Metabolic Features of Cancer Treatment Resistance
A major barrier to achieving durable remission and a definitive cure in oncology patients is the emergence of tumor resistance, a common outcome of different disease types, and independent from the therapeutic approach undertaken. In recent years, subpopu
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Abstract
A major barrier to achieving durable remission and a definitive cure in oncology patients is the emergence of tumor resistance, a common outcome of different disease types, and independent from the therapeutic approach undertaken. In recent years, subpopulations of slow-cycling cells endowed with enhanced tumorigenic potential and multidrug resistance have been isolated in different tumors, and mounting experimental evidence suggests these resistant cells are responsible for tumor relapse. An in-depth metabolic characterization of resistant tumor stem cells revealed that they rely more on mitochondrial respiration and less on glycolysis than other tumor cells, a finding that challenges the assumption that tumors have a primarily glycolytic metabolism and defective mitochondria. The demonstration of a metabolic program in resistant tumorigenic cells that may be present in the majority of tumors has important therapeutic implications and is a critical consideration as we address the challenge of identifying new vulnerabilities that might be exploited therapeutically. Keywords
Tumor resistance Relapse Cancer stem cell Mitochondria Oxidative phosphorylation
Quiescence Metabolism
A. Viale (&) G.F. Draetta Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA e-mail: [email protected] G.F. Draetta Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA © Springer International Publishing Switzerland 2016 T. Cramer and C.A. Schmitt (eds.), Metabolism in Cancer, Recent Results in Cancer Research 207, DOI 10.1007/978-3-319-42118-6_6
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A. Viale and G.F. Draetta
Overview of Tumor Resistance: Old Concepts and New Foes
One of the major challenges in clinical oncology is disease progression due to the resistance tumor cells eventually develop in response to pharmacological treatments. Indeed, it is well established in clinical practice that even the most impactful cancer therapies, with the notable exception of emerging immune checkpoint therapies, are doomed to fail after a transitory response. Ironically, it was this same problem of acquired drug resistance that inspired ground-breaking work some 50 years ago leading to the development of modern chemotherapy. In the 1940s, heroic pioneers in the field of clinical oncology, including Louis Goodman, Alfred Gilman, and Sidney Farber, observed extraordinary therapeutic results in children affected by Hodgkin’s lymphoma and acute lymphoblastic leukemia upon treatment with nitrogen mustard and aminopterin derivatives (Farber and Diamond 1948; Goodman et al. 1946). Sadly, their excitement was short-lived, and it soon became evident that their greater challenge was not achieving remission, but maintaining it. It would be nearly twenty years before Emil Freireich and Emil Frei would find an answer to overcome drug resistance by applying the principles learned by physicians using combined anti-bacterial therapy, to the treatmen
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