Europe Gives the Go-Ahead on Cancer Treatment Pill

Europe have approved the use of a new tumour-agnostic cancer treatment pill which can be administered to both adults and children. But what does this mean and how does it work?

(Vitrakvi® not in image)

Lung cancer, skin cancer, breast cancer, prostate cancer… We are all familiar with many different types of cancer and there are many more for which we may not be. It’s likely that many of you will know the existential dread of sitting in a doctor’s office and just hoping the ‘C’ word doesn’t come up. And it’s likely that even more of you know about the standard treatments for cancer: chemotherapy and radiotherapy. But aren’t we all just hoping that one day we can take a few pills for our treatment? Well, we’re getting there.

In September, the European Medicines Agency approved Bayer’s Vitrakvi®, otherwise known as the equally catchy name: larotrectinib. It was also approved in November 2018 by the U.S. Food and Drug Administration. Larotrectinib is one of a few new tumour-agnostic cancer treatments to be approved around the world recently. And best of all? It comes in the form of easy-to-swallow pills that both adults and children can be treated with.

Vitrakvi® had a 75% overall response rate in clinical trials. 53% of that being a partial response and 22% being a complete response to treatment. It has been designed to specifically treat NTRK gene fusion-related, solid tumour cancers (don’t fret, this is explained later). The treatment is aimed as an alternative to high-risk operations and metastatic cancers (cancers which have spread to other areas of the body).

But what does this all mean and how does it all work?

What Does It All Mean?

Firstly, let’s tackle what all of the technical stuff really means.

Cancer is the result of damaged DNA triggering the uncontrolled division of cells, which divide and divide and eventually amass into a tumour. The body is a very tightly controlled system but mutations in certain genes, known as oncogenes (onco- means relating to tumours), can cause this uncontrolled division, as well as disabling a cell’s natural self-destruct mechanism. Every cell in our body has the ability to essentially destroy itself if it becomes dysfunctional. Cancer is essentially dysfunctional cells which aren’t able to destroy themselves and which continually grow and divide.

The standard chemotherapy you may be familiar with is chosen based on the specific cancer, such as the aforementioned examples (i.e. lung cancer, skin cancer, etc.). These are example of tissue-specific cancers and are named after the bodily tissues where the cancer is found. However, tumour-agnostic (also called tissue-agnostic) therapies will treat a specific type of cancer no matter what tissue it resides in. Tumour-agnostic therapies instead target cancers with specific genetic mutations which have caused said cancer to begin and a tumour to grow. This is also referred to as targeted therapy.

In this case, larotrectinib targets cancers caused by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Stay with me though, this is actually simpler than it sounds.

How Does It All Work?

Like most known genes, the NTRK genes encode for proteins in our cells. In this case, NTRK1, NTRK2, and NTRK3 encode for neurotrophin receptor proteins (Tropomyosin receptor kinase)TrkA, TrkB, and TrkC, respectively. But don’t let all the abbreviations bog you down, these are essentially just proteins which sit in the membranes of our cells and bind to other proteins called neurotrophins. Hence why they are named neurotrophin receptors.

Neurotrophins, again, are just a different type of protein known as growth factors. As the name suggests, these proteins, when bound to receptors like the Trk proteins mentioned above, promote the growth and proliferation of cells; more specifically in this case, neurons (nerve cells). And now we’ve come across our first red flag — growth and proliferation — because as we described earlier, cancer is essentially uncontrolled growth and division (proliferation) of cells. Whatsmore, neurotrophins are known to prevent programmed cell death; our second red flag, as many cancer cells lack the ability to destroy themselves — a process called programmed cell death.

Finally, you may not be familiar with what gene fusions are. In the life cycle of a cell, there is a possibility for parts of two different genes to join and fuse together, creating a fusion gene. This is a type of mutation. This new fusion gene will now encode a new fusion protein. However, NTRK gene fusions can lead to fusion proteins which are essentially permanently ‘switched on’ versions of the Trk protein receptors. Thus meaning, the affected cell will continuously receive signals to grow, divide, and never die. Ergo, cancer.

How Does Larotrectinib Work?

So, now we have an NTRK fusion gene, which encodes for a permanently ‘switched on’ version of the Trk protein receptor, causing a cell to continuously grow, divide, and never die, and therefore become cancerous. So how does larotrectinib treat this type of cancer?

Well, that’s actually the easy part to explain. Larotrectinib binds to, and inhibits the activity of, the Trk fusion protein. Without the ‘grow’, ‘divide’, and ‘don’t die’ signals from the Trk fusion protein, the cancer cell simply destroys itself in a process called programmed cell death. The idea being that the cancer kills itself and the tumour(s) shrinks.

The Future

There are more tumour-agnostic treatments in development right now and it’s likely we’ll see more approved for use in the coming years. This means that there could be more alternatives to high-risk operations and better treatment of metastatic cancers; which are the hardest cancers to treat, with the lowest survival rates.

The future of cancer treatment continues to look more and more hopeful.

Further Reading

Amatu, A., Sartore-Bianchi, A. and Siena, S. (2016). NTRKgene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open, 1(2), e000023.

Chial, H. (2008) Proto-oncogenes to oncogenes to cancer. Nature Education 1(1), 33.

Labi, V. and Erlacher, M. (2015). How cell death shapes cancer. Cell Death & Disease, 6(3), e1675.

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