Research And Grants

Toward a Multimodality Cure for DIPG: Investigation of Intratumoral Drug Penetration and Craniospinal Irradiation.

Diffuse intrinsic pontine glioma (DIPG) is a currently incurable childhood brain tumor that, despite many past clinical trials, has never been shown to respond to systemic chemotherapy. Radiation therapy (RT) is effective in extending life but is not curative; median overall survival is 11 months and long-term survival is extremely rare.1 Preliminary evidence from compassionate use of convection-enhanced delivery (CED) of carboplatin shows this approach is likely to be efficacious at local tumor control and prolonging survival, but distant CNS disease develops (Gill S, DIPG Symposium, 2017). Therefore, a combined local and systemic therapy approach is likely to be required for long-term cure. Major questions related to both chemotherapy and RT must be answered before such a treatment approach can be planned. For chemotherapy, no studies have measured intratumoral drug penetration to determine whether the failure of systemic chemotherapy is due to failure to reach the tumor. Trials continue to test systemic chemotherapy alone, taking resources away from the study of CED and combined approaches. For RT, the current standard of care is focal treatment only, although DIPG clearly spreads throughout the neuraxis,2 which is likely to become a bigger impediment to survival as local tumor control improves. We have established multiple murine orthotopic patient-derived xenograft (PDX) models of DIPG that show local and disseminated tumor, and we have measured intratumoral drug penetration of the chemotherapy agents gemcitabine and selinexor in these models. We have also opened a phase 0 trial of gemcitabine given prior to biopsy in newly-diagnosed DIPG, and we are developing a similar trial with selinexor. We hypothesize that a multimodality approach that includes chemotherapy via CED, along with craniospinal RT (CSI) with a focal boost, will produce long-term cures in DIPG. At this stage, the questions related to this hypothesis that we can answer through clinical and preclinical trials are 1) Can systemic chemotherapy penetrate DIPG adequately to produce a therapeutic effect; 2) Do PDX models adequately reflect drug penetration in humans; 3) Does CED improve drug penetration over systemic delivery; and 4) Does the addition of CSI improve the control of disseminated tumor over focal RT alone. Our objective in this proposal is to advance DIPG research toward an effective, multimodal treatment approach. To pursue this objective, we will accomplish these specific aims and have the following anticipated results: 
 Specific Aim 1: Compare intratumoral chemotherapy delivery between systemic delivery and CED, and between clinical trial subjects and PDX models. We anticipate that systemic chemotherapy delivery will be inadequate for therapeutic efficacy in both clinical trial subjects and PDX models, and will be improved by CED. We will use the two phase 0 trials of gemcitabine and selinexor discussed above and will compare the results to parallel trials run in murine orthotopic PDX models of DIPG, with both drugs given systemically and by CED. 
 Specific Aim 2: Measure the impact of the addition of CSI to focal RT on survival and disseminated disease in PDX models of DIPG. We anticipate that adding CSI to focal RT will decrease the amount of disseminated disease in PDX models of DIPG, although it will not increase survival. We will use a patient-derived PDX model of DIPG to compare disseminated disease, as measured by high-resolution brain MRI and histological review of brain sections from necropsy, as well as survival in mice receiving CSI with a focal boost versus focal RT alone