Opiates, cancer and naltrexone

An interesting paper in Anaesthesiology, (and yes, I know it’s not top of everyone’s reading list), looks at the influence of the mu opiod receptor (MOR) on cancer progression. While you may not have heard of the MOR, you will have heard of the drugs that target this receptor: morphine, fentanyl, heroin and other opiates. These are among the most widely used of pain-relief drugs in current medical practice. In particular these drugs are widely prescribed for cancer patients, either when undergoing surgery or when they are suffering from pain. The question of whether these drugs have an effect on cancer progression is one that is directly relevant to cancer patients here and now. While it has been known for some time that opiate drugs possibly have some indirect effects on disease progression because of the depressive effect on the immune system, the authors of this paper take things a step further and ask whether there is also a direct pro-tumour effect induced by these opiates.

The starting point for this new work is that the authors had worked with the drug methylnaltrexone (part of the same family of drugs as naltrexone), which blocks the operation of the MOR but which does not cross the blood/brain barrier. This means that while methylnaltrexone blocks the operation of opiate drugs, because it doesn’t cross into the brain it doesn’t interfere with the pain relief that opiates are used for. The clinical rationale for using methylnaltrexone is that it doesn’t stop the pain relief, but it does stop constipation and other side effects of opiates.

Reverse Warburg Effect and Breast Cancer Biomarkers

I have written before about Michael Lisanti’s ‘reverse Warburg effect’ theory, and interviewed one of Lisanti’s collaborators in the UK, Dr Anthony Howell of the Christie Cancer Centre in Manchester. Briefly, the theory states that tumour cells ‘cannibalise’ surrounding tissues by creating highly oxidative conditions which force non-cancerous cells into metabolic states that produce nutrients that the tumour cells feed on. This is in contrast to the ‘classical’ Warburg theory, which states that it is the tumour cells which switch metabolic states.

This new theory radically over-turns the conventional view of tumour metabolism and makes a number of predictions which have direct clinical relevance. It also suggests that the traditional explanation of the Warburg effect is due in part to the in vitro models of cancer that have been used – in other words it’s due in part to scientists having the wrong models of cancer to play with. In the test tube isolated cancer cells do exhibit the ‘classical’ Warburg effect as they adapt to those conditions, but in real tumours the conditions are different and evolutionary pressures leads to this ‘reverse Warburg effect’.

While all of this might be of academic interest to the research scientist, does it have any relevance to the patient or the clinician? And the answer is that yes it does, in two distinct ways. The first is the new theory makes some specific predictions on how tumours behave and on how they interact with the surrounding tissues. In particular the theory suggests some new biomarkers that can be used to identify patients at high risk of early breast cancer recurrence, metastasis, drug and hormone resistance and decreased survival. Secondly, and linked to the first point, the new theory suggests some interesting new avenues to explore for treatment.

In a new paper, Lisanti and his team examined tumour samples from 180 triple negative breast cancer patients looking for specific markers related to his theory. The results of tissue analysis showed that having high levels of MCT4 (a marker of hypoxia, oxidative stress and aerobic glycolysis) in the tumour stroma (the cells that surround the tumour) was highly related to a decreased overall survival rate. This is a significant finding, being able to identify those patients at highest risk is vitally important.

The Wrong Models of Cancer - Part 1

There is a commonly held belief that one of the primary reasons for such slow progress in the fight against cancer is financial. Without adequate funds, the story goes, scientists have not been able to make the positive moves towards new treatments that the ‘war on cancer’ has been promising for decades. The reality is, unfortunately, a lot more complicated. The truth is that there is an awful lot of money invested in cancer research – there are billions of dollars of funding from governments, private foundations, the drugs industry and members of the public donating to the cancer research charities. If it was just a matter of money the fight would have been won by now – or at least be further along than we currently are.

If it’s not just a question of funding, then how can we explain why new treatments are so slow in coming? And why are the new treatments that do appear so often disappointing?

One part of the answer, in my opinion, is that scientists have been focused on the wrong targets. As I have previously written, for example in the articles on How To Read A Cancer Paper, much early stage cancer research is done in vitro. Simply put, it means that researchers test new drugs in test tubes. Strictly speaking they’re not test tubes but flat dishes with a layer of growth medium (food and a nice environment for cells to grow on) on them. These flat dishes – often called Petri dishes – then have a layer of cancer cells grown on them. Mostly these cancer cells come from standardised cells lines that represent a particular type and sub-type of cancer – for example hormone resistant prostate carcinoma, or Her2+ breast cancer. While the distant ancestors of these cells will have come from patients, the cells supplied from the standard cell libraries have been grown in cultures from one generation to the next over many, many years. And this is one aspect of the problem.

Breast cancer and Li Fraumeni Syndrome

For women with Li Fraumeni Syndrome (LFS), the threat of breast cancer is ever present. The life time risk of developing breast cancer before the age of 60 is 49% for women with LFS. However, as with all cancers, there are many sub-types of breast cancer, some of them more amenable to treatment than others. So for this reason discovering whether there is a correlation between LFS and particular types of breast cancer is especially important. And the good news is that the picture that a positive picture is emerging from the studies being performed.

The latest paper looks at results from the breast tumour biopsies of 39 women with LFS (and while 39 looks like a low number, this represents the largest sample that has been examined so far). The average age at diagnosis of these women was 32. In all 43 tumours were examined, and of these 32 were found to be invasive ductal carcinomas and 11 were ductal carcinomas in situ (DCIS). Of the invasive tumours, 81% were high-grade, and 84% were hormonally dependent (i.e. positive for ER and/or PR). Additionally, 63% of them were positive for HER2/neu - as were 73% of the less dangerous DCIS tumours. Furthermore, 53% of the invasive tumours were positive for both ER and HER2.

What does this all mean?

It means that the majority of breast cancers in LFS patients are of the types that are more amenable to treatment. In the words of the original paper: 

These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.

The trick now is to take these findings and look to see what it means in terms of chemoprevention. Are there protocols out there that can be adapted to reduce the risk of breast cancer in female LFS patients?