Toward a Multimodality Cure for DIPG: Investigation of Intratumoral Drug Penetration and Craniospinal Irradiation
“We work on a lot of different projects in DIPG, but with our recent Cure Starts Now grants, we wanted to look at some really fundamental questions about how DIPG is treated currently and how we can improve that going forward. So, the current standard of care treatment for DIPG is focal radiation just to the pons and we know that it's transiently effective, but that the tumor always comes back. In terms of chemotherapy, we know that, in terms of oral and IV chemotherapy, that despite hundreds of clinical trials, these have really never shown survival benefit in DIPG, but the convection enhanced delivery in which catheters are inserted directly into the tumor for direct chemotherapy infusion is pretty early in clinical trials, but there are some early indications that it may be efficacious.
The concern is that with these focal treatment approaches that DIPG eventually becomes metastatic and spreads elsewhere in the brain and spinal cord. At that point, focal treatment isn't enough. So, in terms of radiation, we were interested to see whether we could give craniospinal radiation in which we radiate the entire brain and spinal cord and minimize that metastatic spread. We used our patient derived DIPG mouse models and set up an experiment in which some of the mouse got craniospinal radiation, CSI. Some of the mice got focal radiation just to the pons. Then we looked at metastatic disease, both by imaging and on pathology, by looking at the brains and spinal cords under a microscope after the mice died. We show that we were really able to minimize the amount of metastatic disease in the mice who got CSI compared to focal radiation alone.
In terms of chemotherapy, the question we were interested in answering is that maybe the reason all of these clinical trials in DIPG of systemic chemotherapy have failed because no chemotherapy can actually reach DIPG tissue adequately to induce a response. So for this question, in addition to our mouse work, we also set up a clinical trial in which newly diagnosed DIPG patients get one dose of an IV chemotherapy called gemcitabine and then they undergo their standard of care biopsy and were able to measure the concentration of the drug in the DIPG tissue. We've enrolled two patients in the trial so far and we also had some data from a similar adult trial that was run in a similar adult tumor called glioblastoma. Those patients got the same drug and had their resection of their tumor and those scientists showed that gemcitabine was able to reach the adult glioblastoma tumors in concentrations adequately to induce response.
When we looked at our data, we were really surprised to see that in DIPG the gemcitabine also reached the DIPG tissue in adequate concentration to induce response and at the same level or higher than in the glioblastoma tumors in adults. We had some parallel mouse work that we did in which we looked at our mouse models and show that whether the DIPGs had the defining HBK 27 M mutation or whether they were in the pons or the cortex, that the gemcitabine was able to reach the mouse tumors adequately for a response as well.
We then set up a mouse model convection enhanced delivery and use the same drug and showed that when we use a convection enhanced delivery, we were able to get about 50 times the concentration of that drug into the tumor versus the systemic delivery in mice when we controlled for the differences in dosing. So, now what we're working on going forward is combining these treatments, combining CED, systemic chemotherapy and craniospinal radiation to see if we can control not only the focal disease in DIPG, but the metastatic spread as well, to really meaningfully improve survival for DIPG patients going forward.
Thank you for your support of the DIPG research community and thank you to the Cure Status Now, without whom we really couldn't have done this work.”
