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The Cancer Metabolism Beachhead Expands with Metabolomics

inDrug Development

The beat marches on for cancer metabolism with many compelling results and the entrance of molecules into clinical trials. While cancer metabolism is traditionally viewed as a reprogramming of energy metabolism and metabolic pathways that support cell replication and growth, many investigators are realizing that the metabolic processes that allow a tumor to initiate and thrive are even broader than this.

This expanded view is not surprising when you imagine the plethora of adaptations that are required to support the entire life-cycle of cancer – from initiation, to progression, to metastasis. One can imagine the diversity of metabolic adaptations to be even greater considering the requirements for hundreds of different cancer types that are harbored (at least initially) within specific niches throughout the body.

Tumors require an expansive & extremely adaptable “toolbox” to thrive

Although energy metabolism reprogramming is a distinct hallmark of cancer, all 10 contemporary hallmarks actually require the engagement of metabolism at some level. I’d like to share several examples that support that.

Angiogenesis requires metabolic enzymes to initiate vessel sprouting; amino acid metabolism (arginine, tryptophan) is important for immune system evasion; and, a functional connection between mutant p53 and glycolytic enzymes is essential for enhanced replication. The fact that altered metabolism extends beyond energy metabolism reprogramming to other hallmarks was not always appreciated, but it is reflected in many publications in the last year or so.

Using a multi-omic approach that included Metabolon’s metabolomics technology, Jeff Settlemen’s lab at Genentech identified a “metabolic tumor suppressor” while exploring drug-acquired resistance mechanisms related to an elaborate cell biological process. Exploring this process (epithelial-mesenchymal transition) for unique metabolic features would not have traditionally been a first-line approach.

Another emerging, non-standard cancer metabolism front is the immune response. Cancer immunotherapy has produced impressive results and optimism that has not been seen within the oncology community since some of the first successful targeted therapies. A potentially important emerging adjunct for immunotherapy is the metabolism of the immune response.

In work at Harvard Medical School using our metabolomics technology and several additional lines of experimentation, Patsoukis and colleagues1 explored the biology of the two prominent immunotherapy targets PD1 and CTLA4. They illuminated distinct metabolic programs that may provide clues as to T-cell exhaustion and routes to bolster the immune response in immunotherapy.

Chang and colleagues showed that cancer cells can short-circuit the immune response in the local tumor environment by simply gorging themselves on the same substrate needed for a robust T-cell response.

Probably the most interesting intersection of cancer metabolism and immunity, however, arose in work by Zelenay and colleagues.  Here, cyclooxygenase 2 (COX2) – a metabolic enzyme not typically considered a “cancer metabolism” enzyme – was found to be important to immune response evasion. Inhibition of COX2 and a prominent immunotherapy target produced a synergistic effect in vitro and in vivo.

Besides the novel connection of COX2 to immune evasion, this result peaked our interest. In metabolomics work we did last year with researchers at Harvard Medical School, COX was uncovered as a driver of a rare neoplastic (cancer-like) disease – Lymphangioleiomyomatosis (LAM).  This finding, along with many other reports suggesting a reduction of risk of several cancers with COX inhibitors (e.g. aspirin), points to a potential rationale and that it may extend more broadly to different cancer types.

Striking Back with a Combination Approach

Cancer stem cells are another area not traditionally considered in cancer metabolism. In a most intriguing recent paper, however, investigators led by Kazuhito Naka of Kanazawa University in Japan used Metabolon’s technology to find that CML stem maintenance was supported through the accumulation of dipeptides via the upregulation of an oligo/dipeptide transporter. Combining an inhibitor to this transporter with a conventional tyrosine kinase inhibitor (TKI) produced a synergistic effect in vitro and in CML-affected mice. In addition, normal stem cells were insensitive to the transport inhibitor, suggesting high selectivity for this approach. Thus, metabolomics provided a signature that led to a novel combination approach for creating a more durable response in CML patients.

The above are just a brief summary of findings that suggest a growing expansion of the core cancer metabolism beachhead. Core cancer metabolism is still being vigorously explored and is producing important findings in the research setting. Potentially life-saving molecules are also moving into the clinic.

There is, in fact, so much exciting new data that it’s not easy to choose which examples to highlight. In closing, though, I think that a recent publication focused at the epicenter of traditional cancer metabolism merits a mention, though.

NOTCH1 is a key target in acute lymphoblastic leukemia (T-ALL). Using our metabolomics technology, followed by a host of additional experiments, Herranz and colleagues showed that glutaminolysis (a classic core cancer metabolism pathway) was a critical pathway downstream of NOTCH1. The combination of a glutaminase and NOTCH1 inhibitor showed strong synergistic anti-leukemic effects in vitro and in a patient-derived T-ALL mouse model. These results implicate glutaminolysis as a major metabolic feature controlled by NOTCH1 and as therapeutic target for treating T-ALL.

The genetic drivers of cancer should certainly be aggressively explored, but metabolomics – classic cancer metabolism and beyond – is also proving to be an important avenue for uncovering new treatment combinations. I expect that metabolomics will continue to add vital mechanistic insight into this highly diverse, mercurial disease.

For more information see

  1. Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.Nat Commun 6, 6692 (2015).
  2. Chang, C.H. et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 162, 1229-1241 (2015).
  3. Zelenay, S. et al. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. Cell 162, 1257-1270 (2015).
  4. Naka, K. et al. Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells. Nat Commun 6, 8039 (2015).
  5. Herranz, D. et al. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat Med21, 1182-1189 (2015).
  6. Sun, Y. et al. Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells. Cancer Metab 2, 20 (2014).
  7. Li, C. et al. Estradiol and mTORC2 Cooperate to Enhance Prostaglandin Biosynthesis and Tumorigenesis in TSC2-deficient LAM cells. The Journal of Experimental Medicine 211, 15-28 (2014).
  8. Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
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