Co-Director, Children’s Brain Tumor Project
I’ll never forget May 1, 2012 — that was the day I performed the very first procedure in a new clinical trial testing convection-enhanced delivery (CED) of a therapeutic agent in a child with DIPG. More than ten years of my prior lab work, including bench research and animal testing, had me absolutely convinced that this was a safe procedure. Still, with anything so completely new there’s just that tiny seed of doubt, the faintest whisper of “what if…”
What I was not prepared for were the emotional ties that quickly took hold of me. The little girl in the OR that day was Caitlin Downing, whom I had come to love in just a few short weeks of knowing her and her family. Hugs, insightful questions, and smiles from this 5-year-old were gripping. Caitlin’s sister, Courtney, had even joined her on one of her preoperative visits to New York so that she could approve of the doctor who would offer hope.
Imagine my relief when the procedure went exactly as expected, and imagine my heartbreak several months later when the tumor came back to claim Caitlin’s life. But her successful surgery validated every effort that went into this translational project and left no doubt that we should push on.
Today we find ourselves in an exciting position: With 13 children treated so far (all of whom have tolerated the treatment well, with no adverse effects), we have answered critical questions about the technical, surgical, and diagnostic aspect of this drug delivery tactic. Early results have raised awareness from oncologists, neuro-surgeons, radiologists, and pharmacologists from all over the world. The momentum is building rapidly.
So encouraging are the results that we have decided to request a continuation of the study. If the continuation is approved, we will plan to treat a minimum of 12 more children at escalating doses. The study is being positively viewed on a national level. The preliminary results of this trial were presented to the Pediatric Brain Tumor Consortium (PBTC) in Atlanta last month. That group is highly interested in moving the strategy into a “group-wide” study and has assembled a working group, which I am leading, to formulate the best plan.
Even as we modify the current strategy, we are continuing our laboratory and clinical efforts in different arenas. As an example, we are using other strategies for bypassing the blood-brain barrier, which is what prevents us from getting adequate doses of cancer-fighting molecules to a tumor site. In addition to testing CED, we are also pursuing another potential route, using super-selective intra-arterial chemotherapy to deliver medicine directly into the blood vessels of the tumor itself. That new clinical trial is actively recruiting patients, with the first patient treated last month. We will explore every avenue to work toward the same ultimate goal.
We also know that existing worldwide talent offers us a huge potential network that might contribute to therapeutic discoveries. The collaborative clinical effort through Memorial Sloan-Kettering Cancer Center has allowed us to bring this concept to reality at an institution that is no stranger to innovative cancer therapy. Using the best available animals models for DIPG has led us to collaborate with Dr. Oren Becher at Duke University. In fact, Ranjodh Singh, a Cornell medical student, will spend the coming year to use Dr. Becher’s models to test combinations of small molecule inhibitors (drugs that are specific for the molecular driving force of DIPG).
The most recent work of the DIPG Collaborative has led toward DIPG-specific drugs that interfere with the most common genetic and epigenetic changes in these tumors. Dr. Michelle Monje at Stanford University, a renowned expert in defining the origin of DIPG, is working with us to validate some of her most recent laboratory work showing highly promising tumor response rates. We have also recently been connected with experts in nuclear medicine imaging at Yale University who would like to explore the option of using brain-specific EPT imaging on patients treated in our clinical trial continuation. This exciting work represents the most sensitive methods available for assessing drug concentrations in the brain stem of children after treatment with CED.
We are light-years beyond where we were just a few short years ago when I first entertained an idea that many said was fraught with theoretical dangers, technical impossibilities, and prohibitive expenses. We are now at a crossroads and will take the path that merges our experience with worldwide expertise. We will continue to use every avenue possible to avoid another child asking if “Dr. Mark can remove the bump in her brain before she goes to heaven,” as Caitlin did after her groundbreaking surgery.