Research And Grants

Preclinical Evaluation of Systemic and Direct Delivery of a PDGFR-Alpha Antibody

Hypothesis- Genetically engineered mouse models of cancer are useful to elucidate mechanisms of tumorigenesis, and can serve as preclinical models for the evaluation of novel agents.  Rare tumors such as brainstem gliomas (BSGs) require genetically accurate preclinical models, which recapitulate the genetic alterations seen in the human disease, as preclinical tools. Because there are increasing numbers of available novel therapeutics, there is a need to prioritize the best combinations to translate into clinical trials. Although there have been numerous clinical trials evaluating novel agents to treat BSGs, none of them has been shown to significantly affect prognosis.  The evaluation of novel therapeutic agents as well as novel delivery routes that bypass the blood-brain-barrier (e.g. convection enhanced delivery (CED)) in such preclinical models may be predictive of responses in human clinical trials, and may result in progress against BSGs. 
 
Specific Aims  1.  To determine the in vitro activity of a PDGFR-α neutralizing antibody in cell-lines derived from PDGF-B driven BSG 
 
 2.  To evaluate the antitumor activity of systemic therapy with a PDGFR-α neutralizing antibody in the PDGF-B driven BSG mouse model 
 
3.  To evaluate the antitumor activity of convection-enhanced delivery (CED) with a PDGFR-α neutralizing antibody in the PDGF-B driven BSG mouse model   Background- BSGs account for 15-20% of pediatric brain tumors and are the leading cause of death for children with brain tumors. The median survival for these children is less than 1 year after diagnosis.  Despite decades of clinical trials evaluating novel agents to treat this disease, the natural history has not been significantly affected and 90% of children die within 2 years of diagnosis.  Involved-field fractionated radiation to a total dose of 54Gy is the current standard of care for these tumors – however, this treatment modality unfortunately provides only temporary relief of symptoms and has major side effects.    Recent genomic analysis of human BSGs have unraveled that the most commonly reported genetic alteration is platelet-derived growth factor receptor alpha or PDGFRα, which is amplified in 30-40% of BSGs and overexpressed in 67% (Becher et al. 2010, Zarghooni et al. 2010)  
 
Clinical Significance- If systemic treatment or direct treatment using convection-enhanced delivery of a monoclonal neutralizing antibody targeting murine PDGFRα demonstrates a statistically significant survival benefit in the platelet-derived growth factor-B (PDGF-B) driven BSG mouse model, we are committed to working towards translating results from this proposal into a phase I study for children with BSG.   It is worth noting that a similar neutralizing antibody from Imclone, which inhibits human PDGFRα (IC50 < 1nM), is already in clinical trials for adult gliomas as an intravenous infusion (Loizos et al.  2005), and this latter antibody can be readily translated into a phase I clinical trial to treat children with BSG.