A polymeric nanoparticle encapsulated small-molecule inhibitor of Hedgehog signaling (NanoHHI) bypasses secondary mutational resistance to Smoothened antagonists.
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.
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Venugopal
V
Chenna
Chaoxin
C
Hu
Dipankar
D
Pramanik
Blake T
BT
Aftab
Collins
C
Karikari
Nathaniel R
NR
Campbell
Seung-Mo
SM
Hong
Ming
M
Zhao
Michelle A
MA
Rudek
Saeed R
SR
Khan
Charles M
CM
Rudin
Anirban
A
Maitra
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1; D000093542:Gemcitabine
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000071676:Zinc Finger Protein GLI1; D003841:Deoxycytidine; D000093542:Gemcitabine