A polymeric nanoparticle encapsulated small-molecule inhibitor of Hedgehog signaling (NanoHHI) bypasses secondary mutational resistance to smoothened antagonists Academic Article uri icon

Overview

MeSH Major

  • Hedgehog Proteins
  • Nanoparticles
  • Pancreatic Neoplasms
  • Receptors, G-Protein-Coupled

abstract

  • Aberrant activation of the hedgehog (Hh) signaling pathway is one of the most prevalent abnormalities in human cancer. Tumors with cell autonomous Hh activation (e.g., medulloblastomas) can acquire secondary mutations at the Smoothened (Smo) antagonist binding pocket, which render them refractory to conventional Hh inhibitors. A class of Hh pathway inhibitors (HPI) has been identified that block signaling downstream of Smo; one of these compounds, HPI-1, is a potent antagonist of the Hh transcription factor Gli1 and functions independent of upstream components in the pathway. Systemic administration of HPI-1 is challenging due to its minimal aqueous solubility and poor bioavailability. We engineered a polymeric nanoparticle from [poly(lactic-co-glycolic acid); (PLGA)] conjugated with polyethylene glycol (PEG), encapsulating HPI-1 (NanoHHI). NanoHHI particles have an average diameter of approximately 60 nm, forms uniform aqueous suspension, and improved systemic bioavailability compared with the parent compound. In contrast to the prototype targeted Smo antagonist, HhAntag (Genentech), NanoHHI markedly inhibits the growth of allografts derived from Ptch(-/+); Trp53(-/-) mouse medulloblastomas that harbor a Smo(D477G) binding site mutation (P < 0.001), which is accompanied by significant downregulation of mGli1 as well as bona fide Hh target genes (Akna, Cltb, and Olig2). Notably, NanoHHI combined with gemcitabine also significantly impedes the growth of orthotopic Pa03C pancreatic cancer xenografts that have a ligand-dependent, paracrine mechanism of Hh activation when compared with gemcitabine alone. No demonstrable hematologic or biochemical abnormalities were observed with NanoHHI administration. NanoHHI should be amenable to clinical translation in settings where tumors acquire mutational resistance to current Smo antagonists.

publication date

  • January 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3256300

Digital Object Identifier (DOI)

  • 10.1158/1535-7163.MCT-11-0341

PubMed ID

  • 22027695

Additional Document Info

start page

  • 165

end page

  • 73

volume

  • 11

number

  • 1