Monday, 22 December 2014

When less is more

The conventional approach to chemotherapy treatment for cancer is to give the patient a cocktail of different chemo drugs at the maximum tolerated dose (MTD). The idea of MTD treatment is to hit the cancer with the most toxic treatment the patient can stand in the hope that it causes the maximum damage to the disease. Normally a treatment consists of a number of cycles of chemo using a mix of drugs, with the idea that each drug will attack the tumour in a different way – reducing the chance of the tumour surviving the onslaught. And it’s an onslaught for the person receiving the treatment too – most chemotherapy drugs are toxic to a wide range of cells, not just cancer cells. Hence the hair loss, the nausea, the immune suppression, fatigue and the rest of the side effects that makes chemo so hard.

Of necessity a person needs recovery time after each cycle of chemotherapy. Blood counts need to recover, sickness needs to pass, people need to regain some strength. Unfortunately that’s recovery time that tumours can also use to recover. The highest rates of tumour kill tend to be at the least cycles, the later cycles tend to be less effective, particularly if resistance starts to kick in.

However, this isn't the only way of delivering treatment. An alternative approach to chemotherapy has been developing for some time. Low dose metronomic chemotherapy involves many of the same drugs as MTD chemo, but delivered at low doses, often in tablet form, but with no treatment breaks. The continuous dosing is possible because at these low doses the drugs work in very different ways to when they are delivered at MTD levels. The side effects are minimal as the drugs are no longer acting as potent toxins to massively kill cells.

Monday, 15 December 2014

Saatchi Bill and Medical Anecdotes

Opponents of the Medical Innovation Bill (aka as the Saatchi Bill), such as Sarah Wollaston MP, have been very vocal in attacking the Bill by making a number of false claims about what the Bill will do. One such argument is that the Bill will undermine medical progress by doing away with clinical trials, and that instead we will just have to rely on individual anecdotes that arise from doctors using innovative off-label treatments on patients. In fact Sarah Wollaston even referred to the Bill as the ‘Medical Anecdotes Bill’ in her recent speech in the House of Commons.

There are a number of points that to raise in response to this false assertion.

First, there is no intention to replace clinical trials. The Bill is about treating patients with no place left to turn – these are people who have exhausted standard therapies and for whom there are few options left to explore. If a clinical trial is open and the patient is eligible then that is the place to go if it is in the patient’s best interest. There may be cases where it is the right thing to do, just as there are cases when it will not benefit the patient who is offered the additional choice of an non-standard treatment (for example an off-label drug with evidence of clinical activity in the patient’s illness). This will be decided on a case by case basis, what it will not do is force doctors to ignore clinical trials or undermine the trials process.

Friday, 12 December 2014

Not All Journals Are Created Equal

An increasing hazard in science publishing is the increasing number of 'predatory journals'. The term refers to low-quality scientific journals which exist solely to make easy money under the 'author pays' model of publishing. These journals pretend to do peer review and they look and feel like proper academic journals, but in reality they will publish anything to harvest those publication fees. It's a scam, and a successful one given the growth of the number of these journals. The way the scam works is for these journals to solicit papers, to claim they do peer review, then to accept the papers. The authors are billed the article processing and publication fees, and then the paper is published online.

There are multiple dangers in this process. The first and most obvious is that the authors are ripped off - they have effectively just paid for someone to turn there text into a web page. There has been no peer review, no proper scrutiny of the content and the chances are that the paper will be ignored by other academics. If you have a limited budget for publication fees you've just wasted it. If you are starting out in your research career publishing in these journals may seem an easy route to getting some papers to your name, but more knowledgeable colleagues will know what you've done and so the risk is that you damage your career, not enhance it. It is also possible that unscrupulous academics will deliberately use predatory journals to beef up a CV to impress people who don't know about predatory journals - all of which sound eminently respectable to the unsuspecting.

However, the biggest danger is not with academics, but with the general public. Most people are impressed by a paper that is published in a scientific journal. Scammers and snake-oil salesmen can use this to peddle fake medical treatments to desperate patients. Shoddy papers that sound scientifically plausible can be published in predatory journals and then used to convince people that there's some real science behind the scam. If you're not a scientist or someone versed in the medical literature a paper that claims to treat late stage cancer patients and to have miraculous results can be very convincing. The best examples of this are the scammers selling GcMAF as a miracle cure for cancer, autism, AIDS and just about everything else.

How can you, as a reader, verify that the journal paper you are reading is not a piece of junk published in exchange for a few hundred dollars?

Thursday, 27 November 2014

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.

Sunday, 23 November 2014

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.

Monday, 17 November 2014

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.