There are increasing numbers of researchers becoming interested and involved in DIPG research. The Cristian Rivera Foundation plans to regularly interview researchers regarding their work and their vision for DIPG research. Because of his significant and broad focus on DIPG, the first researcher to be featured is Dr. Oren Becher from Duke University. Dr Becher spends 90% of his time in his lab and 10% clinically. His lab focuses exclusively on pediatric DIPG.

CRF: Dr Nazemi, your name recently has made several appearances in the DIPG community as being part of the OSHU contingent of the DIPG Preclinical Consortium and a Friends of Doernbecher grant recipient for a DIPG project. How did you become involved in DIPG?

Dr. Nazemi: As a brain tumor oncologist who takes care of children in difficult situations every day, my most dreaded days are those that start with a call from my neurosurgical colleagues because a child has been admitted to the hospital overnight and the MRI shows a pontine glioma. Because there have traditionally been no surgical issues to be discussed, my colleagues ask me to come meet the family as soon as possible to discuss the diagnosis and expected outcome. In my job, I have learned that giving bad news to children and their families that I have built a relationship with over time is a delicate and difficult art, but giving horrific news to families that I typically have no relationship with is even more difficult. I became involved with DIPG research because of the many times I have had to sit in front of a family and tell them that we expect their child will die within a year and that we had no curative treatment options. The experience of watching parents react to this soul-crushing news has built a passion in me to be a part of the team of people across the country who aim to understand the biology of this disease and find an effective treatment for it.

CRF:  What is the goal of your project, Functional Discovery of Therapeutic Targets in Diffuse Intrinsic Pontine Glioma (DIPG) and how is the research going along?

Dr. Nazemi: As a clinician, the first opportunity I had to get involved in DIPG research came in 2010 when one of my DIPG patients was actively dying at home. Her father asked the simple but amazingly altruistic question if his daugther's situation could somehow benefit other children in the future. He felt she would want this. This led to discussions about DIPG research and how advances in our understanding of DIPG have been limited by the lack of tumor tissue available for study. In the last decade or more, the standard approach at the time of diagnosis of a typical DIPG has been to avoid unnecessary surgical procedures, even tumor biopsy. The resulting absence of tumor tissue for study had essentially halted advances in DIPG research and treatment, despite new advances in molecular characterization of so many other kinds of childhood cancers. Clinical trial designs have had to take a blind "best-guess" approach to testing drugs on patients with DIPG. In response to understanding this dilemma, the parents agreed to have her tumor donated for research purposes following her death. A primary cell culture was immediately established, to allow the tumor cells to keep growing so we could study them.

In this project that I am doing in collaboration with Dr. Charles Keller, our goals are to optimize the conditions for DIPG tumor cell growth and test the sensitivity of DIPG tumor cells to emerging, molecularly-targeted drugs (drugs that work in a more specific and less toxic manner than chemotherapy). Our hypothesis is that there will be a life-saving targeted therapy that will make DIPG a disease that can be controlled with medication. This project is now one component of the DIPG Pre-Clinical Consortium project titled "Rapid Preclinical Development of a Targeted Therapy Combination for DIPG". As we are learning is common from our collaborators, these DIPG cells are very slow-growing in the laboratory, but we are getting close to having enough cells to run the drug-sensitivity panel developed by the Keller Laboratory.

CRF: Do you think that personalized and targeted therapy is going to be possible at anytime for DIPG children?

Dr. Nazemi:  Yes, though I admit I cannot put a timeframe on it yet. We are in a new molecular era for DIPG because tumor tissue is becoming more available for research, because of biopsies done at diagnosis (particularly on the new clinical trial opening that requires a biopsy) and tumor donation at the time of death. This has already resulted in new understanding of the potentially relevant molecular pathways driving DIPG growth, and I expect this era will bring a great amount of useful data. Once we know what the relevant pathways are, we can test drugs that block those pathways in the laboratory and then in patients. The new clinical trial that will be open in many centers, including ours, is paving the way to have treatment decisions based on biopsy results. One can imagine a day where a DIPG is biopsied and tested on a panel that tells us what molecular pathways are over-active, but even more importantly, what drug(s) kill that patient’s tumor cells the most efficiently. Still, there are many difficult steps between here and there.

CRF: As a clinician researcher, what hurdles to you see for DIPG research- both basic science and clinical?

Dr. Nazemi:  The basic science hurdles that are most evident to me are the relative lack of tumor tissue for study, the heterogeneous nature of this tumor (meaning different parts of one tumor can look and maybe behave completely different), and the difficulty of keeping tumor cells alive in the research laboratory. The best type of tumor tissue to study is presumably tumor that has not yet been treated, and of course, this type of tissue is limited by the critical location of the tumor. No one wants to put kids at risk to get large amounts of tumor for research purposes. We hope that biopsies done in the setting of clinical trials will give us enough information to learn from the disease in its natural state (pre-treatment). Even with these biopsies, though, there will be challenges. Each needle biopsy only represents a tiny fraction of the tumor, and may not accurately reflect the important parts of the tumor, so our research on that tiny fraction may be misleading. Also, tumor cells that make it to the laboratory are very difficult to keep alive, and this is a process that is being worked on in several labs.

The clinical research hurdles are also challenging. Clinical trials typically take a long time to develop and get started, and by the time the trial is open, the treatment plan sometimes doesn't take into account the pre-clinical scientific developments that have accumulated in the prior months to years since the trial was first conceived of. Another challenge is that remarkable laboratory findings often do not translate into benefit for the children affected by the disease. For example, one might be able to show that tumor cells treated with drug X all die in the laboratory, but when that drug is used in patients with that type of tumor it shows no effect. With regard to personalized targeted therapy, the specific challenges are related to growing tumors cells efficiently in the lab and designing clinical trials that can evolve as the scientific discoveries emerge. In order to test one patient's DIPG cells sensitivity to a drug panel, we would need to be able to consistently and successfully get a biopsy specimen to the laboratory (which is achievable) and get the cells to grow quickly so we can have enough cells to run on the drug panel. So far, the limiting step is in the rate of their growth, which is perplexing considering how fast this tumor progresses in our patients. Now that we are in the molecular era for DIPG, our basic science colleagues are learning more every day, and our current clinical trial paradigm may slow our progress toward making a difference in the lives of DIPG patients.  

CRF:  Do you have other preclinical or clinical DIPG projects in mind?

Dr. Nazemi:  I have written a concept proposal for an innovative clinical trial design that would address some of the hurdles I mentioned before. It is a Phase II Platform on which three small-molecule inhibitors would be studied in parallel and in combination with radiation therapy. The three drugs to start the study were selected based on the most recent discoveries published by our basic science colleagues, and patients would receive the drug that is most relevant to their tumor's biology (based on a biopsy). Over time, an adaptive design for this trial would allow replacement of treatment arms, as indicated by continual analysis of emerging biology data on this trial and in the field. The goal is provide more rapid assessment of efficacy and safety of small-molecule inhibitors that are deemed relevant and specific to DIPG. In addition, we would attempt to demonstrate that molecular profile-informed treatment assignment can be done quickly in the context of a clinical trial using a DIPG-specific biomarker panel, while continuing to develop a method for tumor-specific drug sensitivity data from primary cell cultures.

This proposal was recently submitted to the Pediatric Brain Tumor Consortium (PBTC) as part of our institution's application to that consortium. It is admittedly a very different approach to trial design, and would require a diverse team of experts to open and maintain. However, I think our traditional approach to trial design has failed us for decades with DIPG, and this disease is worthy of some drastic changes in the way we approach clinical trials.

CRF:  Do you have other preclinical or clinical DIPG projects in mind?

Dr. Nazemi: For families facing this diagnosis who have decided they want to pursue treatment, it is very important to participate in a clinical trial. There is no known curative treatment plan out there and there is no "right answer". Being involved in a clinical trial allows us to learn from each child's journey, which is critically important in the big picture. The treatment outcome of a child treated outside the setting of a clinical trial is impossible to integrate into our overall understanding of the disease or the treatments. If you are at a hospital that does not have clinical trials available, ask your doctor if you can be referred to a center that does. Still, every patient's journey is different and each family's wishes are of paramount importance as they face this overwhelming news and involvement in a clinical trial will not be the right answer for everyone.

For those parents whose child will die of DIPG, the most important thing they can do is deeply consider donation of tumor tissue for research. As a parent myself, I can only hope I will never be faced with such an impossible decision. As a clinician, it is so difficult to know how to ask a parent to consider this type of gift, but it is a very important part of our ability to figure out how to cure this disease. At OHSU / Doernbecher Children's Hospital, we call this a Legacy Gift, because families who have chosen to do this feel that their child's life is making a significant impact in research and leaving a legacy for other kids.

Finally, resources are often the bottom line when it comes to research. If anyone has a talent in or passion for fundraising, find a DIPG researcher and support their work!