Epigenetic Regulation of Cancer in Response to Chemotherapy

How cancer cells recover from chemotherapy and radiation exposure varies. By understanding how this occurs we could develop new means of preventing recovery, improving the response to therapy. It has been previously established that the epigenetic regulation of the genome plays prominent roles in recovery. Epigenetics contributes by establishing and promoting therapy tolerant cell states including stem cell phenotypes, diapause, quiescence, polyploidy, senescence and cytoprotective autophagy. By understanding how epigenetics establishes these states we can therapeutically intervene, suppress their benefits, and possibly prevent recovery. This topic was recently covered in a thematic volume of Advances in Cancer Research edited by VCU and VIMM members Drs. Landry, Das and Fisher. In this volume nine chapters cover important topics related to the epigenetic regulation of recovery from chemotherapy exposure. This volume will serve as a platform for the research community to learn about these phenomena, as well as for the editors to further their own research programs which study recovery.

Preface for Volume

Cancer treatments have evolved and improved significantly over the last 100 years. Over this time frame, therapies (combining surgery, chemotherapy, and/or radiation) have been conceived and validated resulting in significant increases in 5-year survival rates, and in some forms of cancer now being considered essentially curable (early-stage prostate, thyroid, testicular, melanoma, breast). However, despite improvements in cancer treatment, certain cancers, particularly those in advanced stages, remain challenging to treat. Traditionally, chemotherapy and radiation are the standard of care used to treat these advanced cancers, with significantly reduced 5-year survival rates. Relapse, months to years after initial treatment, is a significant contributor to the reduced survival rates for these advanced cancers. How relapse occurs remains a significant clinical problem and it will continue to be a major focus of the cancer research community.

After several decades of intensive research, it is now appreciated that cancer relapse after initial treatment is multifaceted and can occur by many different resistance and tolerance mechanisms. Resistance mechanisms can result from cancer cells acquiring an ability to render therapies ineffective (i.e., cellular quiescence), whereas tolerance mechanisms allow improved recovery from therapy-induced damage after exposure (i.e., cytoprotective forms of autophagy). The underlying molecular basis of these mechanisms can be either genetic, through changes in the DNA sequence, or epigenetic, which results in changes in gene expression. A distinct difference between these two mechanisms is that genetic changes are acquired through mutations, which are permanent, whereas epigenetic changes endure through cellular division, and in many (but not all) cases are reversible.



Over the last several decades, our understanding of epigenetic regulatory mechanisms in both normal development and disease states, especially cancer, has expanded. Many of these mechanisms operate at the level of chromatin to regulate gene expression (i.e., histone-modifying enzymes), or can operate to regulate mRNA transcript stability (i.e., miRNAs). At the most basic level, epigenetic changes alter gene expression to change cellular responses. In the context of acquired resistance, cancer cells can acquire epigenetic changes that render them more resistant to therapy exposure or can make them better able to recover postexposure. Because epigenetic mechanisms are reversible (in the majority of cases), and are created by enzymes with active sites, these changes can in theory be targeted by small molecules to restore the original ground state of gene expression. With this strategy in mind, small molecules that target epigenetic targets (epi-drugs) can be used to alter the ability of cancer cells to be sensitized to or recover from therapy exposure. A wide variety of epigenetic regulators has been targeted successfully either genetically or pharmacologically (when small molecule inhibitors exist) in preclinical studies to alter the sensitivity or resistance to therapy exposure. Some of these strategies have been proven to have efficacy in a clinic setting.

In this thematic volume of Advances in Cancer Research entitled “Epigenetic Regulation of Cancer in Response to Chemotherapy,” the editors asked nine leaders in the field of cancer epigenetics to share their views on how epigenetics can alter the cancer cell response to therapy, and how epigenetics can be targeted to improve responses to therapy.

Chapters in this Volume:

Chapter One - The epigenome and the many facets of cancer drug tolerance

Chapter Two - Epigenetically programmed resistance to chemo- and immuno-therapies

Chapter Three - Targeting epigenetic regulation for cancer therapy using small molecule inhibitors

Chapter Four - Histone deacetylase inhibitors as sanguine epitherapeutics against the deadliest lung cancer

Chapter Five - From ecology to oncology: To understand cancer stem cell dormancy, ask a Brine shrimp Artemia

Chapter Six - Multi-CpG linear regression models to accurately predict paclitaxel and docetaxel activity in cancer cell lines

Chapter Seven - Epigenetic adaptations in drug-tolerant tumor cells

Chapter Eight - The epigenetic regulation of cancer cell recovery from therapy exposure and its implications as a novel therapeutic strategy for preventing disease recurrence

Chapter Nine - Targeting the super elongation complex for oncogenic transcription driven tumor malignancies: Progress in structure, mechanisms and small molecular inhibitor discovery

Funding Sources

The editors would like to recognize support from the following sources; NIH/NCI through 1R01 CA244993 (Sarkar and Fisher), 1R01 CA259599 (Fisher and Wang); National Foundation for Cancer Research (Fisher); Commonwealth Health Research Board (Fisher); SRA from InVaMet Therapeutics, Inc. (IVMT) (Das); Thelma Newmeyer Corman Chair in Cancer Research (Fisher); Department of Human and Molecular Genetics developmental funds (Das); VCU Institute of Molecular Medicine (VIMM) developmental funds (Das, Fisher); and VCU Massey Cancer Center developmental funds (Fisher). DoD BCRP W81XWH1910489 (Landry), a Closing the Gap pilot grant from the Virginia Commonwealth University (VCU) Massey Cancer Center (Landry). In addition, we received internal funds and support from the VCU School of Medicine, the VCU Wright Center for Clinical and Translational Research (Landry).

Publications:

Landry JW, Das SK, Fisher PB. (Eds.). Epigenetic Regulation of Cancer in Response to Chemotherapy. Adv Cancer Res. 2023;1-421. DOI: 10.1016/S0065-230X(23)00035-0

Kumar A, Emdad L, Fisher PB, Das SK. Targeting epigenetic regulation for cancer therapy using small molecule inhibitors. Adv Cancer Res. 2023;158:73-161. PMID: 36990539. DOI: 10.1016/bs.acr.2023.01.001

Bacolod MD, Fisher PB, Barany F. Multi-CpG linear regression models to accurately predict paclitaxel and docetaxel activity in cancer cell lines. Adv Cancer Res. 2023;158:233-292. PMID: 36990534. DOI: 10.1016/bs.acr.2022.12.005

 Appiah C, Singh M, May L, Bakshi I, Vaidyanathan A, Dent P, Ginder G, Grant S, Bear H, Landry J. The Epigenetic Regulation of Cancer Cell Recovery from Therapy Exposure and its Implications as a Novel Therapeutic Strategy for Preventing Disease Recurrence. Adv Cancer Res. 2023;158:337-385. PMID: 36990536. DOI: 10.1016/bs.acr.2022.11.001

 About the Investigators:

Joseph Landry is Associate Professor of Human and Molecule Genetics, and a Member of the VIMM, VCU SOM. Swadesh K. Das is Associate Professor of Human and Molecular Genetics, and a Member of the VIMM, VCU SOM. Paul B. Fisher, MPh, PhD, FNAI, is Professor of Human and Molecular Genetics HMG, Director of the VCU Institute of Molecular Medicine VIMM and Thelma Newmeyer Corman Chair in Cancer Research in the VCU MCC, VCU SOM.