Even I am finding it hard to believe that I would be blogging about cancer research the day after the release of Grand Theft Auto V (that must be the first time ever that GTA has been mentioned in any kind of cancer communication…) but alas, there are important things to report on!

First of all, September is International Blood Cancer Awareness Month, with research released identifying a specific genetic mutation linked with the development of certain leukaemias. Secondly, a radical new approach to reactivating the normal cellular process of self-degradation (something that is usually “switched off” in cancer cells) is attracting attention through an apparent link with a specific gene and disease-free survival of sufferers. Finally, and on the same subject as melanoma, a new concept in immunotherapy is underway using a small implant to combat melanoma. The idea has been tested on mouse models and is now undergoing new trials in human patients with the disease.

B-ALLin’

B-cell acute lymphoblastic leukaemia (B-ALL) is a form of white blood cell cancer involving an excessive number of B-cell lymphocytes. In B-ALL, the lymphocytes involved are at an immature stage (the “blast” stage) and are found rapidly multiplying in the bone marrow. The damage caused by B-ALL comes from the over-crowding of the bone marrow with lymphoblasts, restricting access and maturation of any other blood cell. Eventual metastasis of the cells leads to vital organ damage

File:ALL - Peripherial Blood - Diagnosis - 01.jpg
A Pappenheim stain of a child’s blood sample showing lymphoblasts (purple). The sheer size of the lymphoblasts means over-crowding of the bone marrow can lead to ALL.

Early this month, a study proposed a new genetic defect found in cases of B-ALL. The defect was initially found in several members of the same family, all of which had been treated at the Memorial Sloan-Kettering Cancer Center. A completely non-related family with a supposed susceptibility to the disease, being cared for in a different hospital, also showed the same genetic mutation in all cases.

The genetic defect was found in the PAX5 gene (paired box protein 5) which encodes the B-cell lineage specific activator (BSAP) transcription factor, a protein heavily implicated in for the correct development of B-cells.

Experimentation into the genetic defect found that each study participant exhibited the genetic defect with only the mutated version of the two gene copies being expressed in each participant. Ongoing research is currently underway to identify the incidence of the genetic mutation in whole cancer populations, with emphasis being on it’s hereditary behaviour.

Importance

The importance of the study is huge as ALL is the most common form of leukaemia in children worldwide, affecting 2-5 year olds and older adults. In the UK, ALL is treated successfully in >85% of all children in regards to their 5-year survival rate. In adults, the success rate is much lower, with ~40% showing remission of the disease.

When considering that UK cases of ALL in children has a success rate of >80%, it is easy to disregard these results. ALL in older populations shows ~40% success rates, but then age does greatly effect the chances of treatment success. So what’s the fuss about?

It is when you consider the diagnosis and prognosis implications of these findings, you come to appreciate their importance. If the PAX5 mutation is found to be mainly an inherited defect then screening for the ALL precursor may enable preventative measures to be taken against developing the disease, with treatment regimes being fine-tuned specifically for the defect. Screening for BRCA mutations in breast tumours is a successful example and has already produced a huge impact on the success of current treatment regimes as well as producing more targeted therapies. Knowledge of PAX5 and it’s “master” role in cell development pathways is already extensive so perhaps developing therapies personalised to a PAX5 genetic mutation will push success rates even closer to the 100% mark.

Improving Your Digestion

I have attempted to report on new techniques for a while now but most of them have an underlying theme: attacking the cancer with some form of drug or treatment strategy. This method however takes a completely different route – forcing cancer cells to digest themselves.

Autophagy is a natural process that occurs within cells in order to produce energy to survive in times of starvation. Cells are able to degrade unused machinery and proteins in order to “renovate”. The process is described below.

Components to be degraded are initially taken up into an “autophagosome” which later fuses with a “lysosome”. The lysosome contains enzymes that break the components down in order to release energy.

The study in question has shown the down-regulation of a particular autophagy gene (ATG5) to be responsible for the growth of melanoma in black skin. In this study, a follow-up of 158 melanoma patients showed that lower ATG5 expression caused a lower rate of disease-free survival. In order to test this theory, the proposed tumour environment was recreated in vitro by introducing the BRAF oncogene (known to play a role in autophagy pathways) into normal melanocytes (skin cells responsible for producing melanin). The results proved that suppression of the ATG5 protein encouraged proliferation of the melanocytes, with therapeutic intervention preventing it.

Food for Thought?

Not much more information was disclosed regarding the method of autophagy induction as the article itself has restricted access. However, the available results seem promising. As mentioned before, the idea of having cancer digest itself and do all the work for you is a new way to go about treating the disease. It is much more “outside-of-the-box” than thinking of new ways to kill a cancer cell directly, similar in principle to the theory of synthetic lethalityThe findings present a new way of targeting melanoma as well as possibly diagnosing it, not to mention the potential for treating other types of the disease.

In contrast to the positives, there is however clashing evidence as to whether autophagy can prevent or cause cancer. Some research has led to the belief that the suppression of autophagy can also kill cancer cells due to a build up of unwanted proteins. Consequently, the cell enters into a state of  induced cell death or “apoptosis”. Therefore, it will take quite a bit more research into this method before anything can be set in stone as successful.

No, Not Those Kind of Implants… 

From one novel melanoma-attacking technique to another, this time looking at implants. A small sponge implant is beginning a Phase 1 (human safety) trial in the US to combat melanoma by reprogramming the immune system. The fingernail-sized implant is made from a porous, biodegradable material that displays antigenic features of the cancer on its surface. The thinking behind the treatment follows along the same vein as most immunotherapy; introducing a cancer antigen to the patient’s immune system to train the cells to target their cancer.

The difference with this study is that the “training” of the immune system occurs within the patient. In many examples of successful immunotherapy, the patient’s immune cells are harvested and exposed to the cancerous antigens in a controlled environment. The immune cells then adapt to target the antigens and therefore, upon re-introduction into the patient, the immune cells are able to specifically attack any cells presenting that antigen, i.e. mainly cancer cells. In this study, the theory is to introduce the implant directly under the skin, constantly providing a source of antigen for immune cells to adapt within their own natural environment. Below is a video explaining current immunotherapy approaches:

Promise

With many immunotherapy techniques, a major problem occurs with the length of time that the treatment remains active. Some techniques can seem successful initially and then seem to stop working altogether. One reason may be due to the adaptive behaviour of most tumours, perhaps through down-regulation of previously targeted antigens. This is a cause for concern with this new proposed technique and may indicate failure even before the trials have finished. Phase 3 trials using a cancer vaccine candidate (MAGE-A3) against melanoma have recently proven to be unsuccessful as survival rates in patients were not improved.

However, the saving grace for this technique is that half of all mouse models have shown complete remission of tumours when administered with two implants. To also see a technique as new as this make its way from murine to human trials in such a short amount of time is rather indicative of the potential it is believed to have.

The results to these trials are predicted to be available in 2015 and even then will only indicate whether the implant is safe to administer to humans. With melanoma being the most common and lethal form of skin cancer, let’s hope the wait for this treatment is well worth it.

Read more…

The PAX5 article (preview):   http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2754.html#access

Science Daily report on the PAX5 story:  http://www.sciencedaily.com/releases/2013/09/130908135519.htm

The autophagy article: http://stm.sciencemag.org/content/5/202/202ra123

The melanoma implant story: http://www.independent.co.uk/news/uk/home-news/tiny-implant-which-battles-skin-cancer-to-begin-human-trials-8802566.html

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