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Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1

Melissa E Smith1, Velasco Cimica, Srinivasa Chinni

  • 1Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 22, 2010
PubMed

Insights

Rarerabdomyosarcomas are aggressive pediatric cancers. A new study shows that the drug flavopiridol can shrink some tumors, but resistance may occur due to high cyclin D1 levels.

Area of Science:

  • Pediatric Oncology
  • Cancer Genetics
  • Pharmacology

Background:

  • Rhabdoid tumors (RTs) are rare, aggressive pediatric cancers with poor outcomes.
  • RTs result from INI1 tumor suppressor gene inactivation, leading to dependence on cyclin D1.
  • Current treatment strategies for RTs are lacking.

Purpose of the Study:

  • To evaluate the efficacy of the pan-CDK inhibitor flavopiridol in a genetically engineered mouse model of RTs.
  • To investigate mechanisms of drug resistance in INI1-deficient tumors.
  • To establish Ini1(+/-) mice as a valuable preclinical model for RT therapeutic testing.

Main Methods:

  • Genetically engineered Ini1(+/-) mice were used to model RTs.
  • Positron emission tomography (PET) was employed for noninvasive tumor detection and monitoring.
  • Tumor-bearing mice were treated with flavopiridol, and responses were analyzed using FISH and PCR.

Main Results:

  • PET successfully detected primary RTs in Ini1(+/-) mice.
  • Flavopiridol treatment led to complete regression in some RTs.
  • Drug resistance was observed in other tumors, correlating with elevated cyclin D1 levels and CCND1 copy number amplification.

Conclusions:

  • Ini1(+/-) mice are effective models for studying RTs and testing therapies.
  • Elevated cyclin D1 levels are associated with flavopiridol resistance in RTs.
  • Targeting cyclin D1 may be a strategy to overcome resistance in INI1-deficient tumors.

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