Cancer metabolism: From basic biochemistry to clinical opportunities

Targeting metabolism is a hot topic in cancer drug discovery. The central dogma is that key metabolic requirements of cancer cells (energy production and biomass production) are altered to allow rapid proliferation. This metabolic reprogramming is a potential target for novel anticancer drugs. However, although the abnormal energy metabolism of cancer cells was discovered almost 100 years ago, no such drugs are currently in clinical use - both due to insufficient efficacy and off-target toxicities. The aim of this project was to bring this class of drugs closer to clinical practice by exploring how cancer cells have turned textbook biochemistry into a surprisingly treatment-resistant network of metabolic abnormalities. In addition, we aimed to identify metabolic "soft spots" that can be targeted with novel drugs, thereby improving both clinical efficacy and safety margins. Using magnetic resonance spectroscopy, we explored why specific metabolic pathways are important for cancer cells, and how the cells respond to pharmacological challenges. Furthermore, evaluated relationships between the metabolic and metastatic properties of cancer cells. The project has suggested novel approaches for inhibiting metastatic spread of tumors by inhibiting core metabolic processes. We have already demonstrated how a pro-metastatic protein (S100A4) has a direct impact on tumor metabolism by reducing mitochondrial and increasing the cells' dependency on glycolysis. In this project, we have demonstrated how NMR metabolic profiling can predict the presence of metastases from primary melanoma xenografts. In some melanomas, hypoxia drives metastasis. In addition, hypoxia impacts the tumor microenvironment and the metabolic profile. We have identified metabolic fingerprints that can predict whether or not a primary melanoma xenograft has metastasized to regional lymph nodes or not. We also studied the metabolic enzyme cPLA2. This enzyme is interesting as it is involved in choline metabolism, which frequently is dysregulated in cancer. Furthermore, cPLA2 is involved in generation of lipid messenger molecules and thereby indirectly part of signal transduction cascades in the cell. We found that the cPLA2 inhibitor AVX235 (Avexxin AS) inhibits tumor growth by blocking angiogenesis, and that this happens through other mechanisms than VEGF-inhibiting drugs. The plasticity of cancer cells was studied in prostate cancer cells following treatment with OGT inhibitors in vitro. Here, we demonstrated how the cells' compensatory metabolic mechanisms rescue them from apoptosis when OGT is inhibited. By blocking also these compensatory mechanisms, the growth of the cancer cells were completely inhibited. Interestingly, aggressive subtypes of breast cancer also seem to be sensitive to OGT inhibition. We have also shown how breast cancer subtypes have different sensitivity to blockade of glutamine metabolism. By measuring how different tumor models utilize glutamine, we can contribute to explain why different patients respond differently to glutaminase inhibition. We have performed a study where NMR was used to pinpoint metabolic targets of estrogen stimulation in breast cancer. Interestingly, we identified the metabolic enzyme CHPT1 as a potential drug target, reducing both tumor growth and metastatic spread in an in vivo breast cancer model. However, CHPT1 is regulated by the oestrogen receptor. This makes it a potential drug target in hormone receptor positive breast cancer - but not in hormone receptor negative breast cancer. Finally, we have initiated studies to compare metabolism in metastatic and non-metastatic cancer cells. These studies aim to identify metabolic reactions required for metastatic disease. Current results indicate several potentially metastasis-specific metabolic reactions. The results from this project forms the basis for a new project, where we will use mass spectrometry to map metabolic characteristics in human breast cancer biopsies and look for associations between metabolic properties and patient outcomes.

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Targeting metabolism is a hot topic in cancer drug discovery. The central dogma is that key metabolic requirements of cancer cells (energy production and biomass production) are altered to allow rapid proliferation. Since most cancers converge to the same metabolic phenotype (high glucose consumption and activation of anabolic pathways) it is assumed that cancer can be treated by blocking key biosynthetic pathways. However, drugs targeting metabolism have still not reached clinical use. In this project, we aim to bring this class of drugs closer to clinical practice by exploring how cancer cells have turned textbook biochemistry into a surprisingly treatment-resistant network of metabolic abnormalities. Three topics will be addressed: First, we aim to clarify why some cancers are sensitive to metabolic inhibition whereas others are not. Using isotopically enriched substrates, we will map the associations between oncogenic signalling, flux through key metabolic pathways and response to metabolic inhibitors, thereby describing patterns of metabolic addiction. Second, we will follow up pilot studies indicating that cytosolic phospholipase A2 is a key target in breast cancer. This enzyme is involved in turnover of cell membrane phospholipids, but it also generates lipid messenger molecules. Inhibiting both signal transduction and anabolic metabolism with the same drug may be of great value in cancer therapy. Finally, we will study the interface between metastasis and metabolism. It is hypothesized that the metabolic phenotype contributes to the metastatic process. Inhibiting lactate production may therefore be a good approach for prevention of metastatic spread. Understanding why specific metabolic pathways are important for cancer cells, and translating this information to clinical practice is a key challenge in the project. If successful, our research will guide design of clinical trials and accelerate introduction of metabolic inhibitors to clinical practice.