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Advances in molecular biology have provided a better understanding of the complex cellular pathways that are critical to tumor formation and growth. Laboratory-based assays that can detect biologically relevant molecular alterations in tumor samples, including immunohistochemistry, in situ hybridization, DNA sequencing, gene expression, and epigenetic profiling, have informed the development of new classes of anticancer drugs that target aberrantly expressed molecular pathways. Compared with conventional cytotoxic chemotherapy, molecular targeted agents may offer greater tumor selectivity and different patterns of toxicity as the alterations they target are more common in, or in some cases exclusive to, tumors compared with normal tissues (see Chap. 17, Sec. 17.2). Biomarkers are increasingly used to aid in the selection of patients likely to respond to a particular class of molecular targeted agent and in some cases to identify mechanisms of resistance upon disease progression. Identifying patients likely to benefit is paramount, as targeted therapies comprise a rapidly expanding proportion of health care expenditures with new drugs routinely priced at more than $100,000 per year. Decisions to integrate these agents into routine cancer care must often weigh factors such as clinical benefit, toxicity, quality of life, and treatment cost for their practical application (Schnipper et al, 2016). This chapter will focus on the preclinical development and clinical application of molecular targeted agents and highlight the biologic basis of these therapies.

19.1.1 Preclinical Development of Targeted Agents

The preclinical development of targeted anticancer agents relies heavily on the identification and modulation of cell surface (eg, HER2) or intracellular (eg, PI3K) proteins whose function is altered or essential in malignancy. Various laboratory techniques including next generation sequencing (NGS), protein identification (eg, IHC), and functional genomic screens (eg, RNAi, CRISPR), are used to identify and characterize putative therapeutic targets.

Preclinical testing evaluates initially the biologic activity of novel agents in vitro using human (or sometimes animal) 2-dimensional (eg, cancer cell monolayers) or 3-dimensional (eg, organoids) cell cultures (Dhandapani and Goldman, 2017). The model systems used are selected typically based on their expression of a drug target(s) or tissue of interest, as well as ease of growth or manipulation. Although these models can validate pharmacologic and anticancer (eg, cytotoxic or antiproliferative) effects, as well as provide insights into predictors of drug sensitivity, in vitro systems are limited in their ability to model antitumor activity.

Animal models of human disease represent the de facto standard for preclinical evaluation of anticancer compounds before human testing, yielding important information on tumor response, pharmacokinetics, toxicity, and therapeutic indices. Mouse models of cancer are widely used to evaluate the in vivo efficacy of anticancer drugs. Murine and human cancer xenograft models are described further in Chapter 17, Section 17.4.2. These in vivo systems can recapitulate tumor biology, physiology, and microenvironmental effects to varying degrees but still have limitations as a result of cross-species ...

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