PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma
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Published on: September 26, 2011
Kelly L Barton1, Katherine Misuraca, Francisco Cordero
1Department of Pediatrics, Duke University, Durham, North Carolina, United States of America ; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, United States of America.
Abstract:
Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD-0332991 (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.
Insights
Targeting the cell cycle with CDK4/6 inhibitors like PD-0332991 shows promise for treating pediatric diffuse intrinsic pontine glioma (DIPG) by inducing cell-cycle arrest and prolonging survival, especially when combined with radiation therapy.
Area of Science:
- Pediatric Oncology
- Cancer Genetics
- Molecular Therapeutics
Background:
- Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with no approved treatments.
- Aberrant cell cycle regulation, including D-type cyclins and CDK4/6 alterations or Ink4a-ARF loss, is common in DIPG.
- Targeting the cyclin-CDK-Retinoblastoma (Rb) pathway represents a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of targeting the cyclin-CDK-Rb pathway using the CDK4/6 inhibitor PD-0332991 (PD) in a mouse model of PDGF-B-driven brainstem glioma (BSG).
- To assess the impact of PD on cell-cycle arrest and survival in genetically distinct BSG models.
- To investigate the synergistic effect of PD combined with radiation therapy (RT).
Main Methods:
- Utilized a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model with either Ink4a-ARF deficiency or p53 deficiency.
- Administered PD-0332991 (PD) to assess its effects on cell-cycle arrest in vitro and in vivo.
- Evaluated survival benefit of PD treatment alone and in combination with a single dose of 10 Gy radiation therapy (RT).
Main Results:
- PD-0332991 induced cell-cycle arrest in the PDGF-B; Ink4a-ARF deficient BSG model, but not in the PDGF-B; p53 deficient model.
- A 7-day treatment course with PD significantly prolonged survival by 12% in the Ink4a-ARF deficient BSG model.
- Combined treatment with RT and PD increased survival by 19% compared to RT alone in the Ink4a-ARF deficient BSG model.
Conclusions:
- Targeting CDK4/6 with PD-0332991 is a viable therapeutic strategy for DIPG with Ink4a-ARF deficiency.
- Combination therapy with radiation shows enhanced survival benefits.
- These findings support clinical trials of PD-0332991 in pediatric gliomas with Ink4a-ARF alterations.
