Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

Abstract

Background:The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx).Methods:5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models. The xenografts were treated with radiotherapy (15 × 2 Gy daily fractions over 3 weeks) and weekly cisplatin 4 mg kg−1 concurrently, with or without 5E1 or Sonidegib (LDE225). The Hh inhibitors were administered by subcutaneous injection (5E1; 20 mg kg−1 weekly for 3 weeks), or by oral gavage (Sonidegib; 60 mg kg−1 daily for 3 weeks).Results:We observed that both Hh inhibitors administered with RTCT were well tolerated and showed increased tumour growth delay, and reduced metastasis, with no increase in acute GI-toxicity relative to RTCT alone.Conclusions:Our data suggest Hh can be a valid therapeutic target in cervical cancer and supports data suggesting a potential therapeutic role for targeting Hh in patients undergoing RTCT. This warrants further investigation in clinical trials.

The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer

“…Hh was first reported in Drosophila melanogaster in 1980 and has an important role in embryogenesis ( 36 ). The Hh signaling pathway participates in the invasion, metastasis and drug resistance of a variety of tumor types, including ovarian cancer ( 37 ), hepatoma ( 38 ), cervical cancer ( 39 ) gliomas ( 22 ) and gastric cancer ( 40 ). Zahreddine et al ( 41 ) suggested that Gli1 alone should be sufficient to facilitate UGT1A-dependent glucuronidation of cytarabine and ribavirin and ultimately drug resistance.…”

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

“…In vivo inhibition of Shh pathway by Gli antagonist (GANT61), a Smo-inhibitor, has synergistic effect with radiotherapy in xenograft model of prostate cancer [ 144 ]. A monoclonal anti-Shh antibody, 5E1 or LED225 (Novartis) was able to increase the efficacy of radiation treatment in patient-derived xenograft models of cervical and esophageal cancer [ 145 , 146 ]. Clinically, expression of Shh pathway (Gli1 staining) was associated with the efficacy of esophageal patients treated with chemoradiation and surgery, in two cohorts of patients ( n = 60 and n = 167) [ 147 ].…”

Eupatilin regulates proliferation and cell cycle of cervical cancer by regulating hedgehog signalling pathway

“…Besides, emergency studies have shown that hedgehog signalling disorders commonly lead to cancers in adults, such as medulloblastoma, basal cell carcinoma, small cell lung cancer, and prostate cancer . Notably, hedgehog pathway is upregulated in cervical cancer and is associated with poor prognosis . In cervical cancer, the hedgehog signalling pathway can be regulated by some overexpressed miRNAs or drugs, such as miR‐129‐5p or dihydroartemisinin .…”