Can we trick melanoma? Unveiling novel solutions to relapse.

Cancer is a heterogeneous disease. However, it has some common features across the different existing types. One of those is relapse. Relapse is defined as “to fall back into the state of illness after apparent recovery”. Every day, researchers are trying to understand why and how cancer returns, and so are we at the Oncology Department in Lund University.

A particularly worrying example of relapse happens frequently in melanoma.

About half of all melanomas have changes (mutations) in the BRAF gene. These mutated cells then produce an altered version of BRAF protein, which in turn helps them to grow further. Some drugs target this deficient protein. Patients with advanced stage melanoma, often get tested to see if the cancer cells have a BRAF mutation. One of the advantages of the therapy targeting this protein, is that it is specific for patients who have altered BRAF genes and is very unlikely to work in patients whose melanomas have a normal BRAF gene. This means that there is a predictive test to identify patients responding to the therapy.

Unfortunately, cancer is a very tricky disease and drugs that before the scientific community thought were effective, are now proving to not be enough.

Figure 1 | Melanoma patient before (A) and after single drug treatment, 15 weeks (B) and 23 weeks (C). [Adapted from Wagle et al, J Clin Oncol. 2011 Aug 1; 29(22): 3085–3096]
One example of this is the use of vemurafenib in melanoma. Vemurafenib is a BRAF inhibitor, which inhibits the altered BRAF protein, responsible for the augmented growth of tumours. In the following example, one can see a melanoma patient (A) treated with vemurafenib. After 15 weeks, this patient is apparently completely healed (B). However, 23 weeks after the treatment, this patient was forced to face cancer once again (C).

This unfortunate fact is due to some cancer cells that manage to become resistant to the therapy administered to the patient. In other words, even if the treatment given to the patient is actually effective as shown from an initial tumour regression, this single therapy is not enough to get rid of all the malignant cells composing the tumour. It takes much more than that.

Efforts are being made in order to understand how cells develop this resistance and more importantly, how it can be overcome. Interesting answers are emerging already.
Currently, there are two most promising solutions for recurrence, which we are addressing in our ongoing PhD projects:

  • Combined therapy;
  • Immunotherapy.

Figure 2 | Combination therapy as a strategy to eliminate resistant cells and eradicate tumours. [Adapted from Kaiser (2015) The cancer stem cell gamble. Science 347(6219):226-229]
Figure 2 | Combination therapy as a strategy to eliminate resistant cells and eradicate tumours. [Adapted from Kaiser (2015) The cancer stem cell gamble. Science 347(6219):226-229] 
 Combined therapy is defined as the use of 2 or more pharmacologic agents in a single-dosage formulation. The hypothesis behind this type of therapy is that, considering that a single tumour is composed of malignant cells with different genetic mutations, these might need different drugs to be killed.

In other words, tumour cells that are resistant to one drug, are likely to be killed by another drug, if used in combination.

On the other hand, immunotherapy is a type of treatment currently used to fight cancer, as well as other diseases. It uses some parts of a person’s immune system to either boost it or help training it to attack cancer cells specifically. Immunotherapy works better for some types of cancer than for others. Over the past few years, immunotherapy has dramatically changed the landscape of melanoma treatment.

While everyone knows that finding a cure to cancer is a hard task, it is today an evidence that combining different possibilities and minimising the chances that it comes back, is certainly the correct path to seek.

The future is somewhat bright, although a lot of work and progress still need to be done. Many people around the world, including us, devote daily to this cause, in order to reach the final goal: make melanoma inoffensive.

Useful links:
– American Cancer Society
– Cancer Research Institute

– Written by Adriana Sanna, ESR10 and Rita Cabrita, ESR11