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Published on: July 4, 2017
PTHrP treatment fails to rescue bone defects caused by Hedgehog pathway inhibition in young mice
Jillian L Brechbiel1, Jessica M Y Ng, Tom Curran
1Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Pennsylvania, PA 19104, USA.
Abstract:
The advent of molecular targeted therapies offers the hope of therapeutic advance in the fight against cancer. However, this hope is tempered by recent findings that certain targeted therapies may have unique side effects. The Hedgehog (HH) pathway is a potential target for treatment of several cancers, including basal cell carcinoma and a subset of medulloblastoma. Recent clinical trials in adults have shown responses to HH pathway inhibition in both basal cell carcinoma and medulloblastoma. However, concerns have been raised about the use of HH pathway inhibitors in children because of the role the HH pathway plays in development. Indeed, young mice treated with the HH pathway inhibitor HhAntag developed severe bone defects, including premature differentiation of chondrocytes, thinning of cortical bone, and fusion of the growth plate. In an effort to lessen the severity of bone defects caused by HhAntag, we treated young mice simultaneously with HhAntag and parathyroid hormone-related protein (PTHrP), which functions downstream of Indian Hedgehog to maintain chondrocytes in a proliferative state. The results show that whereas treatment with PTHrP causes a significant increase in trabecular bone, it does not prevent fusion of the growth plate induced by HhAntag.
Insights
Hedgehog pathway inhibitors show cancer treatment promise but cause bone defects in young mice. Co-treatment with PTHrP increased bone density but did not prevent growth plate fusion, indicating potential side effects in pediatric cancer therapy.
Area of Science:
- Oncology
- Developmental Biology
- Pharmacology
Background:
- Molecular targeted therapies offer cancer treatment advances.
- Hedgehog (HH) pathway inhibitors are effective in adult cancers like basal cell carcinoma and medulloblastoma.
- Concerns exist regarding HH pathway inhibitors in children due to the pathway's role in development.
Purpose of the Study:
- To investigate the bone defects caused by HH pathway inhibition in young mice.
- To evaluate the potential of parathyroid hormone-related protein (PTHrP) to mitigate these defects.
Main Methods:
- Young mice were treated with the HH pathway inhibitor HhAntag.
- Simultaneous treatment with HhAntag and PTHrP was administered.
- Bone defects, chondrocyte differentiation, cortical bone thickness, and growth plate fusion were assessed.
Main Results:
- HhAntag treatment induced severe bone defects, including premature chondrocyte differentiation and growth plate fusion.
- PTHrP treatment alone significantly increased trabecular bone.
- Co-treatment with PTHrP did not prevent HhAntag-induced growth plate fusion.
Conclusions:
- HH pathway inhibition can cause significant bone abnormalities in young mammals.
- PTHrP may partially ameliorate some bone defects but does not resolve growth plate fusion.
- Further research is needed to balance the efficacy and safety of HH pathway inhibitors in pediatric oncology.
