Nikki+Janssen

=Determined To Matter: A Battle with Diffuse Intrinsic Pontine Glioma (DIPG) = //Twelve-year-old Shannon O’Hara was determined: determined to get good grades in her seventh grade classes, determined to make the “A” team in hockey, and determined to shape her young life into a meaningful future. After her diagnosis with a uniformly fatal brain tumor, diffuse intrinsic pontine glioma (DIPG), she became determined to make her short life matter. Despite her death a mere nine months after diagnosis, Shannon had her tumor donated for research, something that has opened the encyclopedia of potential lifesaving treatments for future DIPG patients. // Twelve-year-old Shannon O’Hara had just returned home to Minnesota from a spring break trip to New York, eager to finish her seventh grade year and continue golf practice. But something was not quite right. Throughout the school day, Shannon struggled to focus on her school work, and she missed class to see the school nurse about throbbing headaches throughout her first week back at school after her New York City adventures. Her parents, Jen and Dan O’Hara, were concerned about the shift in Shannon’s health, so they took her to the family doctor, who suggested Shannon get her eyes checked, as headaches and trouble focusing are common symptoms of poor vision. The following day, she read through the eye chart with ease, but when following the eye doctor’s pen light from side to side, her eyes did not move smoothly, so she was referred to a neurologist, with whom she met two days later. The neurologist found no signs of abnormalities, but Shannon had an MRI of her brain just to be sure, an anxiety-inducing test for claustrophobic patients, but Shannon fearlessly braved the enclosed tube. Shannon and her family returned to the doctor the next day for the results of the scan. After a week of tests and no diagnosis, they hoped to find out something so their week of doctor appointments could be over and their lives could go back to normal; little did they know, but their lives were about to change forever that day, forcing the O’Haras to adopt a new normal[|1].  The scan revealed a 3.8 centimeter tumor attacking the pons region of Shannon’s brainstem[| 1]. Shannon and her parents sat wide-eyed as the doctor explained the cancer diagnosis. They had gone to the family doctor five days earlier expecting Shannon to need glasses, but here they were less than a week later facing the diagnosis of a brain tumor. Both Shannon and her concerned parents were bursting with questions. The next hour of their lives was the first of many meetings with the neurology and oncology teams at the Mayo Clinic in Rochester, Minnesota, the O’Haras’ hometown. While rare, childhood brain and central nervous system tumors are the second most common type of childhood cancer behind leukemias, accounting for 26% of all pediatric cancers [|2]. Shannon’s tumor, determined to be a diffuse intrinsic pontine glioma (DIPG), was one type of a subset of brain tumors called brainstem gliomas, which account for 10-15% of childhood brain tumors [|3]. Atypical for cancer, DIPG is diagnosed without a biopsy due to “the significant morbidity potentially associated with the biopsies, the limited therapeutic options available based on biopsy results. . . and the widespread availability of MRI with characteristic imaging findings” [|4]. In fact, “routine biopsy as the standard of care was discontinued in the early 1990s” [|4]. Unlike the subtype of these tumors called focal brainstem gliomas, which are localized in one area and considered benign and slow-growing, Shannon’s tumor was quickly spreading throughout the pons region of her brainstem (Fig. 1) and branching out into other areas of her brain like the crab from which the word “cancer” derives [|5][|6]. Its aggression and location in an area of critical brain function (the pons controls breathing, sleeping, hearing, facial muscles, and eye movement [|7]) make DIPG a high-grade malignant tumor that is impossible to remove surgically. Any attempt to remove the tumor would create an extremely high risk of damage to this area, which could result in death or severe physical impairments worse than Shannon’s already present symptom of irregular eye tracking. DIPG is not an inherited cancer and has no known environmental causes, so cases like Shannon’s are unfortunate chance events [|9]. However, for these same reasons, neither Shannon’s parents nor her 10-year-old sister Erin are likely to be affected by it in the future. Median survival for patients with DIPG is 9 months after diagnosis [|10], with a 2-year survival rate dropping below 10% and a 5-year survival rate of less than 1 percent [|11]. Sadly, Shannon’s cancer diagnosis meant that she may not see her next spring break and almost certainly would not make it to high school. This bright and kind hockey and golf enthusiast was not likely to live more than a year or two; nonetheless, she was determined to fight the cancer with every ounce of her being and make her life matter to someone, be it her family for living longer than expected, or her doctors for helping find a better treatment for her disease [|12]. Before she and her family left the Mayo Clinic that day, Shannon’s doctors told her that it was the doctors’ job to worry about her and her job to prove them wrong, so she looked at her doctor and said, “Well, then I’m going to prove you wrong!” [|12] “Shannon the Cannon” [|1], as her family and friends called her, was ready to fight her inoperable, incurable disease as long as she could.

 Next, the O’Haras and their medical team at Mayo needed to discuss treatment options. Although DIPG is 100% fatal, a combination of radiation and chemotherapy are the standard treatments for slowing the progression of the disease and are considered “aggressive palliative care” [|11]. While chemotherapy has shown no significant impact on survival for DIPG patients, it is often given in combination with radiation as part of a clinical trial or as a last hope [|4] [|11]. The doctors discussed these options, noting that the radiation would likely only prolong Shannon’s life by 3-6 months and could carry serious side effects like loss of tongue and eyelid function, including loss of her sense of taste and sight, although these are also side effects of the tumor itself. Despite the high risks and low benefits, Shannon decided she wanted to do everything she could to give herself more time and to help her doctors learn more about DIPG—she even decided she wanted to donate her tumor for research after her death.

 Shannon began a 31-day proton-beam radiation therapy coupled with an experimental oral chemotherapy called Temozolomide [|13]. Shannon and her doctors hoped that the radiation treatments would shrink and kill tumor cells in order to give Shannon 3-6 extra months of life than she would have without treatment. Shannon arrived at her first radiation appointment a week after her diagnosis, but before she could begin the treatment, the radiation technician had to make her a mask that would secure to the table and keep Shannon in position while beams of radiation entered her brain. As the technician placed the mold over her face, Shannon was smiling, so she had to smile through all of her subsequent radiation treatments in order for the mask to fit properly [|1]. Throughout her treatment, Shannon insisted on staying in school to take her exams and finish 7th grade and also managed to attend golf practice and play with the junior varsity team in a few matches. Gradually, though, Shannon got more and more tired, falling asleep at 8:00 p.m. in the middle of family movie nights and activities. The aggressive treatment was taking its toll on the young warrior.

 On June 3, 2011, Shannon had her last radiation treatment, still smiling in her plaster mask. Victoriously, she confidently rang the ceremonial bell to signal the end of her radiation, tired yet still determined to fight her cancer until the end. Shortly after Shannon’s 13th birthday a month later, the toxins meant to shrink the tumor caught up to Shannon, leaving her nauseous and dizzy. When her symptoms increased to include pressure in her head and a tingling feeling in her lips and tongue, Shannon feared that the tumor was attacking her brain again. However, a trip to the emergency room and visits with her doctors offered some relief when they discovered that Shannon needed a higher dose of steroids to reduce the brain swelling that was causing her symptoms. Shannon breathed another sigh of relief when her post-radiation MRI showed a 60% reduction in tumor size, which the O’Haras celebrated with a trip to a local ice cream shop. Hopefully, Shannon would get to try out for the hockey team now. At a later appointment, Shannon’s doctor kept her on the high dose of steroids, which made her face red and prone to acne, not ideal for a middle school girl. Shannon was disappointed to not be looking her best for her first day of school, and she was also tired of wearing her hair in the same high ponytail with a headband to cover the radiation burns. All too soon, however, another follow-up MRI in November showed significant tumor growth, and more serious side effects of DIPG began to ravage Shannon’s body—tremors, numbness, blurry vision, and ringing in her ears. At Shannon’s request, the O’Haras flew to St. Jude Children’s Research Hospital in Nashville to participate in a phase I (testing for drug safety) clinical trial of a drug called Crenolanib that was designed to inhibit tumor cell growth. Shannon’s days were numbered, but her determination to make her devastating circumstances matter in the medical field prevailed. With a better understanding of the specific mutation in DIPG, better drugs can be developed to target tumor-specific markers, so Shannon was going down fighting, no matter the cost [|1]. The Molecular Basis of DIPG: Cancer's Elixir of Life As Shannon’s life clock grew closer to its final toll, treatment options shrunk to hospice care. The clinical trial in Memphis was solely testing the new drug’s toxicity and safety, and Shannon was deteriorating quickly, losing her ability to speak coherently, swallow, and use the right side of her body. Still, Shannon was determined to make her incurable disease curable and requested that her tumor be donated to research after her death. On January 6, 2012, Shannon “The Cannon” O’Hara succumbed to her 9-month battle with DIPG, surrounded by her parents and younger sister [|1]. Her parents made sure to honor Shannon’s request to contribute to DIPG research and had the deadly mass of mutated glial cells removed for analysis. This type of research is a form of cancer genomics, or the sequencing of cancer genomes in order to discover new mutations and differences among tumors of the same type, hopefully opening a new door into cutting edge cancer therapies. Like many cancers, 40-77% of tumors show a mutation in the //TP53// gene, which allows cancer cells to evade death signals and continue to survive despite their mutant condition [|14]. However, chemotherapies designed to target //TP53// mutations have proven ineffective in DIPG patients thus far. Through contributions like Shannon’s, cancer researchers have determined new mutations common in DIPG, namely the //ACVR1// and histone H3 genes as well as miR129-2 that functions in gene expression. Such discoveries could lead to a new era of DIPG treatment that will be more effective than the “aggressive palliative care” option radiation currently serves [|11].

Inside each of the trillions of cells in a human body, coiled tightly within chromosomes one, six, and seventeen, there is a library of genes that encode proteins that wrap themselves around newly synthesized DNA like a security blanket [|14] [|15]. These proteins, histones H3.1 and H3.3, play critical roles in preventing DNA damage, regulating gene expression during development, and determining the fate of a senescent cell [|15]. Mutations in the genes that encode histone H3 may increase the likelihood of DNA damage/mutations from UV light, as histone H3 proteins are required to continue normal DNA replication after genetic insult [|15]. These mutations may also prevent apoptosis of irregular cells and lead to a colony of damaged, immortaltumor cells. H3.3 mutations occur with an astonishing frequency of over 70% in DIPG, while H3.1 mutations are present in 18% of patients with DIPG [|14]. Both histone H3 mutations are considered driver mutations because the simple switch of an amino acid in the protein from lysine to methionine leads to more cancer-causing mutations and demonstrates the fragility of the human genome—one nucleotide switched with another cracks the glass and quickly spiderwebs out to create an entirely new and unstable cancer genome. The histone H3 mutations almost always occur in the 27th amino acid position (denoted K27M) and lead to epigenetic changes in the cancer genome that accelerate other mutations and irregularities such as ACVR1 and miR129-2 up-regulation [|15], [|16]. Despite the absence of a cure or even reliable life-lengthening treatment, the discovery of histone H3 mutations and their linkage to //ACVR1// and miR129-2 mutations have “perhaps been the most important discover[ies] in the field of DIPG” [|14], giving cancer researchers hope for a potential battle tactic for improving the dire statistics of DIPG prognosis.

Now journeying from chromosomes one, six, and seventeen to the long arm of chromosome two, there is a gene, //ACVR1//, that encodes a serine/threonine kinase called ALK2 [|15]. A mutation in //ACVR1// that up-regulates ALK2 causes constitutive BMP-TGFβ pathway signaling (Figure 2),which in turn knocks down a domino train of signals for cell proliferation and survival. A mutation in //ACVR1//, therefore, is like the Sorcerer’s Stone for cancer cells, offering them immortality and limitless progeny. Until recently, //ACVR1// mutations were only linked to fibrodysplasia ossificans progressiva (FOP), a disease where muscle tissue is converted to bone tissue, but  recent analysis of DIPG tumor donations like Shannon’s show activating //ACVR1// mutations identical to those found in FOP in 20-32% of DIPG tumors, suggesting that targeted therapies for FOP could be effective for DIPG and vice versa [|17]. Cancer genomics is not only important for discovering new cancer treatments, but for finding treatments and connections to other disease as well. Furthermore, //ACVR1// mutations appear to be unique to DIPG in terms of cancer genomics, and this exclusive nature of //ACVR1// to DIPG may lead to future breakthroughs in targeted chemotherapies for a tumor that no chemotherapy has been able to infiltrate.  Not only have //ACVR1// and histone H3 mutations been found as common molecular markers of DIPG, but post-mortem studies of DIPG tumors have shown hypermethylation of miR129-2 that results in up-regulation of NG2 in 75% of tumor samples [|19]. NG2 functions as a performance steroid functions in an Olympic athlete—DIPG already has a knack for growing quickly and killing the human whose brain it inhabits, but NG2 gives it an extra boost to ensure defeat of the competitors. Normal miR129-2 controls gene expression, but when hypermethylated, it signals for abnormally high expression of NG2, creating a welcoming home for cancer. Interestingly, high NG2 expression is often related to histone H3 mutations, further supporting histone H3’s role as a driver mutation [|15], [|16], [|19]. Normal brain tissue does not contain NG2, nor is it critical to normal brain function, so current demethylating drugs may safely reverse the process of NG2 over-expression. Such drugs can halt tumor progression by preventing NG2 expression, and, in turn, tumor growth [|19].

These three highly prevalent mutations, histone H3, //ACVR1,// and miR129-2, give oncologists hope for better prognosis in the field of DIPG. A better understanding of the molecular basis of DIPG offers a new perspective on how to treat children with the disease. Considering that the tumor itself is a living entity that desperately wants to survive, researchers can create new drugs to target cancer's elixir of life--the mutations that allow it to survive despite the body’s genetic mechanisms of protection. When these mechanisms fail and cancer takes over, we need to create a stronger, better, and smarter competitor that can beat the steroid-taking Olympian despite its many advantages. An understanding of the mutations in DIPG gives us this option and offers hope of winning the unwinnable race. =Treatment for DIPG: The Hunt for a Cure =

<span style="font-family: 'Times New Roman',Times,serif;">“The origins and lessons of life and evolution are long and complex, but what they basically boil down to is, life will out. Life will always find a way to continue” (20). Consider for a moment that the deadly tumor in Shannon’s brain was alive, obtaining its life-giving nutrients from her in the way a parasite does from its host. It wants to grow and to thrive, but we, more than anything, wish to destroy it. We humans are the predators, and the tumor must mutate and develop mechanisms of outsmarting us in order to stay alive. Although we traditionally see the tumor as the predator and the cancer-ridden human as the prey, “the tumor sees itself as a sweet, cute, fat-cheeked baby just trying to make its way into the world, and we want to stop it, destroy it, tear it from its happy little home like barbarians. To the tumor, we are the soulless, murderous monsters” (20). Thinking of ourselves as “murderous monsters” may seem uncomfortable, but in order to stop DIPG from ravaging the brain, we must put ourselves in the position of a hunter intelligently pursuing its prey and understand the tumor’s defenses so we can destroy and evade them. The high prevalence of ACVR1 and histone H3 mutations and overexpression of the NG2 protein offer some insight into how to best pursue this tumor, but these tactics are still in development in the form of preclinical trials. Today, treatment consists of deflecting tumor-related symptoms, and maybe, if the patient is lucky, offering a short extension of life. While there was little doctors could do to prolong Shannon’s life, new ideas and medications show promise for a better prognosis for future DIPG patients. <span style="font-family: 'Times New Roman',Times,serif;">Like Shannon’s family learned when doctors diagnosed her tumor, a DIPG diagnosis means death within a year or two at best. DIPG tumors invade the brainstem, creating a tangled mess of indistinguishable cells that are “like two colors of wool knitted together” [|21]. Its location in the area of the brain that controls basic life functions such as breathing, heart rate, and swallowing makes it impossible to remove or even attempt to remove surgically, and over 250 clinical trials of chemotherapies have not only failed to provide significant benefit but also subjected patients to undesirable side effects [|22]. Currently, the standard of care for DIPG is intensity modulated radiation therapy (IMRT), a form of radiation therapy that focuses lower intensity photon or proton beams at different angles around the tumor that intersect at the tumor site, maximizing the intensity of radiation to the tumor while minimizing the dose to surrounding healthy tissue (Figure 3). Patients like Shannon go to a clinic for radiation treatments five days per week for six to eight weeks to have beams of radiation enter their skull, hopefully damaging the tumor’s body. However, IMRT is considered “aggressive palliative care” [|11] because it relieves the debilitating symptoms of the tumor for 3-6 months, seemingly benefiting the patient’s prognosis, but soon the tumor once again finds a way to survive despite our body’s defenses: “Life will out” (20). Shannon displayed these classic treatment results when her post-radiation MRI in August of 2011 showed 60% reduction in tumor size, but three months later, another MRI showed significant tumor growth that became too much for her body to handle [|1]. <span style="font-family: 'Times New Roman',Times,serif;">In addition to radiation therapy, most patients with DIPG take an oral steroid such as dexamethasone to reduce swelling in the brain as a result of radiation therapy as well as to relieve headaches and intracranial pressure from tumor growth. Shannon took this drug daily, and it offered her a better quality of life at first, but the side effects became both annoying, and, as a new study has shown, dangerous [|24]. While some side effects of oral steroids such as acne and moon face (a harmless condition where fat builds up along the sides of the face), are merely an appearance-based inconvenience, they can have significant emotional effects as well. Shannon was discouraged about how her medications made her look—she realized that she was dying and the steroid was important to her health, but seeing her puffy reflection in the mirror each morning and knowing she couldn’t at least look normal for the remainder of her life was disheartening [|1]. In addition to these more superficial yet still emotionally taxing side effects, oral steroids are known to cause immunosuppression, mood disorders, diabetes, ulcers, insatiable appetite and obesity, or the opposite—decreased appetite and weight loss [|24]. Such side effects are more extreme and physically debilitating than those of appearance—immunosuppression can worsen disease severity due to the body’s loss of the ability to fight off infections and malignant cells, and a mood disorder, diabetes, or an ulcer adds another major health concern on top of the existing cancer. In an international survey on the use of oral steroids in DIPG patients, almost all patients take steroids at some point during treatment, and most take them throughout the entire course of the disease. Over half of these patients suffered from more than one negative side effect of steroid use [|24]. For a disease whose only effective treatment is considered comfort care, steroid treatment is a contradiction—the drug that is supposed to relieve suffering is actually causing more. Clearly, it is time for a breakthrough in the way we treat DIPG. <span style="font-family: 'Times New Roman',Times,serif;"><span style="font-family: 'Times New Roman',Times,serif;">Despite the numerous failed attempts to improve the grim prognosis of DIPG, a better understanding of its molecular basis has science on the heels of a new treatment. By outsmarting the tumor and figuring out what makes it function the way it does, a variety of new targeted therapies are in the midst of preclinical trials on animals. With the knowledge that histone H3 mutations are present in over 70% of DIPG tumors [|14], new chemotherapy research has been focused on targeting the specific histone H3 mutation, K27M, and the epigenetic changes it causes. Specifically, the K27M mutation leads to hypomethylation of the histone proteins. <span style="font-family: 'Times New Roman',Times,serif;">DNA does not bind as tightly to hypomethylated histones, so nucleotide pairs become easier to transcribe. This ease of transcription allows cells to easily translate and overexpress proteins that prevent apoptosis and allow constitutive proliferation, giving DIPG a way to outsmart its predator in order to survive and thrive. Knowing the tumor’s method of survival allows us to develop a counterattack. A new histone demethylase inhibitor called GSKJ4 has shown remarkable preclinical results in treating DIPG tumors [|22], [|25]. The drug targets the K27M mutation and blocks enzymes from removing methyl groups that, in a normal histone protein, prevent DNA over-transcription that allows DIPG a selective survival advantage. While the drug has only been tested in mice, “administration of GSKJ4 for 10 consecutive days significantly reduced the growth of K27M tumors engrafted in mouse brainstems and significantly extended animal survival” [|25]. No drug has been able to have a significant impact on survival in DIPG patients thus far, so if GSKJ4 were to work in humans, it would be revolutionary in the battle against a tumor that is 100% fatal. //In vitro// testing (Figure 4, right) even shows complete eradication of DIPG cells when treated with the drug, and completely prevents the growth of K27M mutant cells [|22]. Not only does the drug show promise for killing tumor cells, but the effective dose has a low concentration (Figure 4, left), which means fewer and less severe side effects for patients. By targeting a known driver mutation in DIPG, GSKJ4 also blocks growth and survival of cells with other mutations such as ACVR1 and miR129-2, as K27M likely causes additional mutations that occur before DIPG is classified as malignant. <span style="font-family: 'Times New Roman',Times,serif;">The initial findings of GSKJ4’s effects are exciting, but there are important difficulties that lie ahead in the hunt for a cure. GSKJ4 only works in tumors that have the K27M mutation, and the only way to know if a tumor has this mutation is to biopsy it, a procedure with significant risks of morbidity due to the location of the tumor in an area of critical brain function [|4]. A biopsy of the brainstem needs to be carried out “in expert hands and in highly controlled circumstances” [|22], but will provide a wealth of biological information that can offer insights into the tumor’s targetable weak spots. With a knowledge of individual tumor anatomy, drugs like GSKJ4 may be the light at the end of a very long tunnel. There still remains a plethora of clinical testing on humans, but it seems that we are close to having better options than palliative care for the treatment of DIPG. Someday, backed with biological insights on individual tumors, we will plan an attack on our prey and say, “‘Night, ‘night, tumor baby. It has been lovely, but we are done” (20). <span style="font-family: 'Times New Roman',Times,serif; font-size: 11px;">Works Cited <span style="font-family: 'Times New Roman',Times,serif;">1) O’Hara, Jen, and Dan O'Hara. Web log post. Rochester MN O'Hara Family Blog. Blogger, 2011-2016. Web. 17 Apr. 2016. <[]>. 2) ”What Are the Most Common Types of Childhood Cancers?" //What Are the Most Common Types of Childhood// //Cancers?// American Cancer Society, n.d. Web. 22 Apr. 2016. <[|http://www.cancer.org/cancer/cancerinchildren/detailedguide/cancer-in-children-types-of-childhood-cancers>]. 3) //CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2006//. Rep. Hinsdale: CBTRUS, IL. //CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2006.// CBTRUS, 2010. Web. 17 Apr. 2016. <[]>. 4) Vanan, Magimairajan Issai, and David D. Eisenstat. "DIPG in Children – What Can We Learn from the Past?" //Front. Oncol. Frontiers in Oncology// 5 (2015): 1-17. Web. <[]>. 5) American Society of Clinical Oncology. "Brain Stem Glioma--Childhood: Stages and Grades." //Cancer.net.// American Society of Clinical Oncology (ASCO), 2016. 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"Existing Drug May Treat the Deadliest Childhood Brain Tumor, Stanford-Led Study Finds.” //<span style="font-family: 'Times New Roman',Times,serif;">Stanford Medicine News Center //<span style="font-family: 'Times New Roman',Times,serif;">. Stanford Medicine, n.d. Web. 29 May 2016. <span style="font-family: 'Times New Roman',Times,serif;">[|<https://med.stanford.edu/news/all-news/2015/05/existing-drug-may-treat-the-deadliest-childhood-brain-tumor.html>.] <span style="font-family: 'Times New Roman',Times,serif;">22) La Madrid, Andres Morales, Rintaro Hashizume, and Mark W. Kieran. "Future Clinical Trials in DIPG: Bringing Epigenetics to the Clinic." //Frontiers in Oncology// 5 (2015). <[]>. <span style="font-family: 'Times New Roman',Times,serif;">23) //Intensity Modulated Radiation Therapy//. Digital image. //Medical Imaging//. N.p., n.d. Web. 29 May 2016. <[]>. <span style="font-family: 'Times New Roman',Times,serif;">24) Van Zanten, Sophie EM Veldhuijzen, et al. "State of Affairs in Use of Steroids in Diffuse Intrinsic Pontine Glioma: an International Survey and a Review of the Literature." //Journal of Neuro-Oncology// (2016): 1-8. <span style="font-family: 'Times New Roman',Times,serif;"><[]>. <span style="font-family: 'Times New Roman',Times,serif;">25) Hashizume, Rintaro, et al. "Pharmacologic Inhibition of Histone Demethylation as a Therapy for Pediatric Brainstem Glioma." //Nature Medicine// 20.12 (2014): 1394-1396. Epigenetics to the Clinic." //Frontiers in// //Oncology// 5 (2015). <[]>.