The Personalization of Medicine

October 26th, 2010   |   Posted in Relapse,Treatment   |   By: Antonia Palmer   |   0 comments

When neuroblastoma is diagnosed, one of the first steps is to assign a level of risk to the cancer that the patient has. There are three risk categories: low-risk, intermediate-risk, and high-risk. The risk category is determined by a number of factors, namely the histology, stage, and classification of the neuroblastoma. If the resulting diagnosis is within the low or intermediate risk categories, a wide variety of factors are utilized to determine the type of treatment the patient will receive. There is a complicated array that decides the direction of the therapy. In certain presentations of the disease, a “wait and see” approach may be taken to determine if the cancer will regress on its own without any medical intervention. Other low-risk neuroblastomas will be cured with surgery only and intermediate-risk neuroblastomas may require a surgery and chemotherapy combination.

However, if the diagnosis is high-risk neuroblastoma, there is only one course of treatment that is prescribed – everything. The full treatment regime of high-risk neuroblastoma takes approximately a year and a half to complete and encompasses three main phases:

Induction: Six cycles of chemotherapy and surgery (after cycle 5).
Consolidation: High-dose chemotherapy with stem cell transplant (also called Bone Marrow Transplant, or BMT), and 12 cycles of radiation.
Maintenance: Five rounds of immunotherapy and six two-week courses of high-dose oral Accutane.

High-risk neuroblastoma patients experience all of the major modalities of cancer treatment. The goal is to throw everything possible at it and hope that every last neuroblastoma cancer cell has been killed once the treatment is done. This approach is taken because high-risk neuroblastoma remains one of the greatest enigmas in paediatric cancer. Neuroblastoma is described as a “heterogeneous” cancer since it presents itself in so many different ways. Within each major staging of the cancer, there are myriad combinations that can change the overall prognosis for a patient quite dramatically. There are commonalities; however, the nuances in the areas of genetic characteristics, tumour location, chemotherapy response, drug reaction, and side-effects are extensive. It is almost as if every case of neuroblastoma is unique.

Even in its initial presentation, neuroblastoma can exhibit characteristics of resistance to chemotherapy and treatment. Though sadly, the disease will still return in approximately 30%-50% of high-risk patients even though they may have responded well to front-line therapies. Upon relapse, neuroblastoma does not come back as the same cancer as its initial presentation. It returns more virile and aggressive. The neuroblastoma cells may initially respond to chemotherapy drugs; however, it will ultimately become resistant to chemotherapy (or chemoresistant). Chemoresistance is the leading cause of death in relapse (Brodeur, 2003). At this time, there is no cure for relapsed neuroblastoma.

In relapse, there are often particular treatment plans that are followed in the provision of treatment. The following are the drug protocols utilized at SickKids Hospital when a child relapses:

  1. Topotecan and Cyclophosphamide
  2. Irinotecan and Temodar
  3. Vincristine, Topotecan and Cyclophosphamide

The patient begins at step one. If it is found that the neuroblastoma continues to grow with this combination of drugs, the treatment is stopped and they go to step two. If there is a negative response in the second round of drugs, the patient moves onto step three. If the neuroblastoma still does not respond in a positive fashion, the patient will be put in any one of a number of experimental clinical trials, if they are available. The ultimate goal is to find a way to fight back the disease, or at least hold it in a stable state where it is not growing, but also not shrinking.

In the particular case of relapse, the possibility that the cancer will respond to the drug(s) is relatively low and it is truly not known how well the drug(s) will work for a particular patient until they are tried. It is far too often the case that by the time the patient enters step three of the relapse treatment, the tumour has already spread, creating myriad troubling side-effects and an even smaller chance that the cancer will be stopped.

There are a number of theories which attempt to answer medicine’s failure to find a way to stop relapsed neuroblastoma. One theory is that current therapies do not target the right cell populations. Smith and her colleagues (2010) at SickKids believe that cancer drugs must target the tumour-initiating or cancer stem cells to stop neuroblastoma growth and relapse. They suggest that “many solid tumours contain a population of cancer stem cells or tumour-initiating cells (TICs) that fuel tumour growth and seed metastases” (Smith et al., 2010, p. 2). The TICs have been nicknamed the “Queen Bee” cells and are hypothesized to control the “worker” cells. This theory is advanced by the additional speculation that “worker” cells rarely ever form a tumour on their own without the “queen bee” cells. Researchers at SickKids have been able to test approximately 2.7 million different drugs on skin-derived stem cells and on neuroblastoma TICs to compare their impact on healthy and unhealthy cells. The overall goal is to find new less-toxic therapies that target neuroblastoma TICs without harming normal cells. This research has resulted in the identification of two drugs in particular which show a potential to destroy neuroblastoma TICs – Rapamycin and Deca-14. A phase I clinical trial for rapamycin is currently underway.

Another theory centres around the body’s ability to suppress tumours using appropriate cellular responses, and more specifically, the actions of a protein called p53. The p53 protein regulates the cell cycle and also acts as a tumour suppressor to assist in the prevention of cancer in the body. p53 is often called the gatekeeper or guardian because it plays a pivotal role in determining cellular response to a wide variety of factors (i.e., DNA repair, and cell death if DNA repair is not possible) (Kruse and Gu, 2009). If the p53 protein is damaged or abnormal in any way, it is possible that this would be a key factor in the body’s inability to suppress tumour development and respond to chemotherapy (Tweddle et al, 2003; Shang et al, 2010; Kruse and Gu, 2009). p53 inactivation is seen in many cases of relapsed neuroblastoma. The challenge in understanding p53 inactivation is that there are different mutations that can occur to the p53 protein, meaning that different impacts on p53 will result in different degrees of tumour growth and resistance to chemotherapy drugs.

The theories of tumour-initiating cells and p53 suppression are showing promising advances in their research and it is highly possible that both are valid directions to follow in the race to find an answer for relapsed neuroblastoma. The tumour-initiating cell (or cancer stem cell) theory in particular has generated an interesting amount of contention and controversy. Some believe that every tumour cell has the potential to cause cancer growth and proliferation (Eaves, 2008). No matter what, “effective therapy will probably require targeting of all the tumor cell populations by combinational approaches, and a deeper understanding of tumor-initiating and –propagating mechanisms is therefore required” (Tysnes, 2010, p. 510).

We have a number of different points to consider:

  1. Neuroblastoma is a very heterogeneous disease.
  2. Relapse is common.
  3. The cause of relapse is unknown (but there are good theories).
  4. In relapse, it is vital that the right drug is found for the patient in as little time as possible. Spending too much time trying to find the right drug(s) results in wasted time and disease that will progress.

There has to be a better way to address relapse and find the right drug combination for the patient in the shortest amount of time possible. Taking a cookie-cutter approach to such a diverse disease illustrates an old way of thinking about how this disease is treated. We need to look at cancer therapies differently. Namely, we need to take steps towards instituting “patient-specific therapies” (Smith et al, 2010, p. 10), or in other words, personalized medicine.

In a September 2010 presentation provided by Dr. David Kaplan and Dr. Meredith Irwin (The James Birrell Laboratories and SickKids Hospital), they briefly discussed the possible future of cancer treatment and moving in the direction of personalized medicine. In essence, this would entail taking a sample of the neuroblastoma tumour, and then testing drugs on the tumour cells first to see how they respond to a wide variety of possible therapies. Once a drug, or set of drugs, is identified to have a stabilizing or positive cancer-killing effect, the patient would then be put into therapy using these agents.

This type of personalized medicine is being trialed at a number of institutions, with some interesting work being done at the BC Cancer Centre in Vancouver by Dr. Steven Jones and his colleagues. In one particular case, they were able to sequence the genome of cancer cells from a tumour (adenocarcinoma) once the cancer had metastasized and again after the cancer had become chemoresistant (Jones et al, 2010). The researchers were able to compare the two genomes and determine what genetic changes had taken place to make the cancer more virile. Moving forward, Dr. Jones can envision using a technique where “scientists implant tumor cells biopsied from a patient into a mouse, which then grows a tumor similar to the patient’s. Jones’s team could then hypothesize which drugs would work best using the model created from the genome analysis, and test those drugs on the mouse before trying them in the patient” (Singer, 2010). This approach may become another tool for the future; however, there are a number of barriers at this point in time. This work can only be done in institutions which have sequencing facilities and even though the cost of genetic sequencing is coming down, it is still expensive to perform. The work in processing and interpreting the genetic results is also intensive and requires a multi-disciplinary team to work through the full analysis.

Realizing the concept of personalized medicine requires a number of things: that taking the biopsy and testing a number of drugs on it could be done in a reasonable amount of time, that there are the necessary resources to conduct this testing, and that the technology is in place. If relapse happens with neuroblastoma, time is of the essence. When relapse initially occurs, a patient can show few symptoms. If relapse is found early and they are immediately started on the personalized therapy that is known to “work”, the disease could be held in a stable state or may even be eradicated (happens in rare cases). Stopping the spread of the disease early could result in a much better quality of life, and possibly even more time. If the disease is to be held in a stable state, where it is not shrinking or growing, this approach requires a shift in the traditional way of thinking about neuroblastoma. It is not necessarily about killing the cancer, but is about managing the cancer as a chronic disease and keeping it in a stable state within the body.

The ultimate goal is to find a cure for neuroblastoma, at every risk level, and to find a cure for the disease whether it is the first presentation or relapse. Getting to cure will mean a great deal of research, courage, and money. Along this journey, it will be important that more steps be taken to achieve personalized medicine for neuroblastoma. There is nothing better than cure. It is what we all want so deeply that we would give anything necessary to save the ones we love. However, until personalized medicine and cure happen, it may also be important to change how we deal with and look at neuroblastoma. Personalized medicine should be a goal for front-line therapy upon diagnosis and for relapse.


Brodeur, G.M. (2003) Neuroblastoma: Biological Insights Into a Clinical Enigma. Nature Reviews. Vol 3, 203-216.

Eaves, C.J., (2008) Cancer Stem Cells: Here, there, everywhere? Nature, 456, 7222, pps. 581-582.

Jones, S.J, Laskin, J, Li, Y., Griffith, O.L., An, J, Bilenky, M, Butterfield, Y.S., Cezard, T., Chuah, E, Corbett, R., Fejes, A.P., Griffith, M., Yee, J., Martin, M., Mayo, M., Melnyk, N., Morin, R.D., Pugh, T.J., Severson, T., Shah, S.P., Sutcliffe, M., Tam, A., Terry, J., Thiessen, N., Thomson, T., Varhol, R., Zeng, T., Zhao, Y., Moore, R.A., Huntsman, D.G., Birol, I., Hirst, M., Holt, R.A., and Marra, M.A. (2010). Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome biology, 11. Retrieved from

Kruse, J-P and Gu, W. (2009) Modes of p53 Regulation. Cell, 137, May 15, 2009, pps. 609-622.

Shang, X, Vasudevan, S.A., Yu, Y., Ge, N., Ludwig, A.D., Wesson, C.L., Wang, K., Burlingame, S.M., Zhao, Y-J., Rao, P.H., Lu, X., Russell, H.V., Okcu, M.F., Hicks, M.J., Shohet, J.M., Donehower, L.A., Nuchtern, J.G., and Yang, J.(2010) Dual-Specificity Phosphatase 26 is a novel p53 Phosphatase and Inhibits p53 Tumor Suppressor Functions in Human Neuroblastoma. Oncogene, Advance Online Publication, June 21, 2010, pps. 1-9.

Singer, E. (2010) Treating Cancer Based on its Genome. MIT Technology Review. September 13, 2010. Retrieved from

Smith, K. M., Datti, A., Fujitani, M., Grinshtein, N., Zhang, L., Morozova, O., Blakely, K. M., Rotenberg, S. A., Hansford, L. M., Miller, F. D., Yeger, H., Irwin, M. S., Moffat, J., Marra, M. A., Baruchel, S., Wrana, J. L., and Kaplan, D. R. (2010). Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens. EMBO Molecular Medicine, pps. 1-14.

Tweedle, D.A., Pearson, A.D.J., Haber, M., Norris, M.D., Xue, C., Flemming, C., and Lunec, J. (2003) The p53 Pathway and its Inactivation in Neuroblastoma. Cancer Letters, 197, pps. 93-98.

Tysnes, B.B. (2010) Tumor-Initiating and –Propagating Cells: Cells That We Would Like to Identify and Control. Neoplasia, 12, pps. 506-515.

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