Metabolism in Cancer by Thorsten Cramer & Clemens A. Schmitt

Author:Thorsten Cramer & Clemens A. Schmitt
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Keywords

Tumor resistanceRelapseCancer stem cellQuiescenceMetabolismMitochondriaOxidative phosphorylation

1 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 treatment of leukemia. By combining two effective cancer drugs having different mechanisms of action, these pioneers made history by curing their young patients, and the modern chemotherapy was born (Frei et al. 1965). Unfortunately, the path to sustained treatment response would not be so clear for all types of cancer, and the effects of chemotherapy on the majority of solid tumors were minimal due to intrinsic or acquired pleiotropic resistance, as will be further explored in this chapter.

While it was acknowledged early on that multiple factors might be responsible for treatment failure (Brockman 1963; Wilson et al. 2006; Holohan et al. 2013; Zahreddine and Borden 2013), it took until the 1980s before the first insights into the molecular mechanisms that could confer drug resistance were described. Seminal work by Victor Ling’s laboratory demonstrated that DNA transfer from resistant cells to sensitive cells could confer multidrug resistance (Debenham et al. 1982). Furthermore, they linked this phenomenon to a single gene, MDR1, which encodes the P-glycoprotein efflux pump (Riordan et al. 1985). It is now known that P-glycoprotein represents just one member of a large, 48-member family of ATP-dependent transporters, referred to as the ATP-binding cassette (ABC) family, which includes several other pumps known to be involved in the efflux of drugs (Gottesman 2002). Because overexpression of these transporters seemed to play a role in drug resistance, at least in vitro, for the majority of cancer types, significant effort was put in attempting to counteracting their activity and resensitizing cancer cells to chemotherapy. Promising preclinical results prompted a number of clinical trials in different indications and using different strategies (Persidis 1999). Despite positive outcomes in some trials, poor study design, a lack of information about target engagement, and lack of evidence of the impact that MDR1 inhibitors would have had on the pharmacokinetic properties of chemotherapeutic

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