Sam’s Story

Medulloblastoma is a fairly common type of brain cancer originating in the cerebellum. It is most often found in children under 6 years old, and seldom occurs in adults. With an optimistic prognosis, the outlook is rather positive, especially in young children, such as our individual of focus: Sam. Sam is a 14-month old white male who has recently been diagnosed with medulloblastoma. After losing his balance while standing on a set of bleachers, he fell and struck his head on the edge of a bench seat. His parents rushed him to the hospital, expecting at worst head-trauma, and received the weighty diagnosis of cancer. To understand what this means and how it will affect Sam's life, one must examine medulloblastoma as a disease, the treatment options he will pursue, and he molecular basis and cause of the cancer.

It is first important to address the possible origins of this Sam’s cancer. Medulloblastoma has no known environmental causes other than radiation and because Sam has received little to no radiation at his young age, his cancer was most likely not obtained by means of environmental factors. This necessitates that Sam either has a genetic pre-disposition of developing medulloblastoma or simply obtained it by pure chance, but because the parents have no knowledge of a familial history of brain cancer, Sam most likely does not have any predisposition. This only leaves the possibility of coincidental occurrence, typical of medulloblastoma[1] .

But while a specific cause for Sam’s cancer is not currently known, the materialization of medulloblastoma has been linked to cerebellar development. As cells in the cerebellum grow, the signal to proliferate can be overexpressed and lead to the onset of a tumor. These cells will continue to grow and divide, the tumor increases in size and the cells eventually move to the spinal fluid where they can begin to spread to other parts of the body [2] . This could explain why medulloblastoma has greater prevalence in children. Because infants have an elevated level of cerebral development and growth, the cells are growing and dividing at a much faster rate than in adults. The cells therefore are experiencing a higher concentration of the chemicals, called growth factors, which force them to grow. The increased frequency of proliferation could result in an elevated risk of developing medulloblastoma. Consequently, because these cells grow faster, not only is the chance of developing a tumor increased, but the tumors in younger individuals also spread more rapidly.

In order track this spreading, medulloblastoma is divided in four sub-categories based on progression: M0, where the tumor is localized to the cerebellum. M1, in which the tumor cells can be found in the spinal fluid; M2, where the tumor has spread to another location in the brain; M3, signified by small tumor deposits in the spine; M4, where the tumor has spread to organs other than the brain[3] . But while these classifications are necessary to understand and define the tumor, medulloblastoma spreads to other organs of the body only in the rarest of conditions. Unfortunately, at the time of discovery, Sam’s cancer had already metastasized to 3 spots on the spine. Consequently, Sam’s cancer is classified at stage M3, a high-risk tumor. This severely damages the prognosis. From the spine, the cancer can enter other organs, further complicating Sam’s situation.

Sam’s condition is unique in that it exhibits rapid metastasis, for typically the danger of medulloblastoma does not lie in the spreading. Because it disperses infrequently and slowly in most cases, the most pertinent risk is its location. The brain, and cerebellum in particular, is a dangerous place to have a tumor. Related so closely to motor control and vital bodily functions, the cerebellum is a crucial part of the body. When the tumor invades this area, it consumes essential nutrients and crowds the brain, cutting off function, resulting in difficulties in motor ability. Consequently, not only is the presence of the tumor dangerous to general health, but it also creates risks out of everyday tasks. When the cerebellum is compromised in this way, even walking up a flight of stairs becomes a hazard. In Sam’s case, it is very possible his tumor, by pressing up against the cerebellum and compromising his balance, resulted in a loss of stability and caused him to fall from the bleachers. Although interestingly enough, it seems that these risk factors of clumsiness and loss of balance ultimately brought about the discovery of his medulloblastoma, for without this tumble, his parent would not have taken him to the hospital as early.

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Figure I. Post-gadolinium MRI of a 4-year-old with medulloblastoma presenting with morning vomiting and ataxia (Polkinghorn).

With the lethality and specific risks of patients with medulloblastoma in mind, it is important to address the 5-year survival rate, which serves as the general survival rate for cancers. The percentage of children diagnosed with medulloblastoma who survive at least five years averages between 70-80%. However, if the child is said to have “high-risk disease,” as Sam does, the rate is around 60-65%. Further still, if the child is an infant the survival rate decreases to around 30-50%[5] . Because Sam is only 14-months old, and the tumor has already metastasized to three spinal locations, his prognosis is substantially more negative, expectedly less than 30% chance of survival after 5 years.

While this may sound bleak, the discovery of this tumor was extremely fortunate. The symptoms of medulloblastoma are difficult to see in children as young as Sam, where motor skills and cognitive ability are just beginning to develop. The typical signs, such as clumsiness, lethargy, behavioral changes and loss of appetite caused by the tumor pressing on the cerebellum, could be written off as typical infant behavior[6] . Consequently, it was providential that he tumbled off the bleachers, for this medulloblastoma would have been difficult to infer. And although less than a 30% 5-year survival rate sounds dismal, medulloblastoma is significantly more common than other forms of brain cancer in small children and as a result, the current treatments are well developed and new therapies show promise.

There are several ways to treat medulloblastoma, and cancer in general. In order to make an educated decision as to which types of treatment to pursue, one must understand the options. In general, for the majority of cancers there are three ways to handle the disease: surgery, chemotherapy and radiation. In most cases, the patient receives some combination of these three things but occasionally additional treatments are provided or substituted.

The first style of treatment is surgery, which is done to remove the malignant tumor from the brain. This stops the negative effect of the presence of the cancer and hopefully ceases its spread as well. Surgery is particularly effective if the tumor has yet to appear in other parts of the body because it often prevents it from metastasizing at all [7] . However because Sam’s tumor has already moved to the spine and operation on three separate locations would be too much of a shock to the system further treatment will certainly be necessary in order to achieve remission. In medulloblastoma, the removal of the cranial tumor alleviates the pressure on the cerebellum, which helps with partially restoring motor skills and reducing lethargy and nausea. While there are some possible complications such as adverse reactions to drugs and risk of infection (Ibid 7) this is not very likely. Surgery does not typically damage other tissues, causes less fatigue than chemotherapy, and has minute risk of inducing the formation of another tumor, unlike radiation, which drastically increases this likelihood. Because Sam’s tumor has spread to the spine, surgery will be done to remove the tumor in the brain as soon as possible to prevent further metastasis. However, the deposits in the spine will need to be addressed with another type of therapy.

One possible way to deal with the cancer in the spine is radiation. Radiation works by blasting the cancer cells with high-energy particles that damage the DNA. It is very effective in killing cells that are actively dividing, which, consequently makes it an excellent way to destroy tumors. However, there are significant consequences. Because it is extremely effective at damaging cells, it can cause serious complications in in tissues that don’t replicate frequently, such as the brain. Because brain cells do not replenish themselves, damage done by radiation can be long lasting and often permanent. As a result, radiating the brain can cause serious developmental issues, especially for someone as young as Sam. It is said that whole-brain radiation decreases mental capacity by 30 IQ points[8] . On top of that, radiation also increases the likelihood of secondary tumors arising as a result of the DNA mutations inflicted on healthy cells. Due to these complications Sam will not receive radiation until after the other types of treatment have been exhausted, and even then it’s fairly common for a treatment team (the oncologist, parents, and other individuals involved) to decide not to radiate, with the idea that the potential complications combined with the financial burden, and emotional stress don’t justify pursuing the minimal chances of remission.

The last of the three most common treatments is chemotherapy, which essentially seeks to poison the cancer by using specific drugs that kill or prevent the replication of rapidly dividing cells. In this way, it is much like radiation. Both methods attempt to damage the tumor by killing the cells that quickly proliferate. Many different types of drugs fall under this category: Carboplatin and Thiotepa[9] are Alkylating Agents, which damage DNA and consequently prevent the tumor from growing[10] . Vincristine, a Vinca Alkaloid. inhibits the formation of microtubules, resulting in the inability of cells to replicate [11] . Methotroxate is an antimetabolite. These drugs utilize slightly altered and ineffective versions of the chemicals that cells typically use to replicate. Because these non-functional variations obstruct the objective of the functional version, cells cannot divide. Methotroxate, specifically, is a folic acid antagonist. This works by “competing” with the naturally occurring folic acid in the cell preventing cell division [12] . Etoposide and other Topoisomerase Inhibitors interfere with the function of enzymes that cut the DNA to allow copying. The disturbance of these enzymes prevents the cells from copying their DNA and growing[13] .The goal of all of these drugs is to essentially poison the cells by damaging the DNA to the point at which the cells are not able to reproduce. In Sam’s case, because radiation is not a viable option at 14 months, the chemotherapy will be intensive and consists of three separate phases to compensate for the absence of radiation. However, chemotherapy has its drawbacks. None of these drugs can distinguish between healthy cells and cancerous cells and simply affect all highly proliferative cells. Because of this, it is important to carefully select only the chemotherapies that will be most effective, rather than using all options available. To this end, the standard of care for medulloblastoma patients under three years of age simply utilizes Carboplatin and Thiotepa to damage the DNA of the existing cancer cells and Methotroxate to inhibit the replication process[14] . Sam will receive these three drugs during his intensive chemotherapy regimen.

After each round of chemotherapy, Sam will then receive stem cell therapy, which is a crucial step when using the intense chemotherapy necessary in cases such as Sam’s. In this process, the surgeon harvests bone marrow cells before the treatment begins and stores them. After each round of treatment the patient receives the stem cells in order to restore some of the damage done to the healthy cells by the drugs (Ibid 8). Hopefully, these cells increase the capacity of the individual to receive high doses of chemotherapy without excessively damaging the body.
After surgery, radiation and chemotherapy there are several other alternative therapies such as proton therapy, an emerging treatment that utilizes protons to kill cancerous cells. Similar to radiation therapy the tumor is blasted with high-energy particles to damage the DNA in the cancer cells beyond repair[15] . However, in contrast to radiation therapy, proton therapy results in minimal damage to the healthy tissues surrounding the tumor. Where the x-rays used in radiation enter the brain in one side and exit the other, damaging all tissues in the path, proton therapy has the capability of entering the brain hitting the tumor, then stopping (Ibid 15). This has obvious benefits. By being able to target the tumor more directly, the brain growth is not impacted as negatively and the developmental complications involved in radiation can be minimized. However, this type of therapy involves very complex machinery and support from many different fields. Where the other types of treatment are relatively simple to administer, proton therapy requires the assistance many people and a plethora of machinery. In addition to this, treating children is even more complex, in that the targeted areas are smaller and customizations must be made. Due to these complications, currently, proton therapy is not the right treatment for Sam, however, in several years, it will hopefully be a viable option for all medulloblastoma patients.

In order to understand how Sam’s treatment will work and how his tumor came to be, one must address the specific molecular aspects of medulloblastoma, the pathway involved in its development, and the drugs used to address the irregularities in the pathway. Understanding the molecular basis of a cancer is important in both coping with the disease and planning how to treat it.

Medulloblastoma has four molecular variants, called Shh, Wnt, Group C and Group D. Although the discovery of this information has been very helpful in stratifying patients by variation of medulloblastoma, it has also revealed the extreme molecular disparity that exists between the different types and, consequently, showed how much there still is to research[16] . These subcategories all have different gene mutations and as a result have different attributes. Shh variant tumors are special in that they often exhibit desmoplastic medulloblastoma, meaning the tumors have fine fibers that make them firm[17] . This type of medulloblastoma most often occurs in infants, making it likely that Sam has this variation of the cancer. The second group, Wnt, is the least common and results most frequently in classic tumors. Classic tumors consist almost entirely of cells rather than connecting tissue. Wnt occurs most often in 9-12 year olds (Ibid 16). The final two molecular variants, group C and group D, are fairly similar, in that they both result in anaplastic tumors. The cells of anaplastic tumors divide rapidly and express the worst prognosis out of all types of medulloblastoma. Group C is typically seen in 3-5 year olds, while D is seen in 11-15 year olds (Ibid 16). Sam’s tumor is of the Shh variety, as is to be expected given his age group.

Shh tumors get their name from the pathway from which they are derived: the Sonic Hedgehog signaling pathway (Shh pathway). There are several proteins involved in this system, which can go awry in one of two ways: germ line mutations or somatic mutations. Germ line mutations involve mutations in the parents’ cells that divide to produce other organisms. When mutations arise in these, all daughter cells, and consequently offspring, are affected. In this particular pathway, a mutation in the germ line results in Gorlin Syndrome[18] . Individuals with Gorlin Syndrome have an elevated risk of developing carcinomas, however, because Sam has no family history of this and his siblings show no signs of elevated cancer risk, it’s not likely that he has Gorlin Syndrome. Consequently, he must have a somatic mutation, meaning the damage done to the gene causing medulloblastoma came after the cell had divided from the germ line[19] . But to discuss this we must first analyze the Sonic Hedgehog pathway.

The purpose of this pathway is to differentiate cells in the spinal cord and promote their growth and repair (Ibid 13). It begins with the Sonic Hedgehog signal (SHH) arriving at a receptor named Patched (Ptch1). The job of Ptch1 is to constitutively repress the function of the following protein in the sequence, the Smoothened (Smo) receptor. However, when SHH arrives, it signals Ptch1 to stop repressing Smo. Consequently the arrival of SHH activates Smo. This causes the activation of several transcription factors, Gli1, Gli2 and Gli3, which prevents Gli3 from becoming a repressor, as it would if SHH had not activated the pathway. Gli2 and 3 then go on to signal transcription of Gli1, which induces the transcription of related genes. These genes mostly go on to create proteins that enhance cell growth and encourage cell survival (Ibid 19).

Activation of key developmental signaling pathways in MB. The Shh, Wnt, and Notch signaling pathways have been implicated in maintaining the tumorigenic potential of MB BTICs (Ibid 19).
Activation of key developmental signaling pathways in MB. The Shh, Wnt, and Notch signaling pathways have been implicated in maintaining the tumorigenic potential of MB BTICs (Ibid 19).

Because the mutations are localized to the tumor, Sam’s treatment plan is a reasonable way to approach the disease. Sam does not have Gorlin syndrome, which would mean his germ line cells would have the mutation. So, because his mutation was somatic, the tumor cells are the only ones with the mutation that leads to this uncontrolled cell division. Therefore, Sam’s treatment, which will utilize surgery to remove the cerebellar tumor followed by heavy doses of chemotherapy to eliminate the spinal tumors, should kill all cells with this mutation, curing Sam of the disease.
In healthy cells, early in development SHH helps to specify tissue function in the cerebellum. However, at some point Sam incurred a mutation that caused one of these proteins to malfunction and inspire the production of a tumor. Most commonly, this occurs when the PTCH gene, located on Chromosome 9, suffers a mutation, or Chromosome 9q22, the specific location of the PTCH gene undergoes elimination[20] . This diminishes the ability of the ptch1 protein to repress the function of Smo, which leads to the constitutive activation of Smo and production of unrestricted amounts of Gli1 and Gli2 (Ibid 19). These over-produced proteins then go to the DNA and cause unnecessary cell proliferation and renewal. The cell divides uncontrollably and all daughter cells, which have the same mutation, divide uncontrollably as well for the same reason, creating the cancer. This deactivation of the repressors in the pathway is an example of sustaining proliferative cell growth[21] . The malfunction of Ptch1 causes the pathway to be constantly activated resulting in un-regulated cell growth.

However, there are ways to combat this problem. Targeted therapies are types of treatment that function by attacking cells with specific differences that make them cancerous[22] . The goal is for these drugs to recognize and bind cancer cells exclusively and cause irreparable damage or mark them for destruction. One such drug is Vismodegib[23] , which targets Smo. When the mutated Ptch1 fails to deactivate Smo, Vismodegib shuts down the entire pathway by disabling Smo. This drug is used in patients with Basal Cell Carcinoma in advanced and metastatic tumors, but has not yet been approved by the FDA for cases of medulloblastoma. As a result the drug will not be used on Sam in the meantime, and he will proceed with the aforementioned treatment plan, without this targeted therapy. However, clinical trials have shown moderate success meaning this could soon be a possible treatment (Ibid 22).

So far, several experiments have been conducted addressing the toxicity and efficacy of Vismodegib. A Phase I study, done to analyze the toleration of the drug in children, showed promising results[24] . The drug was well received by the subjects at all tested concentrations, encouraging the initiation of the following experiment, a phase II trial. This secondary study found increasingly positive results and concluded that Vismodegib should be a viable therapy for patients with newly diagnosed medulloblastoma[25] . These Phase I and II trials show significant evidence that a Phase III trial should be conducted in order to compare its efficacy and effectiveness with that of the current standard of care.

This drug will not only be more effective than the current method of treating medulloblastoma patients, but will also cause fewer side effects. Because the standard of care today for someone of Sam’s age and cancer progression involves heavy reliance on alkylating agents and antimetabolites to damage the DNA and inhibit replication, the addition or substitution of Vismodegib to target the cancer cells and affect the defective pathway with enhanced specificity would improve survivability. The drug is able to attack the cancer more effectively because it ignores healthy cells and, for the same reason, would avoid the destruction of quickly dividing healthy cells, consequently reducing side effects. The largest potential problem is that the cancer cells will adapt to mutate another pathway. Cancer cells are extremely versatile and often mutate around a pathway that has been regulated by drugs. After Vismodegib eliminates the primary tumor, the secondary tumors could have different mutations that cause them to be unaffected by the drug. To analyze the likelihood of this, Phase IV studies must be done after the drug has been approved to analyze whether the patients will develop secondary tumors resistant to Vismodegib.

It is not known what caused Sam’s medulloblastoma. Although it is known to be correlated with development of the cerebellum in young children, the research has not yet revealed a cause outside of random mutations. To this end, it is difficult to say how these mutations in the SHH gene came about. At some point the gene underwent a change that resulted in the malfunction of PTCH1, which caused the production of an unregulated amount of proteins that encouraged the survival of the cell and formed the tumors. To treat the cancer, Sam will undergo surgery, followed by chemotherapy and possibly radiation. By cutting out the tumor, one hopes to alleviate any harm already inflicted upon the brain and stop the spread of the cells. Although the usage of proton therapy and Vismodegib are not a possibility for Sam, they may soon be likely options that drastically increase the efficacy of the treatment and minimize the destruction of healthy tissues.

The combination of Sam's age and cancer progression give him a 5-year survival rate of less than 30%, but current research of targeted therapies and radiation alternatives could drastically improve this number in the near future.
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