Selectively killing cancer with radiotherapy

Traditional chemotherapy and radiotherapy treatments are extremely harsh on the body. In essence, you’re flooding your body with poisonous chemicals in an effort to kill a selected few cells. The side effects of this are huge, and what people commonly think of when they hear the word ‘cancer’. Hair loss, sickness and susceptibility to infections. This is because traditional chemotherapy targets cells that are multiplying quickly.

The problem with this type of treatment is that it isn’t only cancer cells that divide and multiply quickly. The cells that make your hair, blood and intestines are all constantly dividing to keep up with demand. This means that when we try to kill the tumour cells by targeting their division, we inadvertantly target all the other useful cells that divide quickly too. However, decades later, we’re still using these same therapies.

Targeted therapies reduce the number of side effects experienced by patients. The first of these, tamoxifen, was approved in the 70’s, and since then, a whole host of targeted therapies have become available. A good example of this is Kadcyla, or T-DM1, which combines trastuzumab, a targeted therapy against the HER2 receptor, with emtansine, a cytotoxic chemotherapy agent. The problem with this is that cancer cells are clever. They are able to very quickly evolve and change the way they signal inside and the pathways they use to overcome the inhibition of particular proteins like HER2.

Combining radiotherapy and chemotherapy at the same time came about in the 90’s. Clinical trials demonstrated that using cytotoxic chemotherapy alongside radiotherapy improved patient survival. By using certain cytotoxic chemotherapeutics, like cisplatin or 5-fluorouracil, with radiotherapy at the same time, tumours can be sensitised to treatment more efficiently than if treatment was given one after the other. By combining targeted therapies with radiosensitising agents, off target effects can be minimised even further.

Double whammy

A group of scientists based in San Diego have taken this idea and added an anti-tubulin drug (monomethyl auristatin E, MMAE) to current EGFR and HER2 targeted therapies cetuximab and trastuzumab, respectively. By doing this, they were able to show that this radiosensitised only EGFR or HER2 expressing cells, and not the surrounding healthy tissues. This is great for many reasons, but just one of them is that MMAE is a really toxic drug, so it’s difficult to treat people with it without having loads of side effects.

untitled

The drugs (red) are cell specific, depending on the receptors expressed on their cell surface. C-MMAE targets cell expressing EGFR, whereas T-MMAE targets cells expressing HER2. (Adams et al., 2016)

But how long until it’s in the clinic?

To make their findings more clinically relevant immediately, they tested whether the current targeted chemotherapy for HER2 expressing breast cancers, T-DM1, would have a similar effect. They were able to show that T-DM1 increased the radiosensitivity of HER2 expressing cells at much lower doses than current radiosensitising chemotherapy, while not having off target effects on negatively expressing cells.

The Future

So what does this mean for patients? If doctors are already using targeted therapies linked with maytansinoids or auristatins, like T-DM1, there is a huge potential to control the tumours even better than we currently can, by giving these chemotherapies at the same time as radiotherapy. And as a huge bonus, we’ll be able to give the drugs at much lower doses, with less off target effects and side effects than the current cytotoxic chemo drugs that we use to radiosensitise the cancer cells. Sounds like a win-win situation to me!

If you want to read more about how they did it, read it here. Don’t worry, it’s open access too!

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s