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IGF-1 receptor inhibition by picropodophyllin in medulloblastoma
Sachiko Ohshima-Hosoyama1, Tohru Hosoyama, Laura D Nelon
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Abstract:
The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.
Insights
Inhibition of the insulin-like growth factor-1 receptor (Igf1r) pathway slows medulloblastoma growth. Picropodophyllin (PPP) treatment reduced tumor cell proliferation and increased apoptosis in vitro.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The insulin-like growth factor-1 receptor (Igf1r) is a tyrosine kinase regulating cell growth and survival.
- Elevated IGF pathway activity is implicated in human and murine medulloblastoma.
- A genetically-engineered mouse model overexpressing Igf1r provides a platform to study its role in medulloblastoma progression.
Purpose of the Study:
- To investigate the role of the IGF pathway in medulloblastoma tumor growth and metastasis.
- To test the hypothesis that inhibiting the IGF pathway can slow or halt medulloblastoma progression.
- To evaluate the efficacy of picropodophyllin (PPP) in targeting the IGF pathway in medulloblastoma.
Main Methods:
- Utilized a genetically-engineered medulloblastoma mouse model.
- Administered picropodophyllin (PPP), a small molecule inhibitor of tyrosine kinase, to primary medulloblastoma cultures in vitro.
- Assessed the effects of PPP on tumor cell growth, proliferation, and apoptosis.
Main Results:
- PPP effectively downregulated the IGF pathway in medulloblastoma cells.
- Treatment with PPP significantly inhibited mouse medulloblastoma cell growth in vitro.
- PPP induced apoptotic cell death in primary medulloblastoma cultures.
Conclusions:
- Inhibition of the IGF pathway via PPP demonstrates potential for slowing medulloblastoma progression.
- Targeting the IGF pathway represents a viable therapeutic strategy for medulloblastoma.
- The findings support further investigation into PPP or similar inhibitors for medulloblastoma treatment.
