Cancer Cell Metabolism And Drug Targets

Targeted cancer metabolic pathway anti-cancer drugs achieved great success in malignant cancer treatment, however, inevitably the effect of almost all these drugs is compromised by the development of resistance. Given that recent evidence shows cancer cell metabolic reprogramming occurs after drug treatment, probably, there is a strong relationship between a specific target and particular metabolic pathway remodeling. Understanding the hidden fact and mechanisms under cell metabolism modulated by specific drug targets (in particular those related to precision medicine) may lead to the development of new therapeutic strategies to overcome drug resistance.

This book illustrates various aspects of cancer cell metabolism, including metabolic regulation in solid tumours vs. non-solid tumours, the molecular pathways involved in its metabolism, and the role of the tumour microenvironment in the regulation of cancer cell metabolism. It summarizes the complexity of cancer cell metabolism in terms of the switch from anaerobic to aerobic glycolysis and how mitochondrial damage promotes aerobic glycolysis in cancer cells. The respective chapters provide the latest information on the metabolic remodelling of cancer cells and elucidate the important role of the signalling pathways in reprogramming of cancer cell metabolism. In addition, the book highlights the role of autophagy in cancer cell metabolism, and how metabolic crosstalk between cancer cells and cancer-associated fibroblasts promotes cancer cell progression. In closing, it summarizes recent advancements in drug development through targeting cancer metabolism.

In this volume, the major metabolic alterations identified in cancer and tumor-associated cells are explored, including discussions of former and emerging approaches to drug development in targeting cancer cell metabolism. The metabolic network in cells promotes the generation of both energy and biomass needed for them to grow, divide and differentiate. However, the metabolism of malignant cells generally varies from that of normal cells. These differences provide a platform for the discovery of new approaches to targeting potential vulnerabilities in cancer cells for therapeutic options Some of the significant changes that occur involve ATP production and consumption that modulates the ATP to ADP ratio, hypoxia and the effects of reactive oxygen species on glycolysis, regulation of mitochondrial respiration, induction and suppression of autophagy, and the Warburg effect and “reverse” Warburg effect--these topics and more are discussed in this volume.

Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.

This book illustrates various aspects of cancer cell metabolism, including metabolic regulation in solid tumours vs. non-solid tumours, the molecular pathways involved in its metabolism, and the role of the tumour microenvironment in the regulation of cancer cell metabolism. It summarizes the complexity of cancer cell metabolism in terms of the switch from anaerobic to aerobic glycolysis and how mitochondrial damage promotes aerobic glycolysis in cancer cells. The respective chapters provide the latest information on the metabolic remodelling of cancer cells and elucidate the important role of the signalling pathways in reprogramming of cancer cell metabolism. In addition, the book highlights the role of autophagy in cancer cell metabolism, and how metabolic crosstalk between cancer cells and cancer-associated fibroblasts promotes cancer cell progression. In closing, it summarizes recent advancements in drug development through targeting cancer metabolism.

Development of an effective anticancer therapeutic necessitates the selection of cancer-related or cancer-specific pathways or molecules that are sensitive to intervention. Several such critical yet sensitive molecular targets have been recognized, and their specific antagonists or inhibitors validated as potential therapeutics in preclinical models. Yet, majority of anticancer principles or therapeutics show limited success in the clinical translation. Thus, the need for the development of an effective therapeutic strategy persists.

“Altered energy metabolism” in cancer is one of the earliest known biochemical phenotypes which dates back to the early 20th century. The German scientist, Otto Warburg and his team (Warburg, Wind, Negelein 1926; Warburg, Wind, Negelein 1927) provided the first evidence that the glucose metabolism of cancer cells diverge from normal cells. This phenomenal discovery on deregulated glucose metabolism or cellular bioenergetics is frequently witnessed in majority of solid malignancies. Currently, the altered glucose metabolism is used in the clinical diagnosis of cancer through positron emission tomography (PET) imaging. Thus, the “deregulated bioenergetics” is a clinically relevant metabolic signature of cancer cells, hence recognized as one of the hallmarks of cancer (Hanahan and Weinberg 2011). Accumulating data unequivocally demonstrate that, besides cellular bioenergetics, cancer metabolism facilitates several cancer-related processes including metastasis, therapeutic resistance and so on. Recent reports also demonstrate the oncogenic regulation of glucose metabolism (e.g. glycolysis) indicating a functional link between neoplastic growth and cancer metabolism. Thus, cancer metabolism, which is already exploited in cancer diagnosis, remains an attractive target for therapeutic intervention as well. The Frontiers in Oncology Research Topic “Cancer Metabolism: Molecular Targeting and Implications for Therapy” emphases on recent advances in our understanding of metabolic reprogramming in cancer, and the recognition of key molecules for therapeutic targeting. Besides, the topic also deliberates the implications of metabolic targeting beyond the energy metabolism of cancer. The research topic integrates a series of reviews, mini-reviews and original research articles to share current perspectives on cancer metabolism, and to stimulate an open forum to discuss potential challenges and future directions of research necessary to develop effective anticancer strategies. Acknowledgment I sincerely thank the Frontiers for providing the opportunity and constant support throughout the process of this research topic and eBook production. I gratefully acknowledge all the authors for their valuable contributions. Finally, I would like to thank my brother, Saravana Kumar, G.K., whose personal sacrifices and unflinching encouragement made my career in science possible. References: Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: The next generation. Cell. 144(5):646-74. Warburg O, Wind F, Negelein E. 1926. Über den stoffwechsel der tumoren in körper. Klinische Wochenschrift. 5:829-32. Warburg O, Wind F, Negelein E. 1927. The metabolism of tumors in the body. J Gen Physiol. 8(6):519-30.

Autophagy and Metabolism: Potential Target for Cancer Therapy presents updates on autophagy in cancer metabolism and how it can be used to develop new, more efficient treatments. Written by experts in the field, the book presents recent research and explains how to translate it to the clinical setting. Sections discuss tumor cell metabolism and autophagy as therapeutic targets, autophagy regulation in cancer, signaling pathways in metabolic dysregulation in solid tumors, metabolic stress and cell death pathways, and the role of the tumor microenvironment. In addition, topics cover combined targeting autophagy, metabolism for cancer therapy, and the autophagy effect on immune cell metabolism. This will be a valuable resource for researchers, oncologists, graduate students, and members of the biomedical field who are interested in learning more about the interaction between autophagy and cancer metabolism. Presents valuable and updated information on the mechanisms of autophagy in cancer metabolism Discusses the various metabolic pathways linked with autophagy that can be a major target for chemotherapeutic strategies Explains how autophagy supports tumor growth by activating metabolic phenotypes in cancer cells and the therapeutic interventions available to halt the process