Grants

The DIPG / DMG Collaborative has funded $13,875,993 in DIPG/DMG research.

Interested in applying for a grant from the DIPG / DMG Collaborative? Learn more.


Duke University - $82,049

Date
November 2011
Research Type

Translational

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. 

Doernbecher Children's Hospital - $100,000

Date
November 2011
Research Type

Translational

Rapid Preclinical Development of a Targeted Therapy Combination for DIPG.

Patients with diffuse intrinsic pontine gliomas (DIPGs) have a uniformly dismal prognosis with a median survival of 9 months and long-term survival of less than 1%.  Radiotherapy provides only temporary improvement of symptoms.  No chemotherapy has ever proven effective. Novel therapies are desperately needed in this vulnerable population. Little was known about the biology of these tumors until recently. The availability of autopsy and some biopsy materials from children with DIPGs has finally led to a new understanding of the biology of these tumors. We are now identifying potentially important biological pathways in DIPGs that are readily targetable with currently available molecularly-targeted agents. In addition, we have successfully grown human DIPG tumors from autopsy materials in the petri dish and have developed mouse models of DIPGs – a key resource to functionally testing potential therapies. Since the number of children with this unfortunate disease is limited, and the number of available targeted agents is quite large, we hypothesize that we can identify a promising combination of molecularly-targeted agents using a functional drug screening approach.  We propose first to test the potentially effective molecularly-targeted drugs in the laboratory from DIPG tumors grown in the petri dish (Aim 1), and in mouse models of DIPG, whose biological characteristics we will first delineate (Aim 2).   We will then test the two or three most effective drugs in these models in combination. The ultimate goal is to move the most effective single agent or combination therapy forward to early phase clinical trials in the next 18-24 months. This is the first time that a group of basic and translational scientists and physicians from throughout North America have come together as a consortium to focus on DIPGs and to focus on a bench-to-bedside approach to rationally target therapy for children with DIPGs