I recently attended abcam’s Cancer and Metabolism conference in Cambridge and realise that I haven’t written about it yet.
In a nutshell, the event covered major aspects of metabolic transformation in cancer and attempted to highlight potential therapeutic approaches to target cancer-specific metabolic pathways. The conference allowed me to build on my existing knowledge of metabolism and metabolic signalling in cancer and introduced me to more advanced concepts, novel methods, and emerging technologies to target these pathways.
I was also introduced to a collaborative European wide research project called TRANSMIT: Translating the role of Mitochondria in Tumorigenesis.
The angle they are taking with TRANSMIT is viewing cancer as not only a genetic, but also a metabolic disease.
Personally I think it is a metabolic disease with metabolic solutions and the genetic mutations are as a result of mitochondrial dysfunction. With healthy mitochondria it is my belief that you simply do not get cancer. However… whether it is cause or effect, the focus on cancer metabolism is a huge step in the right direction for me and I am greatly encouraged by seeing this type of event take place and to be able to have these conversations.
The research I came across at this conference was all work that could directly be translated to the patient (‘from bench to bedside’) so I found this more engaging than most conferences I have been to.
More and more now scientists are not only investigating the conribution of oncogenes and tumour suppressor genes (an approach which, as the primary focus over the years has been woefully ineffective), but we are also focusing on the intricate metabolic plasticity that transformed cells undergo to survive the adverse, volatile tumour microenvironment conditions.
The mitochondria is the star player here, and rightly so, because they act as key players in cancer metabolic restructuring due to their crucial role in powering all functions of the cell by producing complex molecules for function, growth and survival. When these normal processes become aberrant, causing dysfunction, as is the case with cancer, this biosynthetic powerhouse of the cell is forced to adapt through more anaerobic respiration, and so is forced to provide energy and metabolites to the cell in different ways.
These cells are very clever and can learn how to survive by using different substrates to stay alive and will become more resiliant with time if provided with the fuel that it needs to thrive. It will then become more able to use alternative substrates for energy as it adapts and learns, and here we have parallels with Darwinian biology. In the absence of nutrients, cancer cells can even scavenge from cellular debris in a process called ‘macropinocytosis’, so this is worth considering with any metabolic therapy, most likely it seems when necrotic tissue is a hallmark of disease as it often is with glioblastoma. That’s my opinion anyway, seems to make sense. Cancer doesn’t want to die, as a result of these metabolic abnormalities we have an occurance of mutations in metabolic enzymes encoded by both nuclear and mitochondrial DNA.
It is my belief therefore, that more solid tumours would be most responsive to any kind of metabolic approach, as they have clear margins, are less diffuse and invasive, and as such have likely not yet progressed to being able to use multiple substrates to become more resilient to targeted metabolic therapies. More aggressive malignancies will likely require a combination approach of dietary manipulation and drugs targetting key metabolic targets in line with what the tumour’s metabolic signature may dictate.
As I began listening to the talks, the main research challenges became eminently clear.
Firstly, we need to continue to learn about the bioenergetic plasticity of cancer in general. We have established that mitochondrial function and respiration play fundamental roles in the development and progression of cancer. The main challenges here are noted below numerically and although of major importance as a primary substrate for most cancers, its not all about the glucose:
1. Many malignancies have been shown to be able to utilise not only glucose, but also glutamine for generating cellular energy and provide metabolic building blocks to proliferate.
2. As stated, many cancers generate most of their cellular energy via mitochondrial respiration and oxidative phosphorylation (OxPhos). Glutamine is the preferred substrate for OxPhos in tumour cells.
3. Cancer cells are remarkably adaptable at using different substrates for fuel. They can even use metabolic substrates donated by ‘stromal cells’ for cellular energy generation via OxPhos. Stromal cells are present in the tumour microenvironment and are not necessarily malignant themselves but can provide the tumour with substrates it needs to keep growing.
4. Bioenergetic plasticity of cancer is a major consideration if we want to attempt to predict, understand and monitor a metabolic approach to treating cancer more effectively.
See below a poster displaying an outline of the work various research groups are undertaking as part of the TRANSMIT project:
How might we achieve this:
1. By targeting metabolic enzymes and coenzymes
2. Learning more about metabolic features of cancer cells in general. This can help us with therapeutic efficacy testing and biomarker discovery.
Primary aims that I could see from this research:
1. Help to overcome chemoresistance
2. Come up with metabolic intervention strategies.
3. Better understand the role of the mitochondria in cancer initiation and progression.
4. Understanding of metabolic signatures of tumours that may respond to the ketogenic diet or specific nutrient deprivation diets.
Dietary and drug strategies covered:
1. An energy restricted ketogenic diet. (high fat, low carb, adequate protein)
Most cancer cells thrive on glucose as major energy source and partly posess dysfunctional mitochondria leading to a reduced ability to metabolise fat. This approach is being studied as an adjunct to the standard of care. It may reduce tumour growth and prolong survival.
2. Amino acid deprivation diets.
- Glutamine (protein restriction, temporary inhibition of enzymes involed likely more suitable)
- Methionine, cysteine
3. Fasting and diets that mimic a fasted state.
4. Drugs and drug targets
- Glutaminase inhibitors as a major target for the majority of cancers. For brain cancer perhaps more important in neuroblastoma (considered a real glutamine hog) and tumours that use up glutamine as the primary or major fuel alongside glucose as major substrates.
- Tryptophan degrading enzymes (overcoming tumour immune resistance)
- Citrin blockers- citrin is upregulated in multiple cancers.
- Targeting other novel metabolic pathways (aspartate, folate, serine, sapienate)
- Dichloroacetate (DCA)- PDK inhibitor (Pyruvate dehydrogenase kinase)- mitochondrial enzyme activated in a variety of cancers. Pyrimidine biosynthesis and growth of SDH (Succinate dehydrogenase) deficient cells is also inhibited by this drug.
- Biguanides and Kinase Inhibitors (KI)- induce opposing effects on key metabolic pathways that fuel cancer (eg. inhibition of mTOR. MTOR regulates mRNA translation initiation).
Areas of focus: TRANSMIT
1. Cancer bioenergetics of different tumours.
I have MR Spectroscopy, for example, and we can identify different metabolic signatures pertaining to different types of brain tumour fairly accurately from this. There may be some problems looking at areas where there is brain damage however, showing false positive results as you may see high signalling activity. It can sometimes be difficult to differentiate between malignant activity and areas of brain damage.
2. How metabolic factors influence how cancer cells adapt to survive and proliferate could identify mitochondrial metabolic biomarkers for characterising the transformation from benign to cancer cells.
What TRANSMIT is working on more specifically:
-Metabolic reprogramming of cancer cells- ie coordination of glutaminolysis and glycolysis.
- Work with cancer cell models, metabolic intervention strategies.
- Improve our understanding of cancer pathology.
- Understanding the role of fumarate hydratase in tumorigenesis.
- The mitochondrial complex 1 driven regulation of the hypoxic response in cancer cells.
- Identifying coenzymes in cancer cells.
