Thursday, 10 July 2014
A theme that I have covered here many times is the potential use of common non-cancer drugs as parts of anticancer drug protocols. Examples that I have covered have included the anti-hypertension (high blood pressure) drug losartan, the anti-fungal itraconazole and the anti-parasitic mebendazole. For the last few months I have been working on a project called Repurposing Drugs in Oncology (ReDO), looking precisely at how we can make more progress in getting these common and low-cost drugs into use clinically against cancer.
I’m happy to report that the first two papers from the ReDO project have been published today, in the open access journal ecancermedicalscience, along with an editorial making the argument for repurposing. The first paper describes the rationale of the project and outlines our thinking in the selection of the candidate drugs, what we hope to achieve in the project and some of the social and political implications involved:
The Repurposing Drugs in Oncology (ReDO) Project
The second paper looks in detail at the first drug on our list – mebendazole. It summarises the evidence for an anti-cancer action of the drug at clinically relevant dosages. Additionally the paper proposes a series of drug combinations for specific types of cancer:
Mebendazole as an anti-cancer agent
The editorial that accompanies the two papers is also online:
Recycling existing drugs for cancer therapy: delivering low cost cancer care
More details on this, including links to some of the clinical trials my colleagues are involved in supporting and links to additional articles, can be found at the project web site:
These papers are just the first, and we hope that in the months to come there will be more publications and a greater intervention in public debates about health policy and drug development in cancer.
Monday, 7 July 2014
A while ago I wrote about the trial of the anti-diabetic drug metformin in individuals with Li Fraumeni Syndrome (LFS) and the importance of starting to look beyond the idea that LFS is just about a defects in the self-destruct mechanism of damaged cells. Another clinical trial in LFS, also at the National Institutes of Health in the United States, is also taking place and this one too is about looking at a different aspect of LFS. The ‘Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome’ study (http://www.clinicaltrials.gov/ct2/show/NCT00406445) is looking specifically at whether a mutated TP53 gene causes metabolic changes in humans, as it does in mice and in test tube studies.
This is not just an academic question – ultimately we are looking to see whether there are factors that can change the cancer risk in individuals with LFS. This is the key idea in my own research on LFS, see for example the paper on ‘Li Fraumeni syndrome, cancer and senescence: a new hypothesis’.
Dr Paul Hwang, one of the investigators on this new trial kindly agreed to respond to a few questions on his work:
Pan: In your experiments you have found that mice with a mutated TP53 gene show different patterns of cellular metabolism compared to mice with non-mutated TP53. How would this difference manifest itself day to day? For example, would you expect to see different responses to exercise and diet?
PH: In a preliminary study of individuals carrying mutations in the TP53 gene (encoding p53 protein), we have observed evidence of increased muscle oxidative metabolism which is carried out by sub-cellular compartments of the cell called the mitochondria. In a mouse model of LFS, where genetic and environmental variables between individuals can be well controlled, we see a marked increase in aerobic exercise capacity which is also dependent on muscle mitochondria. Thus, in individuals with LFS this intrinsic characteristic could manifest itself as higher baseline endurance exercise capacity. Additionally, with exercise training, it could be possible to see a more robust improvement in fitness compared to individuals who do not carry the TP53 alteration. However, it should be noted that there are many different mutations of TP53 that can cause LFS, and it is not known whether our finding of increased oxidative metabolism is applicable to all individuals with LFS. With respect to diet, we have observed that some p53 mutations result in unresponsiveness to nutrient deprivation at the cellular level but how this affects the relationship between diet and cancer in people would only be speculative at this time.