Guest Post - Crowdfunding for Pediatric Cancers

Cesare Spadoni, founder of aPODD (accelerate Paediatric Oncology Drug Development), talks to Pan Pantziarka about the problems in drug development in children's cancers, and about the crowdfunding campaign to find a new treatment for Medulloblastoma.

Pan: What is the aPODD foundation aiming to do?
Cesare: aPODD (accelerate Paediatric Oncology Drug Development) was set up with the mission to speed up the development of better and safer treatments for children with cancer. This is a cause that is very close to my heart. I lost my first daughter to cancer a few years ago. That is when I began thinking about doing something for children with cancer.

Obviously, you can have a positive impact on sick children and their families in many different ways. In my case, because of my professional background in drug development, I felt compelled to do something to address the major problem preventing any further clinical improvement for children and adolescents with cancer: the lack of therapeutic options and the delayed access to the most innovative treatments.

Specific anti-cancer drugs are not developed for younger patients because it is not profitable for industry to do so. This is an area where patients’ organisations may play a vital role. Drug repurposing is certainly an area we are very much interested in. By looking at existing drugs we may be in a position to identify possible new treatments much faster and at a fraction of the cost and risk of new drug development

Pan: How is this campaign different to others?
Cesare: We are looking to identify a potential new treatment for Medulloblastoma, a rather aggressive form of brain cancer that is more frequent in children and adolescents. The current therapeutic options for this cancer are limited and very harsh, including high dose chemotherapy and radiotherapy. The impact on patients may be devastating as the lucky survivors may face severe health problems later in life.

For this project we are partnering with Healx, a company based in Cambridge (UK), which offers very advanced technologies and strong expertise in drug re-purposing. Healx is applying advanced computational biology tools, data analytics and machine learning to make sense of complex biological data sets and match those with the profiles of known drugs.

We are now in the process of finalising a list of drugs that we would like to test experimentally in Medulloblastoma cell lines in view of progressing further with the most promising ones.
We are very excited by these early results and we are really hope that this crowdfunding is successful so that we can proceed as fast as we can.

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.

Q & A With Dr Patrice Forget: Ketorolac and Breast Cancer

In the previous article on this site I wrote about recent work that showed that the use of a cheap, safe and generally available anti-inflammatory pain killer (ketorolac) had the potential to massively reduce the incidence of cancer relapse following surgery. This extraordinary result was discovered by a Belgian anaesthesiologist Dr Patric Forget and colleagues. Now working on a clinical trial to put this finding under test, Dr Forget kindly agreed to respond to a short interview to give us more of background to his research.

PP: What prompted your initial investigations - did you expect to find the results that you found?

PF: The diverse long term effects of anaesthetic techniques and analgesic medications have been suspected for many years. Discrepancies exist about the effect on outcome in humans. Concerning opioids, many data exist, but results are inconsistent. Concerning NSAIDs, animal data are consistent, but no human data are available. Therefore, we investigated it in the prospective patients listing existing in our Cancer Centre. Nevertheless, the magnitude and the repetition of the NSAIDs data were relatively unexpected.

PP: What are the clinical factors that influence the choice of ketorolac versus other medications?

PF: The anaesthesiologists have to make choices for which there are not always evidence-based guidelines. This is the case with single NSAIDs dose in the perioperative period. The usefulness of this single dose in terms of analgesia improvement is still matter of debate. The American Society of Anesthesiology has no definitive recommendations about it. Consequently, in many centres, including ours, some anaesthesiologists use it systematically, and others not.

PP: Your findings suggest that other interventions - such as taking a surgical biopsy - could also have a negative influence on cancer outcomes. What is your view on this?

PF: Inflammatory pathways are implicated in the development of cancer. It is probable that the degree of tissue injury during surgery is associated with cancer outcome. Nevertheless, whether  this effect is mediated by an influence on tumours cells, tumours cells spreading and/or immune suppression is not clear. In all cases, many arguments exist to limit as far as possible the extent of tissue attrition and surgical procedures in cancer patients.

PP: Although the emphasis of your work is on breast cancer, there is evidence that a similar bimodal pattern of relapse occurs in other cancers. Do you think that peri-operative ketorolac can have a similar reduction in relapse in these cancers?

PF: Yes. We have done the same observation in non-small cell lung cancer (NSCLC) (Forget et al, Ann Surg Oncol 2013). In NSCLC, the bimodal pattern of relapse was shown by Demicheli et al. Out data shows that the NSAIDs effect is also present. In contrast, in prostate cancer, no NSAIDs effect was observed (Forget et al, Eur J Anaesthesiol 2011). Concommitantly, no bimodal patter of relapse was shown, in my knowledge, arguing for a different pre-, intra- and/or postoperative cancer pathophysiology.

Interview With Galina Selivanova

Professor Galina Selivanova (GS) heads a research group in the Department of Microbiology, Tumor and Cell Biology of the Karolinska Institute in Stockholm, one of Europe's leading medical schools and research institutes. Her work focuses on re-activating TP53 using small molecule drugs, some of which are beginning to emerge into clinical trials. She is generally acknowledged to be one of the world's leading researchers on TP53 as a medical target in oncology. She is interviewed here: http://www.tp53.co.uk/index.php/interview-galina-selivanova and what she has to say is generally optimistic, which is welcome given how optimism is in precious short supply when it comes to Li Fraumeni Syndrome

Q&A With Dr Stefano Fais - PPI and Cancer

In a previous article I highlighted some recent results of the work of Dr Stefano Fais and his colleagues in using the over the counter gastric acid treatment lansoprazole to stop tumours becoming resistant to chemotherapy. Lansoprazole is one of a family of drugs called proton pump inhibitors (PPI), that are targeted at highly acidic environments in the body - and tumours, as is well known, create very highly acidic microenvironments. As chemo-resistance is a major problem in oncology, leading to treatment failure in many patients, this is important work. Kindly Dr Fais has agreed to answer a few questions for anticancer.org.uk:

PP: Why is it important to focus on the tumour microenvironment?
SF: Because malignant cells are progressively selected within the tumor mass for their ability to survive in a very hostile microenvironment, an environment that is generated by their own metabolism. In fact, in the same microenvironment either normal cells or more differentiated cells usually die. Tumor cells survive thanks to some mechanisms them  to quickly eliminate toxins, which would otherwise be able to kill them if they were free to accumulate.

PP: What has been the pre-clinical experience with PPI treatment and cancer in people?
SF: Proton pump inhibitors actually block a mechanism that on one hand induces acidification of extracellular environment, in turn impairing both the body’s reaction to the tumor and also highly reducing the efficacy of drugs that are neutralized by the acidic microenvironment. In fact, pre-clinical data have shown that PPI can increase the efficacy of current anti-tumor therapies and induce a real anti-tumor effect by depriving tumor cells of a key survival mechanism.

Q&A With Dr Anthony Howell - The Reverse Warburg Effect

One of the fundamental ideas in cancer has been that cancer and normal cells differ in their metabolism. First proposed by Nobel prize-winner Otto Warburg in 1924, the 'Warburg Effect' is the hypothesis that cancer cells generate energy by the non-oxidative (without oxygen) breakdown of glucose (a process called glycolysis). This is in contrast to normal cells, which generate energy through an oxygen-dependent pathway. Tumours use the non-oxidative pathway, which is less efficient than normal metabolism, even in conditions where there is plenty of oxygen available. We can see this greediness for glucose in PET scans, for example, where radioactively labelled sugar is sucked up by tumours and not by normal tissue.

For many years the Warburg effect has been investigated as a possible Achilles heel for tumours, and there is still lots of work being done on ways to attack tumours by interrupting this glycolytic process. Such work ranges from dietary interventions (see for example the article on diets and cancer, and the interview with Dr Gerald Krystal), to looking for drugs which disrupt the process at different points.

However, in recent years Dr Michael Lisanti and a group of colleagues have proposed a fundamental re-appraisal of the theory. They have proposed the cancer cells in advanced solid tumours are able to induce the Warburg Effect in the cells that surround them (the tumour stroma), and that they then consume the by-products of glycolysis produced by the stromal cells. In other words they cannibalise the tissues around themselves, inducing the Warburg Effect so that they can feed off the nutrients produced by the stromal cells. They have termed this new theory, which is a radical departure from what is currently accepted, the 'Reverse Warburg Effect'.

For those who wish to learn more there are a number of freely available papers by Lisanti and co available via PubMed.

Dr Anthony Howell is one of Lisanti's co-authors and a researcher and clinician based in Manchester. He has kindly agreed to an interview so that we can learn more about this new theory and what it may mean in terms of clinical practice. Although the language in this interview is more technical than much of what is published on this site, I feel it's important to bring these new theories and results to as wide an audience as possible.

PP: A recent editorial in the journal Cell Cycle described the work of Michael Lisanti, yourself and others as ‘iconoclastic’. Just how revolutionary is the theory of the ‘reverse Warburg’ effect and the idea of ‘cancer as a parasite’?

AH: Warburg was a great scientist as reflected in the award of the Nobel Prize for his pioneering work on tumour metabolism. His major contribution was to show that tumour cells showed enhanced glycolysis and he thus assumed that mitochondrial respiration was impaired in tumour cells. It certainly looks like this when you put tumour cell lines such as the breast MCF-7 cell line into culture by themselves. These cells have few mitochondria and there is increase in the sugar degradation glycolytic pathway. What Michael Lisanti and his colleagues have shown is that this may be an artefact of culturing the cells alone. When co-cultured with human fibroblasts, the MCF-7 cells synthesise mitochondria and thus use oxidative phosphorylation as their main source of energy. In the body tumour cells are always associated with what is called a supportive stroma derived from the host, so that the co-culture system is a better mimic of what might be happening in-vivo, and indeed we find up-regulation of mitochondria in most breast cancers compared with normal breast tissue. Cultured alone the fibroblasts have a large number of mitochondria. However, when co-cultured with tumour cells they degrade the mitochondria and depend upon gylcolysis. So all these observation are opposite to Warburg’s observations. It is as if the Warburg effect occurs in tumour associated fibroblasts rather than the tumour cells themselves which has lead Lisanti to call what is happening in co-culture ‘The Reverse Warburg Effect’. I think this is where the implication that these observations are iconoclastic comes from.

Q&A With Dr Burt Berkson - Low Dose Naltrexone and Alpha Lipoic Acid

A couple of years ago I found an extraordinary paper in the journal Integrative Cancer Therapies which described a number of cases in which patients with advanced pancreatic cancers had responded to therapy with low dose naltrexone and alpha lipoic acid. It was a paper that positively demanded following up with a clinical trial, but although I checked up periodically no trial was forthcoming. However, the recent LDN Aware DVD included an interview with the man behind that paper, Dr Burt Berkson.

I am pleased to say that Dr Berkson agreed to answer a few questions for Anticancer.org.uk, the first part of which appears below.


PP: Background - how did the LDN/ALA protocol arise?

BB: Alpha Lipoic Acid (ALA)

While working as an internal medical resident at one of the Case Western Reserve teaching hospitals in 1977, I was told by the chief to follow two patients with severe and acute liver damage that resulted from eating hepatotoxic mushrooms. This condition is often fatal and I was told that these patients would surely die.

As a medical doctor it was necessary to follow the orders of the chief; however, as a PhD, I sought new ways of doing things. I called Dr. Fred Bartter (former chief of endocrinology) at the National Institutes of Health and asked him if he knew of anything that would help regenerate damaged organs. He answered that he was working with thioctic acid (alpha lipoic acid, ALA) as a possible treatment for diabetic complications and when given to people with diabetes, it seemed to help heal damaged livers and other organs.

Dr. Bartter sent me a case of ALA for intravenous administration. I picked it up at the Cleveland airport about seven hours after I initially called him. I rushed back to the hospital and injected the ALA into the two patients. I administered this treatment every six hours for 14 days. The patients started to recover and felt much better by the second day and were able to leave the hospital within two weeks with normal liver function. They are still alive and free of liver disease today, 34 years later.

It is interesting to note that some of the chiefs at the hospitals where I practiced medicine seemed to discourage my use of ALA. I was told that with an M.D., and a Ph.D. in cell biology/microbiology, and internal medicine training, I should concern myself with doing infectious disease research and stay out of liver disease.

Dr. Bartter, however, thought our work was very important and told me that some day we might win a Nobel Prize for our human work with ALA. He suggested that I leave Cleveland and come to work with him at NIH. But I was very discouraged by the response that I experienced from the medical community in Ohio. I left the region and moved my family to a rural community not too far from Lubbock, TX.

I became a country doctor, driving from one hospital to another each day, and even delivered babies in people’s houses on isolated ranches. When my children were high school age we moved back to a relatively large city. About fifteen years ago, I opened an integrative medical practice in Las Cruces where I use antioxidants and certain innovative prescription drugs to treat diabetes, chronic hepatitis, rheumatoid disease, lupus and other disorders with exceptionally good results. I also try to support and improve the immune system of people with cancer.

Q&A with Dr Gerald Krystal - Low carbs and cancer

Following my recent article on a recent paper that looked at the effect that a low carb diet had on slowing tumour growth (and if you haven’t read it, I suggest you do that before reading the rest of this…), I contacted one of the authors, Dr Gerald Krystal of the University of British Columbia with a list of questions. Dr Krystal has kindly responded with some more information, which I think is useful for those people considering starting a low carb diet in line with the results of his team’s work.

PP: The low carb diet includes foods high in amylose. Doesn't this make it difficult to translate into a diet people can follow? Are there foods that are naturally high in amylose?

GK: There are many foods that are naturally high in amylose. For example, all legumes (beans, lentils and peas), basmati rice, new potatoes, bananas, whole grains, sweet potatoes, radishes and parsnips. Try and avoid regular "old" potatoes, white rice and white bread (whole wheat bread is not much better….bread with whole grains is the best when it comes to breads but I try and avoid all breads. If you can't resist, sourdough is not bad because of its low pH…if you add a tsp of lemon juice or vinegar to any meal you can lower the glycemic index by about 1/3). Another interesting tip is if you let cooked rice cool it becomes more resistant to digestion so eating sushi is better than eating hot cooked white rice. I would love to see a breakdown of digestible carbs into % amylose and % amylopectin down the road on food products. Also, there are ongoing studies in the US to generate genetically modified potatoes (lacking 2 enzymes that are used to put the branched sugars on the glucose polymer to convert it from a linear glucose polymer (amylose) to a branched glucose polymer (amylopectin, which is more easily broken down). Don't know how you feel about genetically modified foods but this could dramatically lower blood glucose spikes after eating potatoes.

PP: Why is it that so much mainstream dietary advice for cancer patients seems so unhealthy? Why are patients still being encouraged to have high calorie diets?

GK: This drives me crazy as well. The main concern of cancer clinicians today is cachexia (wasting). I understand this is something you want to avoid but I think that lowering our carb and raising our protein intake will have a substantial benefit, especially for early pre-metastatic cancers. In keeping with this I would like to see clinicians substitute amino acid/PBS intravenous drips for the currently used 5% dextrose (glucose) PBS to rehydrate cancer patients.