Abstract
If you are a toxicologist practicing in the pharmaceutical industry, especially if you are immersed in or even in juxtaposition to cancer therapeutics developments, make certain that you have access to the book, if you don’t already have your own copy. If you are a toxicologist who is not attracted to the book because of its title, you might want to flip your curiosity switch and examine the book, especially chapter 6, “Toxicogenomics—A Drug Development Perspective.”
By scientific text standards, the book is small with only 190 pages; but don’t be misled by its size to think it will be a quick read. The 3 editors led 18 other scientists, all but 4 being from companies that either develop and sell pharmaceuticals or provide products and services for biomarker and pharmaceutical developments. By flipping your curiosity switch, you will think you have flipped a light switch! The book contains a perspective of drug development that may be different from your current understanding of drug discovery and development.
The book is divided into 7 chapters; the first, as would be expected, is the introduction and overview of the total treatment. However, more than an overview of the text, it is a clear description of what the exact title of the chapter conveys: “Application of Translational Science to Clinical Development.” In the first chapter, the authors show how genomic biomarkers aid in the drug discovery process by describing how they identify patient subsets and aid in dose selection. Also, the authors point out that adverse drug reactions (ADRs), which are primarily rooted in dose, result in Emergency Department admissions, unnecessary hospital stays, and provide the basis for which drugs are withdrawn from the market. Consequently, managing doses for an individual patient has both clinical and economic benefits, especially when ADRs extract large socioeconomic tolls. Although the chapter is not written specifically for toxicologists, it is difficult to envision dose management for patients without an almost mandatory contribution of toxicology that goes beyond a head nod.
The therapeutic arena in which genomic biomarkers have shown the greatest success for delivering personalized medicines to the patient has been cancer therapy. The reasons for genomic biomarker success in developing drugs for cancer therapies are many, but history will likely show that Personalized Medicine is the most productive application. Therefore, it is appropriate and natural that the second chapter of the book, “Personalized Health Care (PHC) in Cancer” immediately follows the introduction and overview. However, the 3-way convergence of delivering medicine to specific individuals, genomic biomarkers, and cancer treatments within the book is not limited to the second chapter.
The fifth chapter, entitled “microRNA Biomarkers as Potential Diagnostic Markers for Cancer” which speaks to the identification of cancer so that therapies can be implemented, seems to be out of place and would make more sense if it immediately followed chapter 2. Furthermore, the flow of the “2.2 Biomarkers” discussion would serve as a perfect introduction to chapter 5. Separation of the 2 chapters that are focused on diagnostics, therapeutic development, and the patient-specific selection of a treatment is a missed opportunity to reinforce the intimate relationship between genomic biomarkers for therapy and companion diagnostics for the therapeutic agents.
Three other chapters that have a therapeutic focus are personalized treatment for autoimmune diseases (chapter 3), asthma therapy (chapter 4), and translating biomarker discovery into companion diagnostics to partner with the therapeutic agent (chapter 7). Chapter 6, “Toxicogenomics—A Drug Development Perspective” constitutes only 16% of the book, but it will be the most usable and most interesting for all types of practicing toxicologists. Of the 3 chapter 6 authors, 3 have published a comprehensive review on toxicogenomics, giving them credibility and authority. 1
The toxicogenomics chapter begins with an important concept: an increasing amount of money is being spent on developing candidate drugs, while the number of approved drugs has remained constant. Intuitively, the reader would likely agree with the general tenet that costs are increasing and the number of approved drugs is not. However, the authors use data from the Food and Drug Administration, which only speaks to those drugs approved in the United States, while costs are total global expenses for drug development. Using the number of drugs approved in the United States within the context of the total costs in world to develop a drug is inartful at best. The conclusion is likely correct, but it is based on an inappropriate comparison of wrongly selected data. One would expect a glaring error of this magnitude to be avoided in a scholarly text.
The chapter has 9 major subsections and covers topics such as the technology that serves as a foundation for toxicogenomics and how toxicogenomics is used in drug discovery and development, including regulatory integration of toxicogenomics into other applications of genomics. The authors also address the technical challenges facing toxicogenomics, publicly available toxicogenomics databases, and management of the vast amounts of data and information that are being and will be generated in future toxicogenomics programs.
The authors point out that the relationship between genomic biomarkers in drug development and toxicogenomics biomarkers used in toxicity assessments is not seamless. There is a stark contrast between the clear emphasis in cancer therapies and genomic biomarkers use and toxicity biomarkers that are used for identifying target organ toxicity. The purpose or focus of the 2 types of biomarkers is different. Genomic biomarkers, that is therapeutic biomarkers, are focused on individualized or personalized medicine for cancer therapeutic agents, while the greatest focus and emphasis for toxicity biomarkers is centered on drug-induced liver injury or more commonly known as DILI.
With further explorations into the chapter, it becomes apparent that it is not a literary masterpiece. Some sentences defy comprehension and with 3 readings, it would not be surprising for a reader to end up with 4 ideas of what the chapter authors likely meant, for example, “As a marriage of data-rich omics approaches with bioinformatics, toxicogenomics requires expertise from diverse fields ranging from toxicology, genetics, and molecular biology to computational science and bioinformatics [16-18],” the “[16-18]” are reference numbers. There seems to be the circular argument that bioinformatics is an implied contributor of data for toxicogenomics which then requires bioinformatics to do an ill-defined activity once the toxicogenomics data are developed. A sentence has to be more than a string of words, the first one being capitalized and last one followed by a period.
Less than clear prose and a shallow, tech-talk treatment of the topic is not useful information for the toxicologists, for example: “Toxicogenomics is a field of science that studies toxicology with genomics and other high-throughput molecular technologies and bioinformatics [11],” again the number in the bracket is a reference number. The chapter concludes with a comprehensive and current list of 259 references that has extensive redemptive value for the chapter’s prose. However, one could argue that the reference list will go stale quickly and that with electronic capability for literature searching, the usefulness of the reference list evaporates.
The book has value for toxicologists within the pharmaceutical industry. Even if the pharmaceutical toxicologist’s professional environment does not currently focus on genomic biomarkers, this book will keep those toxicologists ahead of the genomic-based pharmaceutical development knowledge curve. This is especially true for those toxicologists in companies that have a focus on products, discovery programs, and product developments for personalized medicine. For toxicologists outside the pharmaceutical industry, the book provides background information on genomic-based biomolecules through casual reading. If a nonpharmaceutical toxicologist has a compelling reason to become knowledgeable of the genomics approach for personalized medicine, the book will be adequate and fulfill that purpose.
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