Diffuse intrinsic pontine glioma (DIPG): A rare childhood brainstem tumor

An interview with Jing Kang

Background on Jing and Lily
Dr. Jing Kang is currently a Global Project Manager, Molecular Diagnostics, QIAGEN based in the UK. She is the mother of two beautiful girls, 8-year-old Lily and 2-year-old Mia. Jing was born in China and first came to the UK in 2003 for her undergraduate studies in Materials Science at Queen Mary University of London. During her final year project, she met her husband, Vineet Jha, who came to the UK from his native India at the same time as Jing. She moved to Germany for a four-year (2007‑2011) industry-based PhD in Berlin, Germany, to learn the field of Molecular Diagnostics. Her research work was focused on bio-conjugation chemistry for nucleic acid and biomarker sensing applications. Upon earning her PhD, she returned to UK and reunited with Vineet. The following year in 2012, their first daughter, Lily, was born while Jing was working as a research associate in Newcastle University.

Lily has been the sunshine and center of the family; even her grandparents came often from India to visit! She has brought the family together in multiple ways, including introducing the parents of her best friends, who have become close, long-term family friends. As a mother, Jing was sometimes worried during pregnancy if everything would be fine and, when Lily was little, Jing was anxious every time Lily was poorly. That mother’s natural anxiety about Lily gradually eased over the years as Lily grew to be a very happy, sociable, and confident child, full of joy and laughter. Jing went back to Industry and started her career as a project manager, having worked in both start-up and multinational biotech companies before joining QIAGEN.

Having lost some close family members to cancer in 2015, companion diagnostics and oncology is something very close to Jing’s heart. And it was the motivation for her to join the Precision Diagnostics franchise when she started at QIAGEN.

While working in the field that would benefit cancer patients globally, there was never a moment Jing was able to imagine her most precious girl was to be diagnosed with a pediatric brain cancer, and one of the most aggressive forms among all, Diffuse Intrinsic Pontine Glioma, DIPG.

While this rare condition affects approximately one in two million children globally, it is the most common, deadly form of brain cancer in children.


Q: Can you briefly describe what first caused you to see a doctor and how the diagnosis was made?

Jing Kang: We first noticed behavior changes in Lily about three months into the first lockdown. The initial, being more clumsy than usual, culminated a few weeks later in Lily struggling to walk in a straight line while playing at the park. The alarm bells rang, and we realized this was something more serious than frustration and boredom from the lockdown and lack of physical activities. In the flurry of assessments and tests, a CT scan produced an abnormal test result, and a subsequent MRI scan revealed a brain tumor in the pons area of the brainstem, leading to diagnosis of DIPG.

Q: How old are children typically when this condition first appears?

Jing Kang: I have never heard of DIPG previously and didn’t know there is such a thing called pediatric brain cancer, let alone DIPG that primarily occurs in children at young age. Diagnosis of DIPG usually occurs between the ages of 4 and 11, with the overall mean age of 7 for first showing symptoms.1 Biomarkers and clinical diagnosis.

“Working on molecular diagnostic tests and biomarkers for oncology can be quite removed from patients – until a case like Lily’s impacts one of our dear colleagues directly,” comments Jonathan Arnold, Vice President, Head of Oncology and Precision Diagnostics at QIAGEN. “It highlights why we do what we do, researching new and better ways of finding and understanding genetic factors in diseases and guiding treatment. To help labs get better results, help doctors make more precise treatment decisions, and give patients and their loved ones a better understanding of what they are facing.”

– Jonathan Arnold on Oncology and Precision Diagnostic support at QIAGEN

Q: What signs or behaviors should alert parents to seek a diagnosis for this or related conditions? What clinical assessments can be made on children to diagnose this condition – e.g., motor skills, balance, eyesight, cognitive skills?

Jing Kang: From own experience, I would say if you notice a change in a child’s balance, eye movement and vision problem within a short period of time, parents should certainly get that checked by doctors. Lily’s symptoms were described by the doctor to be subtle as she mainly had balance issues without vision problem, and it was hard to spot during the lockdown when she wasn’t out much as she typically would be.

I would advise all parents to push hard for quick referral to a neurologist. I have heard anecdotally that people experience a lot of “ping-ponging” from GP to optician, back to GP etc. DIPG is a rapid growing tumor, and symptoms can worsen very quickly. Double‑vision is a typical symptom for children as a first warning sign for DIPG, though this wasn’t the case for Lily. Clinical assessment should include standard neurological examination on motor skills, balance, eye movement, and for confirmation diagnosis by MRI scan.

From Reference 2: Symptoms of Diffuse Intrinsic Pontine Glioma typically present for approximately 1 month before diagnosis, but subtle symptoms may be present for up to 6 months prior to diagnosis. Double vision, Difficulty in controlling eye and eyelid movement, and facial expression, Difficulty chewing and swallowing, Difficulty speaking, Difficulty urinating, Weakness in the arms and legs, Loss of balance, Difficulty walking, Clumsiness, Headaches (especially in the morning), Nausea and vomiting, Fatigue.

Q: Are there any clinical or molecular tests to detect DIPG (Imaging? Genomic?)

Jing Kang: As the name suggests, the condition occurs in the pons area of the brain stem and has very characteristic appearances on the MRI scan. So DIPG is generally diagnosed by MRI without necessarily a biopsy. However, to understand better this disease and its molecular profiles, biopsy can be done thanks to advancement in MRI guided biopsy procedure. And the molecular profile can indicate additional information such as prognosis.

For Lily, a biopsy was performed, and the histology report confirmed the diagnosis. The molecular profiling by sequencing revealed a H3K27M mutation, which is the most common for DIPG patients. Within the histone H3 mutant subgroup, approximately 80% of the subgroup harbors a K27M H3.3 mutation and 20% a K27M H3.1 mutation.3 Lily has the subtype of H3.1K27M, which has a slightly better prognosis, but it’s only marginally different.

From Reference 3: There are other somatic mutations that have been found in DIPG patients, such as (in the order of prevalence) TP53, ACVR1 and PIK3CA, and rarer mutations in BRAF, EGFR, PDGFRA, PPM1D, MED12, KIT, MET, ARID1B, CHEK2, FGFR1 and PIK3R1. In summary, clinical assessment and MRI are the standard diagnostic used to make treatment decisions and, even though more recent years have seen a move to more molecularly based treatments, these are not widely used outside of clinical studies.4

What is Diffuse Intrinsic Pontine Glioma (DIPG)?
DIPG is a type of tumor that starts in the brain stem, the part of the brain just above the back of the neck and connected to the spine. The brain stem controls breathing, heart rate and the nerves and muscles that help us see, hear, walk, talk and eat. These tumors are called gliomas because they grow from glial cells, a type of supportive cell in the brain.

What are the stages of DIPG?
DIPG falls into the Glioma staging system, so they can be classified according to the four stages below based on how the cells look under the microscope. The grades are from the least severe to the most severe.

• Low Grade: Grade I or II means that the tumor cells are the closest to normal.
• High Grade: Grade III or IV means that these are the most aggressive tumors.

The main issue with DIPG is that most of these tumors are not classified by grade because surgery to obtain tissue by biopsy or to remove the tumor is not safe because of the location of the tumor. When these tumors are biopsied, they are usually grade III or grade IV tumors, which tend to behave very aggressively. Most of the tumors are diagnosed by their appearance on MRI.

How common is DIPG?
About 10% to 20% of all childhood brain tumors are DIPG or brainstem gliomas.  They are more common in children between the ages of 5 and 10 years but can occur at any age in childhood. Though more rare, they can also occur in adults.

What are the symptoms of DIPG?
Symptoms usually develop rapidly in the majority of patients because of the fast growth of these tumors. The most common symptoms related to DIPG include the following:

• Problems with balance and walking
• Problems with the eyes (including double vision, drooping eyelids, uncontrolled eye movements, blurred vision)
• Problems with chewing and swallowing
• Nausea and vomiting
• Morning headache or headache that gets better after the child vomits
• Facial weakness or drooping (usually one side)

From St Jude Children’s Research Hospital: https://www.stjude.org/disease/diffuse-intrinsicpontine- glioma.html

Q: What is known about the genetics or epigenetics of this condition? What is known about the impact of environment on the genetics, epigenetics (methylation states), or transcription profiles?

Jing Kang: While the current understanding of the cause of DIPG is limited, the majority of DIPG children have an H3K27M histone mutation, a potential epigenetic link to the condition. Unlike many other cancers, however, no evidence indicates that DIPG is caused by environmental factors (exposure to chemicals or radiation) or specific inherited genetic variations.

Q: Does this condition induce any measurable change in Inflammatory or immune markers?

Jing Kang: Some, but very limited, research has been published in this area, however, one study concluded that “In contrast to adult glioblastoma, the immune microenvironment of DIPG is non-inflammatory and does not contain a significant adaptive immune component. These observations provide important considerations for the design of immunotherapeutic approaches for DIPG.”5

Q: What tissues or body fluids have been assayed for DIPG markers – e.g., blood, cerebral spinal fluids (CSF), others?

Jing Kang: Tissues from biopsy is the standard sample type to be assayed. There have been some studies using CSF, blood, and urine for DIPG, and in recent years, there has been some success using CSF as the sample type, though still not within standard practice.

Q: Has anyone looked at mRNA or miRNA* species, either as markers or for treatment (e.g., to activate or silence a pathway)?

Jing Kang: Therapy development for DIPG was greatly hampered because of lack of therapeutic benefits and molecular studies. Of late, a better understanding of the molecular mechanisms underlying DIPG has opened new pathways to develop therapies for this disease.

As for markers, pilot studies were conducted to detect circulating miRNA in samples from DIPG pediatric patients and miRNA profile in serum samples. The main aim of these studies was to identify novel non-invasive biomarkers that might improve the prediction of disease outcome and therapeutic sensitivity.

Such marker discovery work is at early stages, and somewhat better prognosis prediction is now possible with data from molecular profiling. Linking markers to treatments has yet to advance further.

Q: What treatments are available – either as standard of care or currently in clinical trials?

Jing Kang: Standard treatment is Palliative Radiotherapy, which has been unchanged since Neil Armstrong lost his daughter to DIPG back in 1962. More research work on DIPG therapies has been carried out, particularly in the last decade. Most of this work is still in early phase clinical trials, however, because options are limited, treatment through participating in clinical trials are sought after by DIPG families across the globe.

Different types of treatment for DIPG currently in the clinical trials include:

1. Precision medicine compounds currently in phase 1/2 targeting, e.g., patients with genetic alterations in H3K27M, ACVR1, mTor.
2. Non-selective histone deacetylase inhibitors such as Panobinostat.
3. Convection-enhanced delivery (CED) to penetrate the blood-brain barrier is being evaluated to deliver drugs at high concentrations directly into DIPG tumors. CED involves inserting a catheter directly in the brain stem. One of the most promising trials is CED delivery of a liquid form of Panobinostat (a non-selective histone deacetylase inhibitor we are currently considering for Lily).
4. Early-stage immunotherapy works on peptide vaccine (targeting H3.3K27M), CAR-T, and delivery of Immuno-oncology drug via CED is underway. Immunotherapy, especially CAR-T, is considered a potential game changer for DIPG, however, early‑stage trials have just recently opened.

Q: What are the main challenges on this journey searching for treatment options?

Jing Kang: Like all parents in our position, we faced many challenges, but among the main ones are:

◆ Not enough clinical trials targeting children.

◆ The clinical trials we identified were not recruiting in the UK. This means Lily would need to travel to the US or Switzerland to get a chance. While sites abroad can accept Lily as an international patient, it must be self-funded, and the out-of-pocket costs is in the range of half million British pounds.

◆ There is a lack of a holistic approach and global view in the molecular profiling and treatment plan both:

◆ It took 1.5 months to get results back from Lily’s biopsy, and the assay used by the NHS had a narrower coverage of markers compared to the panel offered by the clinical trial sites abroad.

◆ One open trial in Switzerland requires biopsy to be done on the day the drug is given, therefore Lily was excluded from this trial. This is missed opportunity that you can’t get back.

◆ To enroll into another promising clinical trial in the US, Lily must have been through equal or greater than 54 Gy of radiation therapy; she “only” had 52.5 Gy, one session short. As the tumor area and size would have changed weeks after the radiotherapy, a full new radiation plan would be required to add one more session back, and the hospital is very reluctant to do so.

◆ DIPG Centre in Zurich have planned for three new trials to begin in 2020, for which Lily has been confirmed to be eligible. However, due to COVID, the start of these trials have been delayed by months and timeline is being pushed to 2021. However, DIPG does not pause, and time is of essence to every single DIPG child.

◆ We were told to make memories with our kid, and we had booked family trips to Chesington World Adventures Resort and Center Parcs, which were cancelled due to lockdown. There are Charities supporting children with critical illnesses to fullfill their wishes for example to go to Disneyland, and all this is not possible this year due to COVID.

Despite these challenges, we have come across some amazing DIPG specialists who have the heart and soul to care truly about every DIPG child and their family, like us. They offer continued support and provide advice on treatment options at various stages for Lily. We remain hopeful that Lily will be able to join a trial that prolongs her life and smile.

Lights for Lily

Q: What advice would you give to other parents facing this condition?
Jing Kang: I am not sure if I am in a position to any give advice to anyone yet. It’s more than three months since D-day. I am still in so much shock that life has taken such sharp and unexpected turn. There is absolutely nothing that can prepare a parent for such devastating news, when the doctor tells you there isn’t a known cause; that it can happen to anyone; that it’s just the worst lottery one could have; that there isn’t a cure and expected survival of less than a year. Given the state of play, their overall advice was for us was “to go and make memories with your child.”

I am known as someone who doesn’t easily take no for an answer, and being a parent giving up is not an option. So, I am very glad that I have reached out to DIPG specialists globally and also made contacts with families who have or are going through the same situation. For parents who are facing this situation, be sure to connect with the DIPG community, where support, experiences and tips on different aspects are shared.

Be your child’s best advocate and never give up hope.

Q: Can you discuss your response as a parent to this condition more generally and, more specifically, to raising funds through the Lights for Lily+ campaign?

Jing Kang: My world turned dark the day the doctor told us that Lily has a rare, incurable, inoperable brain tumor and we now have less than a year left with her to make memories. I couldn’t speak, think or breath normally for the first 48 hours. The first few days were filled with various appointments in the hospital and I was autopiloting all the mundane tasks. Then one night in the hospital ward, when Lily was asleep, I decided to speak to some close friends at work, and I found out there are families in and out of the countries who are facing the similar situations and most importantly, there is hope!

I am so grateful that I have received immediate support and help from my friends and colleagues as soon as they became aware of our predicament. Information about some promising clinical trials and treatment options were shared and discussed with us, and an amazing group of our friends have gathered and launched the LightsForLily crowdfunding campaign.

The mission of this campaign is to raise much-needed funding to allow Lily to access lifeprolonging treatment and to illuminate the dark struggle that is DIPG: for the children who receive this terminal diagnosis, their families, loved ones, and the scientists and healthcare professionals all around the world who are working tirelessly to find a cure with very little funding.

Together we can make a difference, and every effort counts.

Q: Any final thoughts?

Jing Kang: All I can say is that life is short and unpredictable. Hug your children, cherish every moment, and celebrate life. Children are truly amazing. Lily’s resilience and smile continue to inspire me every day. Her strength is giving me hope and keeping me strong. I will stay strong for my girls, and I will continue to fight for Lily.

Our sincere thanks to Joanna Love, Arnaud Papin, and Jonathan Arnold for their support and input to this article.

1. Gallitto M., Lazarev S., Wasserman I., Stafford JM., Wolden SL., Terezakis SA., Bindra RS., Bakst RL. Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review: Advances in Radiation Oncology. 2019 Jul-Sep; 4(3): 520–531. [PMC free article]
2. DIPG.org https://www.dipg.org/dipg-facts/symptoms-of-dipg
3. Dufour, Charlotte et al. “DIPG-44. MOLECULAR AND CHROMOSOMAL CHARACTERIZATION OF A UNIQUE SERIES OF DIFFUSE MIDLINE GLIOMAS IN CHILDREN AND YOUNG ADULTS.” Neuro-Oncology vol. 20,Suppl 2 (2018): i57– i58. doi:10.1093/neuonc/noy059.137
4. Kline CN., et al. Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy: Neuro-Ocology. 2017 May; 19(5): 699–709.
5. Lin et al. Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma: Acta Neuropathologica Communications (2018) 6:51 https://doi.org/10.1186/s40478-018-0553-x

General References and Websites
* Identification of circulating miRNAs in DIPG patients as predictors of response to targeted therapy and as classifiers of clinical outcome: https://academic.oup.com/neuro-oncology/article/20/suppl_2/i58/5000473+www.gofundme.com/f/LforL