Li Fraumeni Syndrome and Cellular Metabolism

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.

Pan: Is there evidence that these pathways are connected to cancer incidence?

PH: Experimental data suggest that p53 regulating the mitochondria can influence cancer development -- it could be pro- or anti-tumorigenic, for example, depending on various factors including individual genetic background, cell type and state, etc. Even if LFS p53-promoted mitochondrial activity increases cancer cell proliferation and migration in the laboratory, it is important to base any specific preventive or treatment measures for LFS on the strongest possible human data.

Pan: This trial follows on from the Metformin and LFS Trial - is there a relation between them? Are they part of a strategy at the NIH to focus on LFS?

PH: Actually, the chronology is reversed. Part of the rationale for the National Cancer Institute (NCI) LFS metformin study (ClinicalTrial.gov ID#: NCT01981525) is based on the initial observation of increased oxidative/mitochondrial metabolism in LFS participants of the National Heart, Lung, Blood Institute (NHLBI) LFS metabolism study (ClinicalTrial.gov ID#: NCT00406445) The major impetus for examining the safety and tolerability of metformin in LFS patients is the observation of decreased cancer incidence in patients treated with metformin. These two studies, including that of a third LFS follow up study by Dr. Sharon Savage (ClinicalTrial.gov ID#: NCT01443468), represent the converging and collaborative interests of independent principal investigators in the different sub-institutes of the National Institutes of Health (NIH). In general, the NIH does not direct the research focus of principal investigators but encourages the translational of basic observations made in the laboratory into the clinics.

Pan: A big part of my own work is to move research from looking at LFS in terms of describing it, to looking at what we can do to reduce cancer risk. Do you think your study has implications in this area?

PH: I could speculate on how the preliminary results of our NHLBI LFS metabolism study are connected to cancer development in LFS patients but at this time there is no strong recommendation that I can make. However, I would like to note that our various basic and translational investigations have brought two epidemiologic observations to my attention. First, work by many researchers stratifying tens of thousands of human subjects over many years by cardiorespiratory fitness shows that those who are fittest have less cancer. Based on our studies, I find it intriguing that p53 as one of the most important tumour suppressor genes also promotes aerobic fitness and suspect that it is unlikely to be a simple coincidence. The biological alteration associated with increased cardiorespiratory fitness is likely to have multiple tumour suppressive activities. Second, epidemiologic data suggest that cancer mortality decreases with living at higher altitudes which would be associated with lower exposure to ambient oxygen, the essential substrate for oxidative stress that can damage DNA. p53 as “guardian of the genome” promoting the chemical conversion of oxygen to inert water via respiration in the mitochondria may also not be coincidental. At this point, I would only advocate exercising in moderation and eating a healthy diet as recommended for the general population.

Pan: Is the study open to patients outside of the US?

PH: We would be pleased if individuals from the UK can participate in some of the LFS studies listed above, but because the costs of international travel are borne by the study participants, the expenses could be prohibitive when multiple visits are involved. However, in our NHLBI LFS metabolism study, only one trip with a 2-3 day stay at the clinical research center of the NIH is needed.