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Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma
Tammy Hennika1,2, Guo Hu1, Nagore G Olaciregui3,4
1Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America.
Background:
Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG.
Methods:
A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo.
Results:
In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice.
Conclusion:
Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.
Insights
Panobinostat effectively targets diffuse intrinsic pontine glioma (DIPG) cells in preclinical models, but systemic toxicity limits its survival benefit in H3.3-K27M-mutant tumors. Further research is needed to optimize dosing for this pediatric brain cancer.
Area of Science:
- Oncology
- Pediatric Oncology
- Neuro-oncology
Background:
- Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brainstem tumor with limited treatment options.
- Panobinostat, a histone deacetylase inhibitor, has shown preclinical promise for DIPG treatment.
Purpose of the Study:
- To evaluate the efficacy and toxicity of panobinostat in preclinical models of DIPG.
- To confirm and extend previous findings on panobinostat's activity against DIPG.
Main Methods:
- Utilized a genetic mouse model and an orthotopic xenograft model of DIPG.
- Assessed panobinostat's effects on cell proliferation, viability, apoptosis, and target inhibition in vitro and in vivo.
Main Results:
- Panobinostat demonstrated potent anti-tumor activity in vitro and target inhibition in vivo.
- Systemic administration led to significant toxicity at higher doses, necessitating dose reduction.
- Reduced, well-tolerated doses did not improve overall survival in mouse models.
Conclusions:
- Panobinostat is an effective targeted agent against DIPG cells in vitro and in short-term in vivo studies.
- Toxicity associated with systemic administration may explain the lack of survival benefit in H3.3-K27M-mutant DIPG models.
- Dose de-escalation due to toxicity may have limited the observed efficacy in prolonging survival.
