Midtveisevaluering - Ida Sofie Grønningsæter

ABSTRAKT

Cellular metabolism as a therapeutic target in AML

Oxidative phosphorylation is a highly efficient metabolic pathway, that generates more adenosine triphosphate (ATP) compared to alternative fermentation processes such as glycolysis. While normal cells, in the presence of oxygen, generally rely on oxidative phosphorylation to generate ATP for energy, cancer cells are more dependent on alternative metabolic pathways, mainly glycolysis (the so- called Warburg effect) as an energy source. Why cancer cells prefer other, less energy efficient metabolic pathways than oxidative phosphorylation is still not fully understood, but it is widely accepted that the cancer cells´ ability to alter their energetics in order to meet the metabolic demands of rapid proliferation and survive stressful conditions is crucial for cancer development, and alterations to cellular metabolism is today recognized as one of the hallmarks of cancer. The main metabolic pathways used by cells to gain energy, besides oxidative phosphorylation and glycolysis, are glutaminolysis, fatty acid β-oxidation, the pentose phosphate pathway and the lactate synthesis pathways. The dependency of cancer cells on a specific metabolic pathway to gain energy may be a targetable vulnerability in cancer cells that can be exploited when generating new therapeutic approaches.

Acute myeloid leukemia (AML) is an aggressive blood cancer, with a poor overall survival. It is characterized by abnormal clonal differentiation in the bone marrow, resulting in impaired hematopoiesis and bone marrow failure. Although AML is the most common acute leukemia among adults, it is a relatively rare disease, with an incidence (3 per 100,000) that increases with age. This reflects on the poor prognosis, since most elderly patients cannot receive curative treatment, and will only get an attempt on stabilizing treatment. These patients will normally only survive 2-6 months. Other reasons for the poor survival of patients are due to refractory disease and disease relapse. AML  is a heterogeneous disease, both with regards to morphology, growth characteristics, epigenetics and cytogenetics. Cytogenetics is also commonly used to divide AML into subtypes, and may predict response to treatment. Treatment and prognosis vary among different AML patient subgroups. A few studies have recently shown that leukemia cells with certain cytogenetics may rely on specific metabolic routes for their growth and survival. Our hypothesis is that certain AML patient subgroups have common metabolic characteristics, and these AML subgroups may either have a more extensive adaptive capacity, or some AML subgroups may be more sensitive towards metabolic-targeting drugs. Our aim is that this project will provide knowledge about the metabolism of AML cell populations to reveal potential metabolic drug targets, so it may be possible to stratify the patients according to their metabolic phenotypes/capacities which may in turn serve as a common therapeutic target.