Inhibition of Hedgehog Signaling Antagonizes Serous Ovarian Cancer Growth in a Primary Xenograft Model

Abstract

BackgroundRecent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.MethodologyWe utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Principal FindingsBoth compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.Conclusions/SignificanceIPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.

A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission

“…Hence, a correlation between Hedgehog ligand expression and clinical benefit could not be determined. There are several possible explanations for why fewer patients on this study seemed to have Hedgehog ligand overexpression compared with prior studies (19,21) conducted on banked tumor specimens. For example, it is possible that Hedgehog ligand overexpression is associated with chemotherapy resistance that could prevent patients from achieving CR (and therefore being eligible for this study).…”

“…In contrast, excessive or inappropriate expression of the Hedgehog ligand has been implicated in the pathogenesis of other sporadic cancers including pancreatic and other gastrointestinal, prostate, lung, and ovarian cancers (14)(15)(16)(17)(18)(19). Recent studies have shown a paracrine mechanism of Hedgehog pathway activation in some tumor types, wherein Hedgehog ligand secreted by tumor cells acts on neighboring stromal cells, subsequently contributing to tumorigenesis ( Fig.…”

“…20). Furthermore, both Hedgehog ligand protein expression and mRNA expression are increased in a subset of ovarian cancer specimens (19,21). The naturally occurring Hedgehog pathway inhibitor cyclopamine has been shown to decrease proliferation rates and induce apoptosis in ovarian carcinoma cell lines (22).…”

“…The naturally occurring Hedgehog pathway inhibitor cyclopamine has been shown to decrease proliferation rates and induce apoptosis in ovarian carcinoma cell lines (22). A recent study has shown inhibition of serous ovarian cancer xenograft growth by the Hedgehog pathway inhibitor IPI-926, when given in combination with chemotherapy and then as maintenance therapy (19).…”

Chemoresistance in Cancer Stem Cells and Strategies to Overcome Resistance

“…Inhibition of Hh signalling decreased spherogenicity in CD133+ glioma CSCs, decreased self-renewal in Aldefluor+ B-ALL cells, and inhibited clonogenicity of multiple myeloma CSCs [121,122]. In addition to depleting Aldefluor+ cells, Hh inhibition also decreased metastatic spread in a xenograft model of pancreatic cancer and inhibited the growth of human serous ovarian tumor xenografts [123,124].…”