In the PINC - stopping the reverse Warburg Effect

There was an interesting report recently on some work in the US looking at the use of a common anti-malarial drug and breast cancer. The drug in question is chloroquine, which is both cheap and widely used throughout the world. Aside from its action against the parasite that causes malaria, the drug is also known as an inhibitor of autophagy, which is a cellular state in which the cell digests parts of itself, normally as a survival mechanism in the face of lack of nutrients or damage to cell components. 

The study in question is called the PINC trial (Preventing Invasive Neoplasia with Chloroquine), which is specifically looking at women with ductal carcinoma in situ (DCIS), which is a pre-cancerous condition that is often picked up through breast screening. DCIS has the potential to progress to fully blown breast cancer. Part of the problem of the over-diagnosis of cancer associated with breast screening is that currently there is no way to be sure which DCIS lumps are going to become life-threatening cancer and which will remain harmless. The PINC trial is about treating women with DCIS who are waiting for surgery with chloroquine for four weeks and then to assess the effect this has on the DCIS lump. More details on the trial are available here: http://clinicaltrials.gov/ct2/show/NCT01023477


While the trial has yet to report it’s findings, the initial signs are looking positive. If chloroquine can stop DCIS lesions from developing into invasive cancers that would be a major step forward for women. Stopping cancer before it develops is a much better strategy than simply turning every woman with a DCIS lesion into a cancer patient because you don’t know how the lesion is going to develop.



Why should stopping autophagy halt the development of cancer? One explanation lies in the theories being developed by Michael Lisanti and his co-workers (which I have covered here and here ). In a fundamental reworking of accepted theories of tumour metabolism and cancer progression, Dr Lisanti and his group have shown that tumour cells act on the tumour microenvironment to push the cells surrounding the tumour to switch to a different metabolic pathway, and that these cells generate high-energy by-products which the tumour cells feed on to grow and multiply. This is the opposite of the currently accepted theory (called the Warburg effect), in which it is tumour cells that engage in this alternative metabolic pathway, in contrast to normal cells. In effect the tumour cells enter into a parasitic relationship with the non-cancer cells around them.


This new theory, called “two compartment tumour metabolism”, describes the complex sequence of events that lead to this metabolic coupling between cancer cells and the cells in the stroma around the tumour. And this is where we find the link between the PINC trial and Dr Lisanti’s work. Autophagy is how the cells around the tumour respond to the highly inflammatory environment that the tumour cells create. Interrupt this process and you can break the metabolic shuttling of nutrients from the surrounding tissues to the tumour. This is what the “two compartment tumour metabolism” theory predicts, and this is, hopefully, what is being shown to happen in the PINC trial.


Stopping autophagy is one avenue of approach, but the theory also suggests that stopping the tumour cells creating the inflammatory environment around then can stop the surrounding cells from being cannibalised by the tumour. And this is an avenue of approach that is going to be explored by some of Dr Lisanti’s key collaborators, here in the UK. 


This new work will also focus on women with DCIS waiting for surgery. Instead of chloroquine, the women will take a range of anti-oxidants that will counter the inflammation produced by the cells in the DCIS lesions. If the anti-oxidants stop the cells surrounding the DCIS lumps from switching metabolic pathway it should stop the parasitic relationship forming and therefore the DCIS cells will not have the fuel they need to progress and become invasive cancer cells.