2nd Annual Meeting of the International Society of Cancer Metabolism (ISCaM)

av Ellin-Kristina Hillert, 16 - 19 september 2015

I attended the 2nd annual meeting of the International Society of Cancer Metabolism (ISCaM) on the topic of Metabolism and Microenvironment in Cancer Plasticity from the 16th to the 19th September 2015.

The topic of metabolism has only recently become relevant to my research project, as we have discovered that the b-AP15 molecule and its derivatives (VLX1570), whose mechanism of anti-cancer activity I am investigating, may impact the mitochondria of cancer cells. The drug is therefore one of the many different approaches currently being developed that specifically target the altered metabolism of cancer cells in order to produce more effective treatments.

The conference itself consists of over 60 different talks, several of which were highly interesting. For example two talks concerned the possible repurposing of existing drugs to be used to aid in cancer treatment.

Michael Lisanti from the Centre for Cellular Metabolism in Manchester spoke about the possibility of using existing antibiotics such as doxycycline, which are already FDA-approved, to target the mitochondria of cancer cells. This is a possibility since the mitochondria of eukaryotic cells evolved from bacteria and still share several of their characteristics, which can be exploited by using antibiotics. The antibiotics would inhibit mitochondrial protein translation, which has been shown to be essential for cancer stem cell propagation and may be responsible for driving tumor recurrence.

On a similar note Michael Pollak from the Department of Oncology at McGill University in Quebec spoke about repurposing drugs currently used in the treatment of diabetes for treatment of cancer. Primarily the biguanide drug metformin had previously been shown to have antineoplastic activity. This is due to biguanides inhibiting oxidative phosphorylation at complex I in the mitochondrial electron transport chain, and inhibits gluconeogenesis in the liver. However high dosage would be required, making cancer treatment with metformin most suitable for liver, GI and GU tract cancers, which would be exposed to the highest dosage of treatment due to the circulation and excretion process of the drug. The drug’s effect on the cancer itself may have to do with a reduced amount of available insulin, leading to energetic crisis in the cells, which are often highly addicted to glucose. This may have cytostatic or cytotoxic effects, depending on the cell type.

Another interesting talk, and an approach to cancer metabolism I had not previously been aware of, was the presentation by Paolo Sassone-Corsi from the Centre of Epigenetics and Metabolism at the University of California. His keynote lecture concerned the circadian rhythm and its influence on transcription/translation, metabolism and by proxy also cancer. A body’s circadian rhythm has the task of adapting the organism to the time of day, guided by an intricate transcription-translation system utilizing epigenetics. This allows the organism to adapt to nutritional input and metabolic fluctuations. Examples included restricted feeding of mice, which was shown to phase shift the circadian gene expression of the liver, ultimately changing hepatic metabolism. Not only does enforcing a different circadian rhythm alter metabolism, but it also increased the incidence of cancer in SCID mice, indicating that further investigating this angle on metabolism and cancer may provide critical insights into novel approaches on cancer treatment and metabolic disorders.

Stefano Indraccolo’s talk on resistance to antiangiogenic therapies in cancer was of personal interest to me, since I have previously worked with angiogenesis and VEGF signaling in tissue engineering. A common treatment for cancer is to inhibit the VEGF receptor in an attempt to slow or stop tumor growth by preventing angiogenesis. However, Prof. Indraccolo’s research has shown that tumor cells with highly glycolytic metabolism can confer resistance to this treatment, which will ultimately select for glycolytic tumour cells not susceptible to VEGF blockade, shifting the metabolism of the tumor. This example of tumor metabolic plasticity is and indication of the need for more options in cancer treatment targeting the metabolism.

Additionally there was a lot of talk about what the Lisanti group called the “Reverse Warburg Effect” where the cells in the surrounding tumor stroma are the ones undergoing glycolysis to produce high energy metabolites, such as lactate, that feed the cancer cells’ oxidative metabolism. The metabolites are then imported into cancer cells by the monocarboxylate transporter 1 (MCT1), allowing them to produce more ATP and become more aggressive. Since cancer cells in this kind of metabolic state are engaging in OXPHOS, and not in glycolysis like a lot of other cancer cells, they may be more susceptible to mitochondrial targeting, such as by our prospective drug VLX1570, which we believe to be more effective on more mitochondria-dependent cell lines.  Additionally I believe it be worth considering co-treatment with an inhibitor of glycolysis. Due to the metabolic plasticity of cancer cells, inhibiting glycolysis may shift them back towards engaging in oxidative phosphorylation, and may therefore also make them more susceptible to VLX1570.

In addition to the broad range of talks offered at this conference I had the chance to attend a lunch workshop with one of the guest speakers, Angela Otto, where we discussed the advantages and disadvantages of several viability assays used in laboratories. Having never used a viability assay before this information will undoubtedly be useful to me in the future.

Furthermore, attending this conference gave me that chance to present a poster of my research at my first international conference, over the course of three days. This also gave me the opportunity to discuss my research and with my peers from different backgrounds, which has given me new insights and ideas about my project.

Finally, being such a small conference, it gave me the chance to network and make new contacts, making attending this meeting a very enriching experience for me.