EphA3 a New potential target in high risk Gliobastoma

In the February issue of Cancer Cell, an Australian team (Dr Bryan Day and his colleagues) published findings implicating the Eph receptor, EphA3 in high risk Gliobastoma, which they highlight is the most commonly occurring brain cancer and has median survival rates of less than 15 months.

Source: Cancer Cell 23, 238-248

Eph receptors normally help neurons during embroyonic development, but is not expressed at high levels later in development. However, these receptors are re-expressed in some cancers.

This research paper focused on one such receptor in particular called EphA3. This study analysed the expression EphA3 in 80 patient biopsies and in cells derived from patients. They also explored the effect of knocking out the expression of EphA3 using shRNA technology (remember that term from the previous post!). Mice were also transplanted with cancer cells under the skin in one set of experiments and directly into the skull in the second set of experiments and then EphA3 was knocked down to try to rescue them.

Below are some of their key findings:

• EphA3 is highly expressed in gliobastoma especially in the most severe type called mesenchymal glioblastoma

• When EphA3 expression was knocked down in patient cancer cells, these cells could no longer form tumours

• Of the mice that had cancer cells transplanted under their skin, all mice receiving EphA3 knockdown survived for more than 100 days without tumour formation whereas all mice not receiving EphA3 had tumours of 1cm diameter (at this point they had to be sacrificed). One one mice (there was six in total for each group) that recieved the EphA3 knockdown had a small tumour when the experiment ended at day 140 when the experiment ended.

• Of the mice that had cancer cells transplanted into their skull, all mice receiving EphA3 knockdown treatment survived and had no tumours at day 145 when the experiment ended.

Below is a biopsy of the mice brain, where you can see that on the left side, there is a clear and large tumour. This is because this side did not receive any EphA3 knockdown. The right side on the other hand did receive EphA3 and as you can see it appears normal with no tumour formation.

Source: Cancer Cell 23, 238-248

They then went on to target the receptor usign radioactive EphA3 monoclonal antibody which targets the EphA3 receptor without having to knockdown the EphA3 gene expression. This treatment destroyed the tumours in mice and prevented them from regrowing. Importantly, targeted the cells that initiated the tumour.

This finding is exciting because EphA3 would make an ideal therapeutic target against Glioblastoma. Dr Day and his collegues ended the paper by saying: "What might then be the benefits of therapeutic targeting of this cell-surface receptor? EphA3 is expressed at low targets in adult tissues, making it relatively tumor specific. More importantly, our results suggest that such therapy can eliminate the tumor-initiating cells, thereby stopping the tumour at its source."

Targeting TGF-beta 1 signalling in Pancreatic Cancer

Pancreatic tumours are a particularly horrible type of cancer with 5-year survival rates less than 5% and it is one of the leading causes of death from cancer. Pancreatic cancer received international awareness in 2011, when Steve Jobs the co-founder and CEO of Apple died after his tumour returned. 

One of the key biological pathways that is altered in pancreatic cancer is the TGF-beta signalling pathway. 

Normally this pathway regulates and keeps the cell growth and proliferation in check. This pathway also suppresses the immune system so that a balance can be achieved where the white blood cells can fight infection and detect cancerous cells but without harming and attacking your own healthy normal cells. TGF-beta can also cause a cell to commit apoptosis, which is a form of cell death. Finally, TGF-beta causes angiogenesis, which means that it promotes a blood supply to the cells, allowing nutrients to reach the cells. 

So  basically the TGF-beta pathway, suppresses the immune system and promotes angiogenesis (blood supply), however it also leads to cell death (if the cell is out of control) and stop the cell from growing and proliferating.

Below is a detailed schematic of the pathway. Don't worry about the details here, but the key thing to get from this image is that this pathway has different components that ensure the functions of the cell that I described earlier take place.

Source: http://www.genome.jp/kegg/pathway/hsa/hsa04350.html

In pancreatic cancer, parts of the TGF-beta pathway that cause apoptosis (cell death) and inhibit cell growth are mutated whereas TGF-beta itself and the other parts of the pathway are elevated. In this way, pancreatic tumours exploit the TGF-beta to its benefit, so their environment now has a rich supply of blood, the white blood cells are not suppressed.

So in summary, the pancreatic cancer (and other forms of cancer btw), cunningly benefit from the good parts of the TGF-beta pathway whilst avoiding the 


In the latest issue of the journal Cancer Research, a German research team led by Professor Max Schnurr published their findings where they knocked out the expression of the TGF-beta gene using shRNA technology (we might talk about that in another post) and at the same time activated the immune system in mice models of pancreatic cancer.

Source: Ellermeier J et al. Cancer Res 2013;73:1709-1720

A group of 20 mice had no treatment. A group of 16 mice had the TGF-beta knockdown treatment only. And a third group of 15 mice had both the TGF-beta knockdown AND the activation of the immune system.

Here is the key finding:

Source: Ellermeier J et al. Cancer Res 2013;73:1709-1720 

The above graph is called a survival curve and the different coloured lines represent different groups of mice. The important lines are the black line which represents mice that did not get any treatment (no knockdown of TGF-beta). The green line represents mice that had TGF-beta knockdown. The red line represents mice that had both the TGF-beta knockdown AND the activation of the immune system treatment. 

As you can see the untreated mice (black line) do not do so well. By 40 days, they had to be killed because the tumour was so bad. 

The mice who recieved TGF-beta knockdown treatment alone did much better and survived on average 39% longer.

The mice who recieved the combined treatment of TGF-beta gene knockout and immune system activation did even better and survived on average 58% longer than mice who recieved no treatment. Importantly, the pancreatic tumour completely regressed in 33% of mice.

Of course treating mice is a long way off from doing the same in humans, however the findings in this paper opens up potentially novel targets 

Hi, welcome to Scientific Mania!

This is an exciting blog where I will highlight some of the latest and most interesting key scientific and medical findings especially research into cancer biology, treatment, drug targets, patient management. translational and clinical findings etc...

Often these findings will have been published in the same month or even week and often the mainstream media does not cover these kinds of stories.

Here are some of the kind of research, I am talking about:

Biomarkers that can predict whether a person suffering from cancer can beat the disease or not.

New cellular treatments and drug targets that may one day reach the clinic.

...And much more!