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Powering Off Cancer

June 9, 2017, by Costas Lyssiotis

Costas Lyssiotis, Assistant Professor at the University of Michigan.

Costas Lyssiotis is an Assistant Professor at the University of Michigan with appointments in the Departments of Physiology and Medicine. Research in the @LyssiotisLab is focused on understanding the biochemical pathways and metabolic requirements that enable tumor growth in Kras-driven pancreatic cancer, and translating those findings into new cancer therapies.

Cancer cells survive and grow according to their own schedule, while managing to survive in inhospitable environments under immune cell attack. The associated survival and growth processes are metabolically demanding. Renewed interest in this concept has led to important discoveries about the ways that cancer cells are powered. On-going studies now hope to leverage these insights to turn the power off on cancer.

In principle, this idea is not new. In fact, its origin is nearly 100 years old and is based on the observation that, relative to normal cells, cancer cells avidly consume glucose and metabolize it without using oxygen. Today we know this phenomenon as the Warburg Effect. However, even in Warburg’s time, this observation presented a bit of a conundrum. Productive glucose metabolism was thought to require oxygen metabolism in mitochondria, the cell's power source. This led Warburg to believe that cancer was somehow a disease of damaged mitochondria.

A century later, we now know that mitochondria are so vital that cancer cells cannot grow without them. The role of mitochondria in cancer extends well beyond their classical role of making the bioenergetic currency ATP. Mitochondria are also the primary source of the basic building blocks from which lipids, nucleotides, and proteins are derived.1 Recent insights reveal that mitochondria can regulate cell signaling and gene expression by tuning the rates of metabolic reactions.2

Building from this logic, if we were able to shut down the mitochondria, could we not power down cancer cells? This, of course, is the mechanism by which cyanide and other poisons act. Which brings us to the biggest challenge: can we power down cancer cells without killing healthy cells? Indeed, emerging data from numerous preclinical studies illustrate that targeting mitochondria may be a new and powerful approach to treat cancer.

Like all cellular functions in cancer, utilization and dependence on mitochondrial processes varies by cell/tissue of origin, genetic background, and ‘stemness’. Several recent studies have revealed contexts in which targeting the mitochondria is uniquely efficacious. This research highlights themes that are now being elaborated upon to determine the most effective means to harness mitochondrial-targeted therapies in cancer. These ideas and therapies are just now being tested in patients and hopes are high.

For example, metformin, one of the most widely prescribed drugs in the United States, is a mitochondrial inhibitor. Metformin is used by millions of Americans to manage blood glucose levels in type 2 diabetes. Intriguingly, recent retrospective epidemiological studies have suggested that people on metformin have a reduced incidence of many different types of cancer.3 For this reason, and our evolving understanding of the role of mitochondria in cancer, there is significant interest in the repurposing of metformin for cancer therapy. Preclinical and clinical studies testing the utility of metformin, however, have been mixed and difficult to interpret. This almost certainly owes to its pharmacological properties. Outside of the liver, where it acts to regulate blood glucose, metformin is not widely tissue penetrant. Exceptions include renal (e.g. kidney, bladder) and gastrointestinal (e.g. intestine, colon) cell types, which express the machinery to import metformin. The more promising results with metformin have been in the diseases of these organs. Importantly, this has helped to focus where metformin may ultimately have clinical utility.

Given the constraints imposed by tissue penetrance, metformin analogs with greater availability are now also being explored in cancer. For example, in BRAF mutant melanoma models, treatment with the tissue-penetrant metformin analog phenformin synergized with BRAF pathway inhibitors to regress established tumors. The synergistic activity owed in part to the targeting of slow cycling cells by phenformin. These exciting studies have prompted clinical trials with phenformin (Clinical Trial ID: NCT03026517).

In cell culture-based studies, where metformin can be delivered at a concentration that penetrates cells, metformin exhibits selective toxicity to cells with ‘stem cell’ properties. These cells tend to be more metabolically quiescent and rely on mitochondrial oxidation for bioenergetics. These observations are consistent with the mechanism of metformin and its analogs, which inhibit complex I of the electron transport chain, the machinery that makes ATP.

The antibiotic doxycycline has also been found to target cancer cells that are more dependent on the mitochondria. The utility of doxycycline as an antibiotic is derived from its ability to inhibit bacterial protein biosynthesis. Mitochondria are believed to have evolved from bacteria that were engulfed by and adapted to live symbiotically within a host cell. Accordingly, mitochondria have their own protein biosynthesis machinery. These share homology with bacterial ribosomes, including the ability to be inhibited by antibiotics like doxycycline, albeit at higher doses. In fact, doxycycline is one of the safest and most effective antimicrobials, and efforts are now on-going to develop more potent drugs designed around doxycycline for cancer therapy.5

Beyond repurposing efforts with well-known drugs, more recent work is now being done to develop and implement new mitochondrial inhibitors for cancer therapy. For example, a study in pancreatic cancer revealed that cells sensitive to treatment with chemotherapy use a non-mitochondrial metabolic pathway, glycolysis, to generate energy.6 In contrast, the chemotherapy-resistant cells are uniquely dependent on mitochondrial energy production, and, accordingly, highly susceptible to death by mitochondrial inhibition. Furthermore, it was found that the cells which remained after tumor debulking exhibited tumor initiating capacity and were responsible for disease relapse. In mouse models of pancreatic cancer, tumor debulking led to initial shrinking, which was later accompanied by disease relapse. In contrast, while treatment with an inhibitor of mitochondrial energy production alone had no discernible effect, the combination eliminated tumors and prevented relapse in the majority of animals.

The mitochondrial inhibitor oligomycin was used in these studies. It is much more potent than metformin and doxycycline, and for the same reason, it is not safe for use in humans. Based on these studies, a new, potent and safe inhibitor of mitochondrial bioenergetics, IACS-010759, was developed. Initial studies with this drug showed it to be highly effective and easier to dose in preclinical blood cancer models.7 IACS-010579 is now being tested in phase I clinical trials (Clinical Trial ID: NCT02882321). Promising results in these trials would open the door to testing mitochondrial inhibitors against residual disease, like the pancreatic cancer stem cells described above.

Insights into mitochondrial metabolism in cancer have revealed safe drugs that are being repurposed for cancer. Such insights have also provided new drug targets and the impetus to design cancer metabolism-based targeted therapeutics. It will be exciting to see if these methods to block mitochondrial metabolism can safely and effectively power down cancer.

Selected References
  1. Vander Heiden MG, DeBerardinis RJ, Cell 168 657 (2017); PubMed

    [PubMed Abstract]
  2. Chandel NS, Cell Metab 22 204 (2015); PubMed

    [PubMed Abstract]
  3. Klil-Drori AJ, et al., Nat Rev Clin Oncol 14 85 (2017); PubMed

    [PubMed Abstract]
  4. Eniu A, et al.,  ESMO Open 1 e000030 (2016); PubMed

    [PubMed Abstract]
  5. Peiris-Pagès M, et al., Oncoscience. 2015 Aug 24;2 696 (2015); PubMed

    [PubMed Abstract]
  6. Viale A, et al., Nature 514 628 (2014) PubMed

    [PubMed Abstract]
  7. Molina JR, et al., Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics (2015); https://tinyurl.com/y9nojnp4

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