Cancer cachexia is one of the main causes of death among cancer patients with advanced metastatic tumors. Cachexia is characterized by a loss of body weight in general and muscle mass in particular that affects the patients’ strength and ability to tolerate anti-cancer treatment. From studies performed in animal models of cancer cachexia it has been known since the early 1990’s that ammonia levels in the blood is increased by more than 100% during cachexia (Chance, Zhang, Foley-Nelson, & Fischer, 1991), indeed administering ammonium salts to healthy animals induces cachexia-like symptoms, including loss of skeletal muscle mass (Chance, Zhang, Foley-Nelson, & Fischer, 1991). Furthermore, in 2010 it was shown that ammonia is a molecule capable of inducing autophagy in cell-based model systems (Eng, Yu, Lucas, White, & Abraham, 2010). From the same study it was concluded that the ammonia released to the medium is derived from glutaminolysis, a process in which glutamine is converted to α-ketoglutarate with the concomitant release of two ammonium molecules per molecule of glutamine, see fig 1.
Fig 1
Several types of cancer cells have been shown to rely heavily on the use of glutaminolysis (Wise & Thompson, 2010) in addition to their dependence on glucose. It has also been shown (Pavlides et al., 2010) (Martinez-Outschoorn et al., 2010) that tumor cells are capable of inducing autophagy in cancer associated fibroblasts (fibroblasts that are recruited to the tumor that are known to enhance tumor growth). This has led to hypothesis that tumors can promote their own survival and growth by extracting nutrients and energy from surrounding tissue. Cachexia would be the extreme case where metastatic tumors throughout the body are able to induce a systemic autophagic response, causing the degradation of skeletal muscle and other tissue. The autophagy in the surrounding tissue would promote the release of glutamine into the blood. That glutamine is in turn used by the tumor cells to fuel their growth, with the concomitant release of more ammonia and more autophagy induction, see figure 2.
Fig 2
Sprint Bioscience is currently pursuing two projects that target this vicious cycle of glutaminolysis and autophagy.
The first project is to develop an autophagy inhibitor by targeting the class III phosphatidylinositol 3 kinase Vps34. This protein is central to the signaling processes in autophagy activation (Lipinski et al., 2010). We have conducted a fragment screen against the human Vps34 kinase domain and solved co-crystal structures of the fragment hits in complex with Vps34. We have performed thermodynamic profiling of the fragment hits and are currently running a structure-based fragment expansion program. We have also shown activity in a cell-based model system for studying autophagy inhibition.
The other project targets the first step of glutaminolysis, the conversion of glutamine to glutamate catalyzed by the enzyme glutaminase. A number of fragment hits have been identified and thermodynamic profiling, crystallization and structure determination is currently ongoing.
References
- Chance, W., Zhang, F., Foley-Nelson, T., & Fischer, J. (1991). Hyperammonemia and anorexia in Morris hepatoma-bearing rats. Physiology & Behaviour, 50:397-401.
- Eng, C., Yu, K., Lucas, J., White, E., & Abraham, R. (2010). Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Science signaling, 3:ra31.
- Lipinski et al. & Yuan, J. (2010). A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions. Developmental Cell, 18:1041-1052.
- Martinez-Outschoorn, U. et al. & Lisanti, M. (2010). The autophagic tumor stroma model of cancer or “battery-operated tumor growth”: A simple solution to the autophagy paradox. Cell cycle, 9:4297-306.
- Pavlides, S. et al. & Lisanti, M. (2010). The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle, 9:3485-505.
- Wise, D., & Thompson, C. (2010). Glutamine addiction: a new therapeutic target in cancer. Trends in BIochemical Sciences, 35:427-33.
