Alveolar Soft Part Sarcoma - The Reverse Warburg Effect In Action?

Alveolar soft part sarcoma (ASPS) is a rare cancer - rare even among soft tissue sarcomas - that is slow growing but hard to treat. When the disease metastasises the prognosis is generally grim and there are few options for treatment if surgical resection is not possible. A new paper, published in the journal Cancer Cell, describes work in a mouse model of the disease which may ultimately have important therapeutic consequences.

A team at the University of Utah have created a mouse model of ASPS, by fusing two strands of DNA to create a fusion gene which forms tumours in the mice in which it is implanted. What's more the resulting disease behaves very much like ASPS in humans, including producing very similar genetic profiles. Intriguingly the mouse tumours formed preferentially in areas of the body which had high concentrations of lactate. In humans this tends to be in the skeletal muscles as lactate is a by-product when our muscles are straining for energy in low oxygen conditions. In the mice the areas with the highest lactate concentrations were in the skull.

Generally tumours are believed to generate excess lactate as a by-product of their metabolism - this is known as the Warburg effect. And yet here the tumours seem to be feeding off the lactate produced by non-cancer cells. As one of the researchers, Kevin Jones explains: "It's unusual to find a cancer using lactate this way. The ASPS cells grow preferentially where they are bathed in high concentrations of lactate."

The most likely explanation is that this is yet another example of the reverse Warburg effect, first described by Michael Lisanti and his team. This is a topic of huge importance as it revises what has been seen as a core component of our understanding of cancer. In this model of cancer, the tumour cells act on non-cancer cells to change their metabolism so that they emit lactate and glutamine, which the tumour cells use as a more powerful fuel source.

This does open up opportunities for intervention, however. If we can interrupt that 'metabolic shuttle' between lactate consuming tumour cells and stromal cells they are 'farming' then we can starve the cancer cells and so slow - or possibly even halt - tumour growth.

Cimetidine as an anticancer drug - New ReDO paper

The latest paper from the ReDO project has just been published. Our focus for this paper is the well-known antacid cimetidine (trade name Tagamet, but now available as a generic). The paper summarises the extensive pre-clinical and clinical evidence that shows cimetidine has huge potential in cancer treatment. It has multiple mechanisms of action and there is clinical trial evidence that it is associated with a survival in colorectal cancers.

The paper is published as open access at the journal ecancer.

The press release provides a few more details:

How a common antacid could lead to cheaper anti-cancer drugs

The cancer solution in your medicine cabinet

A popular indigestion medication can increase survival in colorectal cancer, according to research published in ecancermedicalscience. But in fact, scientists have studied this for years - and a group of cancer advocates want to know why this research isn't more widely used.

"Cimetidine is an interesting drug as it's very safe, very well-known, and has clinical results in cancer that have been confirmed in a number of trials," says Pan Pantziarka, lead author of the paper and member of the Repurposing Drugs in Oncology (ReDO) project.

Fecal Transplants In Medicine

I've mentioned on here before that fecal transplants represent a potential new addition to medical practice. The idea is that we can transfer whole ecosystems of gut bacteria from one individual to another, and in doing so transfer the beneficial side effects that 'good bacteria' can bring to the immune system.

I take a much wider look at the topic in an article at the science and technology website The Register.

Bisphosphonates in non-bone tumours

Bisphosphonates are a class of bone-targeted drug that act to slow the turn-over of bone (bone resorption). These drugs, including zoledronate, ibandronate and others, are standard treatments for osteoporosis and other bone diseases. And, as I have mentioned previously on this blog they have increasingly found use in cancer treatment to help control bone-related problems - both from metastatic disease to the bone and in primary bone tumours. There is also increasing evidence that as well as controlling bone pain and reducing fractures, these drugs have some very positive effects on overall survival. For example there is now evidence that zoledronate (also called Zometa or zoledronic acid) gives a survival advantage even in early stage breast cancer. Now this is something of a surprise because the effects are there even when there are no bone metastases, so the drug must be acting on non-bone tumour tissue - how is this possible?

New light has been shed on the matter by some recent work that convincingly shows that zoledronic acid is taken up by cancer associated cells outside of bony metastases. Some clever lab work has shown that zoledronic acid attaches itself to tiny crystals of calcium (microcalcifications) outside of the bone. These microcalcifications are then eaten up by tumour associated macrophages, immune cells that actively encourage and support tumour growth. Once these macrophages have swallowed the microcalcifications with the zolderonic acid attached the drug can get to work and interfere with their function. In other words, the drug doesn't affect tumour cells directly, it affects the cells that provide some of the life-support that tumours require. The lab work on mice was also confirmed on a tumour sample from a breast cancer patient.

Book Review - p53 : The Gene That Cracked The Cancer Code

Keywords: Cancer, p53, Li Fraumeni Syndrome Title: p53 : The Gene That Cracked The Cancer Code Author: Sue Armstrong Publisher: Bloomsbury Sigma ISBN: 978-1472910516

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If any single gene deserves a biography, it’s TP53 (more commonly known as p53). This is the gene, memorably christened the ‘guardian of the genome’ by David Lane, one of its co-discoverers, which is the tumour suppressor that is most commonly lost or mutated in cancer. It’s also the gene most commonly mutated in the rare and deadly cancer predisposition condition called Li Fraumeni Syndrome. Science writer Sue Armstrong has crafted that biography, delivering a book that is engaging, interesting and has a real page-turning quality that you might not expect for a book on the workings of a single gene.

Adopting a largely historical narrative, the book explores the evolution of our understanding of cancer via our expanding knowledge of p53. Early on, before the structure of DNA was unravelled, scientists explored the viral transmission of cancer in animal models – sarcoma viruses could reliably infect animals with tumours. If it worked for animals, they reasoned, why not for people? How did the virus create tumours? Investigations showed that these viruses triggered changes in cells that eventually developed into cancers. Individual genes and pathways were discovered that were termed oncogenes – these were the culprits that caused cancer.

But of course most cancers that develop in people are not virally transmitted, but as technology and scientific tools expanded the theories developed and changed. Our understanding of DNA spawned a revolution in our thinking, including our thinking about cancer and the role of genetic change. When it was first discovered – independently by multiple groups – p53 was assumed to be just another oncogene, a driver of cancer development.

The Burzynski Con

There is a lot wrong with current oncology practice and the research that underpins it. The pace of change is slow. Promised breakthroughs fail to deliver what they initially promised. The clinical trials process is slow and getting slower. Patient needs remain unmet and patients are dying while regulations multiply and conspire against change. But with that in mind, that doesn't mean that science is wrong, that clinical trials are wrong or that there are 'cures' out there which the drug companies are suppressing. As I have written before, there is no such thing as a miracle cure.

Unfortunately there are some people who take what are valid criticisms of the clinical trials process or the lack of progress in oncology and then imagine that there are conspiracies at work to deliberately stop progress happening. And of course there are some people out there who will use that to their advantage. Probably the most notorious example of this is a man called Stanislaw Burzynski.

Burzynki came up with the idea that there were chemicals in the body, which he called antineoplastons, which could be effective against cancer. His idea was that people with cancer were deficient in these antineoplastons, and that by taking them externally they could mount an effective defence against cancer. It's a simple idea, but rather than go through the normal process of testing, Burzynski set up a clinic and began treating patients very early on. He has been doing this for decades, and still there is no proof that his treatment works. In the years that he has been operating his Burzynski Clinic in Texas, he has treated many thousands of patients, at great financial cost to them. It's not a cheap treatment. And, despite what he says, it's not non-toxic either, patients have died from the side effects of his treatment. And still there is no evidence that this stuff works.