Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.

Abstract

BACKGROUND:

Recent 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.

METHODOLOGY:

We 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 FINDINGS:

Both 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/SIGNIFICANCE:

IPI-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.

• Authors: Christopher K McCann, Whitfield B Growdon, Kashmira Kulkarni-Datar, Michael D Curley, Anne M Friel, Jennifer L Proctor, Hana Sheikh, Igor Deyneko, Jeanne A Ferguson, Vinod Vathipadiekal, Michael J Birrer, Darrell R Borger, Gayatry Mohapatra, Lawrence R Zukerberg, Rosemary Foster, John R Macdougall, Bo R Rueda
• Journal: PloS one (PLoS One) Vol. 6 Issue 11 Pg. e28077 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22140510 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GLI1 protein, human
• Hedgehog Proteins
• IPI-926
• RNA, Messenger
• SHH protein, human
• Transcription Factors
• Veratrum Alkaloids
• Zinc Finger Protein GLI1
• cyclopamine

Topics

• Animals
• Cell Proliferation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Hedgehog Proteins (genetics, metabolism)
• Humans
• Maintenance Chemotherapy
• Mice
• Neoplasms, Cystic, Mucinous, and Serous (drug therapy, genetics, pathology)
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects)
• Stromal Cells (drug effects, metabolism, pathology)
• Survival Analysis
• Transcription Factors (genetics, metabolism)
• Veratrum Alkaloids (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• Zinc Finger Protein GLI1