Periodic Reporting for period 2 - ONco-Energetics_OFF (Dissection of Bioenergetic Plasticity of Tumors)
Okres sprawozdawczy: 2021-09-01 do 2023-02-28
• What is the problem/issue being addressed?
Designing more effective and safer therapies for cancer relies on identifying how cancer cells differ from normal ones and then exploiting this knowledge to specifically kill cancer cells. One such important difference is cellular metabolism. Cancer cells differ from normal ones in their high need for energy and biomass to fuel their rapid growth rate. The early work of German scientist Otto Warburg in 1920s showed that cancer cells also differ in the way they meet these high metabolic demands. Two major energy producing pathways in the cells are termed Glycolysis and Oxidative Phosphorylation (OXPHOS). Warburg suggested that cancer cells have tendency to rely on glycolysis. This suggested that inhibiting glycolysis may be a viable strategy to specifically eliminate cancer cells. However, this strategy has had limited clinical success so far and a century later and despite considerable efforts, until now only handful drugs targeting this differences in energy production of cancer have made it to clinical testing. A potential reason for the limited success of glycolysis inhibition is that some cancer cells exhibit “metabolic flexibility” which refers to their ability to engage both glycolysis and OXPHOS to adapt to metabolic challenges and the local nutritional conditions in the microenvironment. However, very little is known about the molecular switches that coordinate this process. Those switches must sense different metabolic challenges and rapidly orchestrate switch among different metabolic pathways to guarantee maintaining energy production, a crucial process for survival. ONco-Energetics_OFF aims to identify those switches by dissecting the mechanisms of metabolic plasticity and further investigates the potential links with drug resistance and metastasis.
• Why is it important for society?
Cancer accounted for an estimated 9.6 million deaths in 2018. The financial costs of cancer are high for both cancer patients and for society as a whole, making it an economical problem as much as it is a health and social problem. Cancer is tightly linked to metabolism and lifestyle. Around one third of deaths from cancer are due to the leading behavioral and dietary risks: high body mass index, lack of physical activity, tobacco use, and alcohol use. Impaired metabolism, obesity, hyperglycemia and hyperinsulinemia have a role in cancer development, progression and prognosis, and indeed diabetic and obese patients have an increased risk of developing certain cancer subtypes. The project has a realistic and immediate potential for developing safe, effective and novel therapeutic approaches based on cancer metabolism to tackle the problem of cancer. The proposal also exploit repositioning drugs already clinically-approved for the new use in cancer, dramatically reducing the cost and enhancing chances for success. The proposal thus has the realistic potential to immediately impact on the healthcare and social sectors as well as the economy.
ONco-Energetics_OFF aims to unravel novel insights between metabolism and cancer and investigates potential links with drug resistance and metastasis, two most devastating processes in cancer management. This much needed knowledge will enable us to design, test and validate more refined therapeutic approaches for targeting cancer bioenergetics. The project thus offers realistic promises to deliver clinically relevant findings. Targeting metabolism can also be achieved through dietary intervention, adding to the attractiveness of this approach. Translational potential is illustrated by the initiated clinical trial based on data from the preparatory phase of this project.
• What are the overall objectives?
1-To identify the molecular signature of bioenergetic plasticity.
2-To analyse the contribution of metabolic crosstalk between tumor cell subpopulations to bioenergetic plasticity of tumors.
3-To examine the implications of bioenergetic plasticity in drug resistance and metastasis and to exploit the knowledge to design and validate therapeutic approaches targeting tumor metabolism
•
Designing more effective and safer therapies for cancer relies on identifying how cancer cells differ from normal ones and then exploiting this knowledge to specifically kill cancer cells. One such important difference is cellular metabolism. Cancer cells differ from normal ones in their high need for energy and biomass to fuel their rapid growth rate. The early work of German scientist Otto Warburg in 1920s showed that cancer cells also differ in the way they meet these high metabolic demands. Two major energy producing pathways in the cells are termed Glycolysis and Oxidative Phosphorylation (OXPHOS). Warburg suggested that cancer cells have tendency to rely on glycolysis. This suggested that inhibiting glycolysis may be a viable strategy to specifically eliminate cancer cells. However, this strategy has had limited clinical success so far and a century later and despite considerable efforts, until now only handful drugs targeting this differences in energy production of cancer have made it to clinical testing. A potential reason for the limited success of glycolysis inhibition is that some cancer cells exhibit “metabolic flexibility” which refers to their ability to engage both glycolysis and OXPHOS to adapt to metabolic challenges and the local nutritional conditions in the microenvironment. However, very little is known about the molecular switches that coordinate this process. Those switches must sense different metabolic challenges and rapidly orchestrate switch among different metabolic pathways to guarantee maintaining energy production, a crucial process for survival. ONco-Energetics_OFF aims to identify those switches by dissecting the mechanisms of metabolic plasticity and further investigates the potential links with drug resistance and metastasis.
• Why is it important for society?
Cancer accounted for an estimated 9.6 million deaths in 2018. The financial costs of cancer are high for both cancer patients and for society as a whole, making it an economical problem as much as it is a health and social problem. Cancer is tightly linked to metabolism and lifestyle. Around one third of deaths from cancer are due to the leading behavioral and dietary risks: high body mass index, lack of physical activity, tobacco use, and alcohol use. Impaired metabolism, obesity, hyperglycemia and hyperinsulinemia have a role in cancer development, progression and prognosis, and indeed diabetic and obese patients have an increased risk of developing certain cancer subtypes. The project has a realistic and immediate potential for developing safe, effective and novel therapeutic approaches based on cancer metabolism to tackle the problem of cancer. The proposal also exploit repositioning drugs already clinically-approved for the new use in cancer, dramatically reducing the cost and enhancing chances for success. The proposal thus has the realistic potential to immediately impact on the healthcare and social sectors as well as the economy.
ONco-Energetics_OFF aims to unravel novel insights between metabolism and cancer and investigates potential links with drug resistance and metastasis, two most devastating processes in cancer management. This much needed knowledge will enable us to design, test and validate more refined therapeutic approaches for targeting cancer bioenergetics. The project thus offers realistic promises to deliver clinically relevant findings. Targeting metabolism can also be achieved through dietary intervention, adding to the attractiveness of this approach. Translational potential is illustrated by the initiated clinical trial based on data from the preparatory phase of this project.
• What are the overall objectives?
1-To identify the molecular signature of bioenergetic plasticity.
2-To analyse the contribution of metabolic crosstalk between tumor cell subpopulations to bioenergetic plasticity of tumors.
3-To examine the implications of bioenergetic plasticity in drug resistance and metastasis and to exploit the knowledge to design and validate therapeutic approaches targeting tumor metabolism
•
Despite the challenges imposed by the COVID19 pandemic, most of the tasks outlined in the revised Description of the Action are being carried out in accordance with the time plan:
We have successfully completed the metabolic profiling of a wide panel of cancer cell lines and subjected them to further analysis that is expected to unravel candidate mediators of metabolic plasticity according to plan.
We unraveled unexpected links between biogenetic program of cancer cells and their migration properties, indicative for a link between metabolic program and metastatic potential.
We discovered several novel combinatorial approaches to target bioenergetics plasticity and are carrying on our planned investigation of potential roles for a protein called PP2A in mediating the tumor-restraining effects of these combinations.
We investigated the novel functions we discovered for the pro-survival protein Mcl-1 in the regulation of cellular metabolism and gained unprecedented insights. Mcl-1 is a protein frequently detected in high levels in tumors and has been shown to contribute to tumor progression and resistance to treatment. However, the tumor promoting functions of Mcl-1 have been mainly attributed to its role in impeding programmed cell death, a process triggered in cells to counteract malignant transformation. We discovered other unexpected functions for Mcl-1 cellular metabolism that contribute to its tumor-promoting functions and dissected the associated molecular mechanisms.
We have successfully completed the metabolic profiling of a wide panel of cancer cell lines and subjected them to further analysis that is expected to unravel candidate mediators of metabolic plasticity according to plan.
We unraveled unexpected links between biogenetic program of cancer cells and their migration properties, indicative for a link between metabolic program and metastatic potential.
We discovered several novel combinatorial approaches to target bioenergetics plasticity and are carrying on our planned investigation of potential roles for a protein called PP2A in mediating the tumor-restraining effects of these combinations.
We investigated the novel functions we discovered for the pro-survival protein Mcl-1 in the regulation of cellular metabolism and gained unprecedented insights. Mcl-1 is a protein frequently detected in high levels in tumors and has been shown to contribute to tumor progression and resistance to treatment. However, the tumor promoting functions of Mcl-1 have been mainly attributed to its role in impeding programmed cell death, a process triggered in cells to counteract malignant transformation. We discovered other unexpected functions for Mcl-1 cellular metabolism that contribute to its tumor-promoting functions and dissected the associated molecular mechanisms.
Very little is known about the mechanisms of metabolic plasticity. ONco-Energetics_OFF is (one of) first large-scale systematic study that will yield a comprehensive chart of bioenergetic adaptations of cancer cells and will identify associated molecular mechanisms and links to metastasis and drug resistance. This unprecedented understanding is much needed given that only handful drugs targeting tumor energetics are in clinical use so far. The insight gained will be a significant contribution to the field of tumor metabolism and cancer biology.
By its completion, the project is expected to have answered three key scientific questions:
1-Why some cancer cells are bioenergetically-plastic while others are committed? What are the differences in metabolic machineries and oncogenic switches between both?
2-How heterogeneous tumor cell subpopulations are in terms of bioenergetic plasticity? Does metabolic crosstalk contribute to bioenergetic plasticity of tumors?
3-What are the implications of bioenergetic plasticity in drug resistance and metastasis and finally how to design approaches to target this plasticity?
By its completion, the project is expected to have answered three key scientific questions:
1-Why some cancer cells are bioenergetically-plastic while others are committed? What are the differences in metabolic machineries and oncogenic switches between both?
2-How heterogeneous tumor cell subpopulations are in terms of bioenergetic plasticity? Does metabolic crosstalk contribute to bioenergetic plasticity of tumors?
3-What are the implications of bioenergetic plasticity in drug resistance and metastasis and finally how to design approaches to target this plasticity?