Saron+Araya


 * Courage in the Face of Adversity: **
 * A Young Boy's Battle with Diffuse Intrinsic Pontine Glioma **

__The Caner __
That Dakota Bell loves all things sports was clear in his all-encompassing baseball card collection and involvement with team sports. With the help and support of his family, especially his older brother Jordan, Dakota was competing at his best in hopes of one day getting to play on the same high school baseball team that Jordan played on. His parents, Vern and Tracee Bell were involved members of the parish, even volunteering in their children’s classrooms whenever given the opportunity. Tracee was a kindergarten teacher at a near by elementary school while Vern owned a small jewelry business. Their lives were normal by all accounts. Dakota was a popular, fun-loving kid with no issues in school. So it was an odd occurrence when Dakota did not finish his in-class assignment.

Like his classmates, Dakota was practicing his cursive letters when his right arm and hand stopped responding to him. He explained as well as any 6 year old could the odd sensation in his arm and why he could not finish his in-class work. With a call to his parents, Dakota was rushed to the ER. It was not until later that week that the rest of his 1st grade class would be told that their classmate Dakota would not be rejoining them for the rest of the school year.

Dakota Bell was diagnosed with a brain stem glioma at the age 6. This particular type of cancer usually targets the glial cells that surround the brain stem and provide the structural support along with the nutrients needed for nerve cells to function properly. Consequently, symptoms and side effects of this type of cancer include numbness in one or both sides of the body, dizziness, nausea and vomiting, headaches that begin in the morning, vision and hearing problems and many more due to improper circulation of blood to the infected areas of the brain that control these functions ([|1]).



For Dakota, not only was this tumor cancerous but it was also incredibly invasive and quickly progressed; a type of tumor called a [|diffuse intrinsic pontine glioma] (DIPG) ([|2]). A typical prognosis for this type of cancer is quite poor because of its difficulty to treat due to its placement on and throughout the brainstem. Any sort of surgery could be detrimental to the “neural structures vital for arm and leg movement, eye movement, swallowing, breathing, and even consciousness” ([|3]). For Dakota, it seemed that they had caught the cancer early enough for the doctors at Children’s Hospital in Denver, CO to give a more hopeful prognosis. The doctors explained that while the tumor had begun to spread throughout the brainstem itself, it had not reached other portions of brain. His localized tumor was small but growing rapidly, as do many DIPG’s creating a sense of urgency among his family, friends, and doctors. Although patients diagnosed with childhood brain and nervous system cancers have shown a 5-year survival rate of 72% ([|4]), his doctors recommended an aggressive radiotherapy treatment, known to extend survival rates in these patients, along with a chemotherapy regimen ([|3]). Because those with DIPG’s have shown an over all 10-month survival rate from the initial diagnosis ([|5]), chemotherapy was used even though its effectiveness on DIPG’s is still unknown ([|3]).

While his treatment began, members of Dakota’s community also began to ask questions about the cause of his cancer. Both Jordan and his younger sister Mattie were healthy, happy kids. His cancer seemed to share no correlation with the health of his family and community. Commonly, brain stem gliomas can result from having neurofibromatosis type 1, a genetic disease that causes tumors and brown spots to form on the skin along with tumors on nerves and “developmental changes in the nervous system” ([|2]). Because this genetic disorder is so rare and the only known risk factor for this specific type of cancer, Dakota’s sudden illness was explained simply as a random, isolated incident.

__The Molecular Basis __
“Diffuse intrinsic pontine gliomas (DIPGs) found in children have extremely low survival rates, with less than 20% of patients surviving two years after diagnosis (7).”  This statement, for Mr. and Mrs. Bell, must have been difficult to hear out of the mouth of the doctor responsible for the treatment and care of their six-year-old son. But the bleak statistic above is such because of the many challenges faced when treating a brain stem tumor. Targeted chemotherapies have shown no increased survival and surgical therapy is not recommended because of the placement of the cancer on the brain stem. The only beneficial therapy to date is radiation therapy because of its ability to treat cancers across the blood-brain barrier (8). This therapy attacks all hallmarks of cancer because of its ability to prevent continued growth of cancer cells by damaging DNA and other cellular components irreparably. And while radiation therapy can be localized to the specific tumor site, it can also affect surrounding tissue, giving rise to iatrogenic mutations and subsequent secondary tumors. The mechanism in which these specific cancers arise is an active area of research but some of the mutated components have been identified.

 DIPGs have frequently been found to posses a mutation in histone H3 genes along with mutations in the ACVR1 gene or TP53 pathway interference, signifying uniformity in the formation of these tumors (see Figure 1). Histones are proteins residing at the center of nucleosome assembly in eukaryotes in which DNA is wrapped around the proteins in order to better consolidate the genetic information in the cell. Mutations in the histone encoding genes show an increased prevalence in DIPGs (greater than 70%), more so than any other mutations found in these cancers ([|9]). Most childhood DIPGs contain a K27M mutation in histone H3.3, where a lysine is replaced by a methionine in amino acid 27 (10). This particular mutation is defined as a gain of function mutation that “leads to inhibition of the activity of polycomb repressive complex 2 (PCRC2)” ([|9]). The function of PCRC2 is to govern “the establishment and maintenance of cells, tissue and organ identity, contributing to the correct execution of the developmental programs” through the use of epigenetic gene repression ([|11]). More specifically, PCR2 is responsible for regulating gene expression by methylation of the lysine (amino acid 27) in histone H3.3 ([|10]). Without a lysine present, PCR2’s function is hindered, which may cause unregulated transcription and subsequent increases in proteins responsible for sustaining proliferative cell growth. Similarly, with a K27M mutation in histone H3.3, it is hypothesized that this histone protein may cause “dysregulation of PRC2 complex member EZH2 and resultant changes in global methylation” ([|9]). Because EZH2 is the catalytic subunit playing an active role in the function of the PRC2 protein ([|10]), a mutation in this subunit could result in improper methylation patterns that would cause transcriptional errors and a possible surplus of transcripts coding proteins responsible for sustaining proliferative cell growth. Although this mechanism remains largely unknown, it is agreed that it may be a driving mutation in this specific type of cancer. An enabling characteristic of cancer is genomic instability, which could also be caused by the mechanism hypothesized above.

 Another important mutation found in some (20-30%) DIPG’s is a mutation in the ACVR1 gene that encodes a bone morphogenetic protein (BMP) type I receptor: ALK2. This particular mutation has been correlated with patients of a younger age and extended survival rates (7). The mutated ACVR1 gene constitutively activates the cytoplasmic portion of the ALK2 receptor ([|12]), while also increasing the phosphorylation of downstream components of the signaling cascade such as SMAD proteins, responsible for binding the promoters of BMP ([|12]), which keeps them in an active formation and increasing other regulatory signals in the BMP developmental signaling pathway (see Figure 2) ([|9]).



<span style="font-family: 'Times New Roman',Times,serif;">The constant activity of the ALK2 receptor keeps downstream proteins activated and heightens gene expression responsible for maintaining growth signaling, giving rise to the cancer. While a mutation in this gene may be an “oncogenic driver” of DIPGs, it is not a driver mutation involved in the initial formation of the tumor but “provides a selective advantage in the presence of other critical mutations” (7). This particular mutation is representative of a way in which a cell could sustain proliferative growth signaling by elevating ALK2 receptors and activating other intracellular signaling pathways.

<span style="font-family: 'Times New Roman',Times,serif;"> Mutations in histone H3 genes have been shown to interfere with the TP53 cell-signaling pathway responsible for cell cycle arrest and apoptosis ([|13]). While the exact mechanism remains unknown, it seems these mutations target this pathway in hopes of resisting cell death by deactivating the TP53 protein and allowing the mutated histone H3 genes, specifically those with a K27M mutation, to continue its epigenetic mutilation of the human genome for a longer period of time and “drive tumor formation” ([|13]).

__<span style="font-family: 'Times New Roman',Times,serif;">Treatments and Outcomes __
<span style="font-family: 'Times New Roman',Times,serif;">Though researchers may be developing a more complete understanding of these processes and the specific mutations described above, treatment targeting these altered brainstem cells is and will continue to be the largest barrier in tackling childhood DIPGs simply because of tumor location and “diffuse infiltration and swelling of the brainstem” (8). But the first obstacle comes in the form of diagnosis and screening. Screening for this type of cancer is almost always impractical because of the procedures one would have to undergo. MRI and CT scans have been used to diagnose DIPGs, but not for means of screening because both of these procedures are costly and time intensive, limiting the value in screening for this cancer regularly. The short amount of time between the onset of clinical symptoms and diagnosis (2-3 months) is also another preventative factor when determining the pros and cons of screening (8). The chances of this cancer being caught early because of its easily observed symptoms and its uniformly fatal prognosis are also factors that limit the amount of screening done for this cancer.

<span style="font-family: 'Times New Roman',Times,serif;">Similarly, MRI and CT scans are the standard in which DIPG’s are diagnosed. In the past, stereotactic brainstem biopsies were used to diagnose these cancers. A stereotactic biopsy is a procedure in which a computer helps to form a digital 3D image of a target area in the body where a piece of tissue is removed to be studied by a pathologist. This procedure is helpful in determining if the tumor mass is cancerous. But due to the high morbidity rates linked to this procedure because of the resultant side effects of removing cells on the brainstem, it was dropped as a standard diagnostic tool in the 1990’s (8). In contrast, recent research and technological advances have helped decrease the harmful effects of stereotactic biopsies and some experts even recommend this procedure for atypical tumors. Biopsies of the tumor can lead to better diagnosis and identification of mutated genes and systems which can be targeted with other therapies (8).

<span style="font-family: 'Times New Roman',Times,serif;">Surgical resection is almost always advised against because of the possibility of destroying central nervous system functions. Currently, the standard of care for these types of tumors in newly diagnosed individuals is “fractionated focal intensity modulated radiation therapy (IMRT) to the tumor along with 1-2 cm margins” (8). These treatments are most often preformed once a day five days per week for a six-week period and can prolong survival by 3-6 months. IMRT is a treatment that uses proton and photon beams of radiation to specifically follow the shape of and target the tumor mass ([|14]). This treatment is beneficial for averting damage to surrounding healthy tissue and preventing any other harmful side effects. One such side effect of this treatment is the development of a peri-tumoral edema, which “induces neurological deficits and intra-cranial hypertension”, or high blood pressure in the brain ([|15]). This can be combated with steroids, specifically corticosteroids, which help in reducing these symptoms. Conversely, the uses of steroids have their own set of side effects including “sleep disorders, mood and behavioral changes, insatiable appetite, weight gain and Cushing’s syndrome, often accompanied by disfiguring striae and a ‘moon face’, completely changing the appearance of the child” ([|16]). In fact, over half of patients experience steroid induced side effects but the expenditure of these drugs on patients while receiving radiation treatment is short lived (along with the symptoms) and gradually slowed as the RT session expires (8).

<span style="font-family: 'Times New Roman',Times,serif;">It is in this way that Dakota’s DIPG was treated. He received standard dosages of radiation so as not to expose his body to unnecessary toxic levels of radiation. Although many studies have been preformed in which the efficacies of higher levels of radiation were tested, none showed any marked improvement in survival (8). Equally, about 70-80% of patients showed marked improvement in their neurological state as a result of the IMRT (8). In conjunction, re-irradiation, a secondary round of radiation, has been shown to help control local tumor growth. In one study, a group of patients were treated with chemo-radiotherapy along with radiation therapy then later treated with re-RT. The “time to initial progression from the completion of first RT was 4 to 18 months and the time interval between initial RT and re-RT was 8–28 months” (8). Although these results have yet to be replicated in a clinical trial setting, the significant increase in time before tumor progression after treatment speaks to the promising effects of re-irradiation.

<span style="font-family: 'Times New Roman',Times,serif;">Historically, the use of chemotherapy, both as a neo-adjuvant therapy or used concurrently with RT, has shown no significant survival advantage over the use of radiation therapy alone (8). Many different chemical cocktails have been studied in clinical trials in the hopes of finding a combination that proved effective. And while most studies showed no effect, some showed an increased overall survival in DIPG patients (8). Because of these inconclusive results, chemotherapy is not recommended as a standard treatment of care and is only encouraged when partaking in a clinical trial. Interestingly, research has been done in finding techniques to permeate the blood-brain barrier (BBB), one of the major obstacles in treating DIPG’s. The most promising method is to “reversibly disrupt the junctions formed by the endothelial cells to enhance their penetration through intercellular junctions” (8). This can be done through the use of osmotic agents or other substances meant to target “membrane receptors that alter BBB permeability” (8). With the BBB diminished, it is theorized that targeted chemotherapies have an increased chance in reaching the cancerous mass and providing the proper treatment.

<span style="font-family: 'Times New Roman',Times,serif;">Clinical trials are often encouraged due to the lack of valid treatments available for this cancer. Because most of these trials (involving some sort of chemotherapy) show no adverse affects on patients’ health, I would recommend these treatments. An example being neo-adjuvant and adjuvant treatments with Temozolomide (TMZ) along with RT showing increased overall survival in some studies and no effect in others (8). Although clinical trials were not available to Dakota, his willingness to participate and assist in any way he could is something to be both admired and, hopefully, imitated. Studying the efficacy of a new drug in a clinical trial takes a sufficient amount of time and resources. These trials should therefore have access to the most qualified candidates in order to obtain worthwhile results that are beneficial in better treating this cancer.

**<span style="font-family: 'Times New Roman',Times,serif; font-size: 120%;">Aperçu ** <span style="font-family: 'Times New Roman',Times,serif;">It is for this reason that people should engage in the strides and advances of the scientific community. Without the support and cooperation of all, cancer will continue to remain an enigma relentless in its eradication of human life, determination, and optimism. Dakota’s kindness and vulnerability can set a precedent for the way all people view cancer and its possible treatments: <span style="font-family: 'Times New Roman',Times,serif;">//With faith in humanity’s ability to overcome even the most unconquerable of obstacles//

__<span style="font-family: 'Times New Roman',Times,serif;">References __
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<span style="font-family: 'Times New Roman',Times,serif;">(2) "Childhood Brain Stem Glioma Treatment." National Cancer Institute. N.p., 26 Aug. 2015. Web. 18 Apr. 2016. <span style="font-family: 'Times New Roman',Times,serif;"><http://www.cancer.gov/types/brain/patient/child-glioma-treatment-pdq>.

<span style="font-family: 'Times New Roman',Times,serif;">(3) FIsher, Paul Graham, and Michelle Monje. "Brain Stem Gliomas in Childhood." <span style="font-family: 'Times New Roman',Times,serif;"> Brain Stem Gliomas in Childhood. N.p., 10 Apr. 2010. Web. 23 Apr. 2016. <span style="font-family: 'Times New Roman',Times,serif;"><[]tumor-types-and-imaging/item/81-brain-stem-gliomas-in-childhood>.

<span style="font-family: 'Times New Roman',Times,serif;">(4) American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015. <[|http://www.cancer.org/acs/groups/content/@editorial/documents/document/acsp c-]044552.pdf>

<span style="font-family: 'Times New Roman',Times,serif;">(5) Jansen, Marc H., Sophie E. Veldhuijzen Van Zanten, and Esther Sanchez Aliaga. "Survival Prediction Model of Children with Diffuse Intrinsic Pontine Glioma Based on Clinical and Radiological Criteria." Neuro-Oncology. Oxford University Press, 17 Jan. 2015. Web. 23 Apr. 2016. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483042/>.

<span style="font-family: 'Times New Roman',Times,serif;">(6) "Diffuse Intrinsic Pontine Glioma (DIPG)." Weill Cornell Brain and Spine Center. Ed. Zhiping Zhou. N.p., Nov. 2014. Web. 23 Apr. 2016. <http://weillcornellbrainandspine.org/condition/diffuse-intrinsic-pontine-glioma-dipg>.

<span style="font-family: 'Times New Roman',Times,serif;">(7) Wu, Gang, Alexander K. Diaz, Barbara S. Paugh, Sherri L. Rankin, Bensheng Ju, Yongjin Li, Xiaoyan Zhu, Chunxu Qu, Xiang Chen, Junyuan Zhang, John Easton, Michael Edmonson, Xiaotu Ma, Charles Lu, Panduka Nagahawatte, Erin Hedlund, Michael Rusch, Stanley Pounds, Tong Lin, Arzu Onar-Thomas, Robert Huether, Richard Kriwacki, Matthew Parker, Pankaj Gupta, Jared Becksfort, Lei Wei, Heather L. Mulder, Kristy Boggs, Bhavin Vadodaria, Donald Yergeau, Jake C. Russell, Kerri Ochoa, Robert S. Fulton, Lucinda L. Fulton, Chris Jones, Frederick A. Boop, Alberto Broniscer, Cynthia Wetmore, Amar Gajjar, Li Ding, Elaine R. Mardis, Richard K. Wilson, Michael R. Taylor, James R. Downing, David W. Ellison, Jinghui Zhang, and Suzanne J. Baker. "The Genomic Landscape of Diffuse Intrinsic Pontine Glioma and Pediatric Non-brainstem High-grade Glioma." Nature Genetics Nat Genet 46.5 (2014): 444-50. Web.

<span style="font-family: 'Times New Roman',Times,serif;">(8) Vanan, Magimairajan Issai, and David D. Eisenstat. "DIPG in Children – What Can We Learn from the Past?" Front. Oncol. Frontiers in Oncology 5 (2015): n. pag. Web.

<span style="font-family: 'Times New Roman',Times,serif;">(9) Panditharatna, Eshini, Kurt Yaeger, Lindsay B. Kilburn, Roger J. Packer, and Javad Nazarian. "Clinicopathology of Diffuse Intrinsic Pontine Glioma and Its Redefined Genomic and Epigenomic Landscape." Cancer Genetics 208.7-8 (2015): 367-73. Web. <http://www.sciencedirect.com/science/article/pii/S2210776215000642>.

<span style="font-family: 'Times New Roman',Times,serif;">(10) Khuong-Quang, Dong-Anh, Pawel Buczkowicz, Patricia Rakopoulos, Xiao-Yang Liu, Adam M. Fontebasso, Eric Bouffet, Ute Bartels, Steffen Albrecht, Jeremy Schwartzentruber, Louis Letourneau, Mathieu Bourgey, Guillaume Bourque, Alexandre Montpetit, Genevieve Bourret, Pierre Lepage, Adam Fleming, Peter Lichter, Marcel Kool, Andreas Von Deimling, Dominik Sturm, Andrey Korshunov, Damien Faury, David T. Jones, Jacek Majewski, Stefan M. Pfister, Nada Jabado, and Cynthia Hawkins. "K27M Mutation in Histone H3.3 Defines Clinically and Biologically Distinct Subgroups of Pediatric Diffuse Intrinsic Pontine Gliomas." Acta Neuropathologica Acta Neuropathol 124.3 (2012): 439-47. PubMed.gov. Web. <span style="font-family: 'Times New Roman',Times,serif;"><http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422615/>.

<span style="font-family: 'Times New Roman',Times,serif;">(11) Mozgova, Iva, Claudia Köhler, and Lars Hennig. "Keeping the Gate Closed: Functions of the Polycomb Repressive Complex PRC2 in Development." The Plant Journal Plant J 83.1 (2015): 121-32. Web. <span style="font-family: 'Times New Roman',Times,serif;"><http://onlinelibrary.wiley.com/doi/10.1111/tpj.12828/abstract>.

<span style="font-family: 'Times New Roman',Times,serif;">(12) Taylor, Kathryn R et al. “ACVR1 Mutations in DIPG: Lessons Learned from FOP.” Cancer research 74.17 (2014): 4565–4570. PMC. Web. 24 May 2016. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154859/>

<span style="font-family: 'Times New Roman',Times,serif;">(13) Nikbakht, Hamid et al. “Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pontine Glioma.” Nature Communications 7 (2016): 11185.PMC. Web. <span style="font-family: 'Times New Roman',Times,serif;">< http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823825/>

<span style="font-family: 'Times New Roman',Times,serif;">(14)"Intensity-modulated Radiation Therapy (IMRT)." - Mayo Clinic. N.p., 9 Apr. 2015. Web. 29 May 2016. < http://www.mayoclinic.org/tests-procedures/imrt/basics/definition/prc-20013330>

<span style="font-family: 'Times New Roman',Times,serif;">(15) Kourilsky, Antoine, Guillaume Bertrand, Renata Ursu, Jennifer Doridam, Ciprian Barlog, Thierry Faillot, Emmanuel Mandonnet, Catherine Belin, Christine Levy, and Antoine F. Carpentier. Impact of Angiotensin-II Receptor Blockers on Vasogenic Edema in Glioblastoma Patients. Journal of Neurology J Neurol 263.3 (2016): 524-30. PubMed.org. Web. <span style="font-family: 'Times New Roman',Times,serif;"><http://link.springer.com/article/10.1007/s00415-015-8016-9/fulltext.html>.

<span style="font-family: 'Times New Roman',Times,serif;">(16) Sophie E. M. Veldhuijzen Van Zanten, Ofelia Cruz, Gertjan J. L. Kaspers, Darren R. Hargrave, and Dannis G. Van Vuurden. State of Affairs in Use of Steroids in Diffuse Intrinsic Pontine Glioma: An International Survey and a Review of the Literature. J Neurooncol Journal of Neuro-Oncology (2016): n. pag. PubMed.gov. Web. <http://link.springer.com/article/10.1007/s11060-016-2141-x>.