The horrific side effects of many cancer treatments are all too well known: hair loss, muscle wasting, loss of appetite – and many more. The reason that the majority of cancer therapies have such broad and devastating effects on the health of the patient is that these treatments are often what is known as non-specific: that is, although they will hopefully eventually kill the tumour – they will also kill a vast amount of healthy tissue in the process. To try and minimise the side effects of cancer treatments, scientists are working hard to try and understand precisely what goes wrong inside cancer cells to allow them to develop into tumours, and therefore arm themselves with the knowledge to develop better, more specific treatments for the disease. In this blog, Laura Godfrey, a DPhil student in Tom Milne’s lab in the WIMM, describes work from their group (done as an equal collaboration with Marina Konopleva’s lab at MD Anderson in Texas) which hopes to do just that.
Patients diagnosed with an aggressive form of blood cancer called MLL-rearranged (MLL-AF4) leukaemia have an extremely poor prognosis.
MLL-AF4 develops when the DNA inside a cell breaks and re-joins with another section of DNA, creating a fusion of two sections of the genetic code which aren’t usually found next to each other (imagine pages falling out of a book and being replaced in the wrong order: the text would be readable, but the story would no longer make sense).
MLL-AF4 is extremely difficult to treat. Even following aggressive current treatment regimes, such as chemotherapy and bone marrow transplantation, it is very unlikely that patients will survive long-term. This is primarily because treatments currently used in the clinic are often non-specific and do not directly target the underlying cause of the disease, resulting in toxic side effects which are extremely harmful to the patient.
One example of a more targeted therapeutic approach is the use of BCL-2 inhibitors, which are currently being used in clinical trials for other types of leukaemia. BCL-2 is a protein which helps to keep cells alive, and is found in higher levels in cancer cells than in normal cells.
In a recent collaborative study with Dr. Konopleva’s lab, published in Cell Reports, our two labs together investigated whether BCL-2 inhibitors could be used for the treatment of MLL-AF4 leukaemia. We first demonstrated that the BCL-2 protein is also found at high levels in MLL-AF4 leukaemias, as seen in other forms of the disease.
Then, using leukaemia cells grown in the lab, we discovered that reducing the levels of the BCL-2 protein killed the MLL-AF4 leukaemia cells. To further investigate whether using BCL-2 inhibitors could really work to kill leukaemia cells in the body, we tested whether BCL-2 inhibition alone or in combination with other chemotherapy drugs could be used to treat mice with MLL-AF4 leukaemia.
And it worked. Treating mice with MLL-AF4 leukaemia with the BCL-2 inhibitor alone resulted in a reduction in the size of the tumour. Moreover, when used together with other chemotherapy drugs, the leukaemia was decreased by up to 70%. This suggests that the BCL-2 inhibitor could be used as a novel therapy for MLL-AF4 leukaemia in conjunction with other chemotherapeutic drugs.
Although BCL-2 inhibitors could be used with other chemotherapy drugs for the treatment of MLL-AF4 leukaemia, this is still not a perfect therapy. Broad chemotherapy drugs, such as those used in this experiment in combination with the BCL-2 inhibitor, may have reduced the size of the cancer – but they are still toxic and will therefore still have a negative impact on healthy cells. Therefore it was pivotal to try and understand why the levels of BCL-2 are higher in MLL-AF4 leukaemia cells compared to normal cells, and therefore increase the specificity of the treatment even further.
Work by others has identified another protein, called DOT1L, which plays a role in regulating gene targets in MLL-AF4 leukaemias. We were able to show that DOT1L is essential for regulating the levels of BCL-2. Interestingly, a DOT1L inhibitor is currently in stage I clinical trials. To test whether the DOT1L inhibitor could be used synergistically with the BCL-2 inhibitor we co-treated MLL-AF4 leukaemia cells with both inhibitors. In comparison to treating the cells with the BCL-2 inhibitor alone, the combination of the two drugs inhibited the growth of the leukaemia cells much more effectively. This indicates that DOT1L inhibitors could be used as a potential therapeutic approach to specifically target MLL-AF4 leukaemia in combination with BCL-2 inhibitors.
In this study we have shown that by understanding the precise changes that occur inside cancer cells which lead to the development of tumours, we may be able to develop novel therapies to selectively target and destroy these cells, leaving the patient’s healthy cells alone. This holds the potential to developing therapies that are more targeted and less toxic for the patient, providing hope for those who are diagnosed with this devastating disease.
Post edited by Bryony Graham and Tom Milne.