / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors; D020349:Surface Plasmon Resonance
D001549:Benzamides; D005295:Ferrocyanides; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); C000170:ferric ferrocyanide