Our research investment into AML

Brian Huntly is the Professor of Leukaemia Stem Cell Biology and Head of the Department of Haematology at the University of Cambridge. He combines the running of a laboratory group with his practice as a Consultant Haematologist in Addenbrooke’s Hospital. We've funded Professor Huntly at various points since 2002 to continue the search for new information and a better understanding of AML that will hopefully lead to new ways to treat the disease.

Siân Morgan, our Research Strategy Manager spoke to Brian about the progress we’ve made so far, and what the future might look like for people with AML.

Professor Huntly: AML remains a typical example of a “complicated” cancer, where multiple mutations work in concert to alter the function of cells. To illustrate this, there are over 100 genes that can be mutated in AML. This means that, in effect, each AML case is slightly different. We are currently mapping the individual and combined effect of mutations in an attempt to understand them better and how to target them. With the help of funders such as Blood Cancer UK, we are making excellent progress.

We can demonstrate a prime example of how understanding a cancer can help dramatically improve patient outcomes with a form of AML called acute promyelocytic leukaemia, or APML. APML happens when two genes are sewn together, called a “gene-fusion”. Identifying this and how it subsequently stops the process of making mature blood cells has allowed us to develop novel “non-chemotherapy” drugs that block the function of the gene-fusion and causes the destruction of the cancerous cells. This has dramatically improved the outcomes of APML, which was one of the most quickly fatal AML subtypes, but where now more than 90% of patients can be cured.

Cancer treatment is moving towards personalised therapy, where the treatment given is specifically designed for the patient; matched to the behaviour of their tumour and the mutations that it contains, but also matched to them in other ways – to their general health and fitness and to the likelihood of them having side-effects to specific therapies. We are making excellent progress; many of the new AML therapies that have been approved by the FDA and regulators in Europe and the UK are specifically targeting mutations and are showing promising results. So, the situation is changing in AML, but we still need to learn how to use the new drugs in combination and need further new therapies. Taken all together, I feel that there is great hope for significant improvements in AML survival over the next 5-10 years.

The key challenges we need to overcome are:

1) How AML develops, and can we intervene to stop other conditions becoming AML (e.g. MDS)

We know many of the mutations that cause AML, but not how they occur. Understanding better how the mutations develop would allow us to prevent them, particularly in blood cancer we can more easily control, such as myeloproliferative disorders (MPN) and myelodysplastic syndrome (MDS) that can progress to often-fatal AML. In addition, we know that specific mutations are the drivers and “Achilles heel” of cancer cells and we need to know how to specifically target these mutations. Targeting these driver mutations may allow us to destroy pre-cancerous cells before they grow into full blown cancers.

2) Tackling drug resistance

Blood cancers, and AML in particular, often initially respond very well to chemotherapy, with the majority of patients going into a complete remission. However, most will relapse, with the relapsed disease usually resistant to standard therapies. We are beginning to unravel the roots of the development of this resistance. This knowledge will allow us to identify better treatments for relapse and perhaps more importantly this will help us find better treatments to give people the first time round to prevent relapse happening.

Acute promyelocytic leukaemia (APML) is a huge success story from AML research. APML is a type of AML and today is >90% cured without “formal” chemotherapy. At one point APML had the worst prognosis, but it has been transformed in the last three decades. This is an exemplar of what can be achieved if we truly understand a disease.

We cannot apply the exact same principles to other forms of AML, as these have different abnormalities, but can apply the same approach: a proper understanding of these abnormalities will allow for rational therapies to be designed. The main principle of APML therapy is to restore the property of differentiation; the ability of the cell to develop into a mature functional blood cell rather than being stuck at the ineffective immature level.

It has become apparent that some of the mutations that drive AML when present in combination with other mutations (usually 3-5 mutations are present within an AML cell), can be found when studying DNA in blood samples in people who show no signs of anything abnormal. Moreover, although the presence of these single mutations increases the risk of AML development, sometimes manyfold, this outcome is not inevitable, in fact the majority do not progress to AML. Understanding what drives this further progression should allow us to identify those at highest risk and will hopefully allow us to understand and target processes that contribute to development of AML.

Excitingly, this would raise the possibility of preventing AML, or at the very least treating it earlier. Treatment of cancers earlier in their development has had a dramatic effect to improve outcomes in other forms of cancer and would hopefully yield similar results in blood cancers. Therefore, understanding how AML initiates and progresses is a key question in haematology.

Yes, three or four years ago, there was only one drug that had received Federal Drug Association (FDA)* approval to treat AML in the previous 20 years. Over the last 4 years there have been another 8 approved, some of which are showing real promise. Ourselves and others will be studying the impact of these drugs on survival rates and determining which drugs will suit which patients best to better personalise therapy, thereby improving outcomes and reducing toxicities.

*Note: the FDA is the licensing authority for medical drugs in the US

I think that every AML patient will have a battery of tests performed, both addressing characteristics of their tumour and of their personal makeup, to identify individual treatment plans for each AML patient. I suspect that although intensive chemotherapy and bone marrow transplant will still have a role to play, that more patients will be treated with therapy that specifically targets the mutations contained within their tumour. Although bone marrow transplant is the first form of immunotherapy (a therapy that utilises the immune system to target the tumour) I think that we will also develop more specific and readily controllable immunotherapies to better treat AML and other blood cancers.

For the majority of AML cases in younger patients, I do think that this is achievable. Even for those very aggressive AML subtypes and/or those that occur in very elderly patients where treatment options are limited. I think that the next generation will witness massive improvements in what can be offered to patients, making AML less of a “death sentence” than was previously the case.

Yes, of course. Research into new drugs is often performed first in an ‘AML model,’ as this is where the survival figures tell us there is most clinical need. However, this does not mean that it’s always solely relevant for AML. For example, often drugs that end up being used in myeloma or lymphoma are drugs tested first in AML diseased mice, to see if they’re effective.

Moreover, more basic AML research often also informs how other cancers develop (both other blood and non-blood cancers).

Finally, AML occurs when blood cell development goes wrong and studying the mutations in AML has shed light on ‘master regulators’ for normal blood development. The study of AML has therefore educated scientists greatly about normal blood development and has provided insights into many areas where it can ‘go wrong’. For example, many of the ‘master regulators’ required for blood differentiation (the process of blood maturation from a stem cell into multiple different types of specialist mature cells) were first discovered as they are regulators that go wrong in AML.

Out of all blood cancers, AML is one of the most aggressive and generally has the lowest survival rates, due to its quick fatality if not controlled. Acute leukaemias tend to progress quickly, hence the reason that they are called acute.

AML is the most common type of acute leukaemia that people are diagnosed with and even today only has around a 20% 5-year survival rate. For this reason, scientists many years ago decided to start their research here. AML research has also had a much wider impact than simply informing on one disease, so other disease types have also greatly benefitted from the investment in AML.

Lots! Some reasons include:

Sample collection is easy - AML is both a blood and bone marrow disease, meaning samples can be collected via taking a blood sample from someone who has AML. Taking a blood sample is much easier and far less painful for a patient than a deep biopsy.

This makes it easier to do research on because it is much easier to get samples. Blood is in fact one of the easiest tissue samples to take from a patient.

Single cell analysis is easier - unlike solid tumours, it is easy to isolate a single blood cell without lots of processing of the sample. That’s why blood cancers are easier than others to study at a single cell level.

Available data - AML was the first cancer genome to be sequenced, and hence the genetic and DNA structural data (cytogenetic) available is far greater than any other cancer. Therefore we know a lot more about genetic abnormalities in this cancer.

Good scientific models have been developed – for all the reasons mentioned above, better AML models (e.g. in mice) have been developed and have been in use for a far longer period of time than other cancers. Therefore, these models are well developed.

Ultimately, AML research has and continues to have a huge impact beyond just AML.