A novel therapy for certain breast cancers isn’t the same as a ‘major breakthrough’

Researchers from King’s College London have identified a molecule crucial to the growth of breast cancer that they say could be targeted by drugs to help treat patients resistant to chemotherapy.

The study, which has been published in the journal Nature Medicine, identifies the role of a molecule called PIM1 in driving and controlling triple-negative breast cancers.

Triple negative breast cancers – so called because they lack the three receptors which are normally used to classify the disease – are more aggressive than other types of breast cancer. They are more common in younger women, and account for around fifteen per cent of all breast cancer cases. Approximately 7,500 women in the UK are diagnosed every year.

This form of breast cancer can’t be treated with traditional drugs, such as Herceptin and Tamoxifen, meaning that the only options open to patients are chemotherapy, radiotherapy and surgery.

During chemotherapy, breast cancer cells are damaged which triggers a ‘death signal’ inside the cell. This process, known as apoptosis, is essential if the therapy is to work.

The KCL researchers have discovered that the molecule PIM1 has been hijacked and is being over-produced in the majority of triple-negative breast cancers, which helps them to survive by making them more resistant to these ‘death signals’.

This hijacking helps triple-negative breast cancers to survive by making them more resistant to the ‘death signals’ prompted by chemotherapy. The findings help to explain why a significant group of triple-negative breast cancers are very aggressive and resistant to chemotherapy.

Triple-negative breast cancers become addicted to PIM1 to survive, whereas the molecule has little impact on the functioning of normal cells. This suggests that PIM1-inhibitors could be a targeted way of hitting triple-negative breast cancer cells and making them more sensitive to other therapies.

Professor Andrew Tutt, who led the research, explains the significance of the findings: ‘Many triple negative breast cancers are very resistant to chemotherapy and are ‘driven’ by genes that are very difficult to target with drugs.’

‘We have shown that PIM1, a molecule for which drugs are already in trials in other diseases, is so important for what makes a triple-negative breast cancer cell malignant that they become addicted to it. PIM1 also rescues them from the cliff-edge of death caused by chemotherapy by controlling these ‘driver’ and ‘death protection’ genes — genes that are themselves difficult to drug.’

‘It is early days but as PIM1-inhibitor drugs have already been discovered they may give us a new way to hit these cancer genes. The hope would be that these drugs could strip triple-negative breast cancers of their defences so that they can be pushed over the cliff by other breast cancer treatments.’

Instant analysis

This was a study that looked specifically at TNBCs, or Triple Negative Breast Cancers. Ordinarily, there are three receptor types that a cancer may express which can then allow a therapy to be targeted towards the cell line that has overgrown and therefore can turn off the growth of these cancer expressing cells – and allow the cancer to be stopped, or at least reduced in progression. These receptors are Oestrogen, Progesterone, and Human Epidermal Growth Factor receptor-2 or HER2. This allows for effective targeted therapy, of which some of the names will be familiar – Tamoxifen and Herceptin, for example. However in TNBCs the mainstay of therapy is often chemotherapy, towards which a lot of these tumours are resistant, and the prognosis is therefore poor. 

However, in these cells when looked at in-vitro, an over expression of a particular set of cancer causing genes, or Oncogenes, has been identified in an areas where a particular oncogene lives, called PIM1. 

The study sought to show the link that PIM1 had a protective function in TNBC cells, and whether there was a link between other oncogenes – in particular one labelled MYC. 

As you can see from the TLAs (three letter acronyms), it was a highly technical paper, mainly outlining how the gene expression was shown in the laboratory and showed the evidence to prove that there was a clear over expression of this particular oncogene when compared across three different tissue data sets. 

The study assessed three different areas: expression of the oncogene in TNBCs in particular; expression of PIM1 in cells that resisted cell death and showed to propagate growth of this particular cell type; and that PIM1 inhibited the activation of cell death – a normal bodily mechanism which goes wrong when cancer is generated, and ‘cell death’ is ‘turned off’. 

When the PIM1 receptor was silenced, it managed to reduce the amount of cell growth in six out of seven of the PIM1 cell lines, and in two of four of the non TNBC models, which showed a level of dependence on PIM1 in addition. One cell line in particular, SUM159 had low expression of PIM1 and therefore the effect on reducing the colony formation of these cells was not as strong. 

Subsequently the study looked at the usage of a PIM kinase inhibitor – a drug used in leukaemia and myeloma. This reduced cell growth and survival in these particular studied cells, other than cells with SUM159, which only had a partial reduction. Looking at how the cells adapted under increased usage of the PIM kinase inhibitor, another molecular pathway to allow cell survival was identified. 

In summary, the PIM Kinase inhibitor AZD1208 inhibited a major pathway in which TNBCs can be propagated and therefore identifies a new agent in the treatment of TNBCs. 

However, it has to be cautioned, that this is not a ‘major breakthrough’ or a ‘new treatment’ that will treat the ‘incurable’ breast cancers as some sensationalist papers will invariably claim. 

There are alternate pathways and cell lines that are driven despite PIM1 being inhibited, and therefore thought needs to be given to this also. However, in some particular cell lines that express MYC and MCL1, it will offer a novel therapy that requires further investigation and may show promise in treating a particular type of breast cancer that is notoriously difficult to treat. 

Research score: 4/5

RM