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Cancer Therapeutics

Figure 15.2  Preclinical tumor models for precision oncology. Patient-derived xenografts (PDXs), tumor organoids, and conditionally reprogrammed low-passage tumor cultures can be initiated by transplantation of either surgical specimens or needle biopsies into severely immunocompromised mice (PDXs), or disaggregation of tumors in carefully defined culture media that facilitates the growth of tumor cells with stemlike qualities. These approaches provide low-passage tumor models for molecular characterization, target validation, and drug screening; all three model systems provide a closer approximation of in vivo tumor biology than previous large-scale cell line panels and can be adapted for in vivo imaging, pharmacodynamic studies, and “preclinical” clinical trials of novel targeted therapeutic agents or combinations. The techniques for separating large numbers of circulating tumor cells (CTCs) and cell-free tumor DNA (cfDNA) have progressed rapidly and now represent viable approaches for obtaining malignant tissue for DNA sequencing and/or pharmacodynamics to supplement biopsies of metastatic disease or when biopsy sampling is not practical. 2D, two-dimensional; 3D, three-dimensional.

of anticancer agents. 44 However, new in vivo models generated by transplantation of surgical or biopsy specimens of human tumors into severely immunocompromised NOD/SCID/IL2R  null (NSG) mice, denoted as patient-derived xenografts (PDXs) (see Fig. 15.2), have been developed over the past decade; altered natural killer cell maturation in thismouse strain improves engraftment rates (now aver- aging 50% to 60%) for many common solid tumors. 45,46 Importantly, early passage PDXs have been shown to retain histologic and genetic characteristics of the tumor of origin as well as therapeutic profiles consistent with these expression patterns. 47,48 Furthermore, recent studies have demonstrated the ability of PDX models used at scale to both validate known therapeutic targets and to confirm efficacy profiles appropriate for the drug classes investigated. 49 The context of the prior treatment profiles of the patients whose tumors were used to derive the PDXs can also be compared to results following expo- sure to the same drugs in PDX models. 50 DNA and RNA sequencing data from PDX tumors provide the opportunity to prospectively in- terrogate the role of specific mutational and expression profiles in the therapeutic activity of novel targeted agents in a histology-agnostic fashion. In this way, “preclinical” clinical trials using PDX models could accelerate the pace of cancer drug development. It is important to point out, however, that there are limitations associated with the use of PDX models to support a precision

offer the possibility of repeating mutational or protein-based mo- lecular profiles not only before (to determine a true baseline) but also during treatment, including at the time of disease progression, using small volumes of blood. 38,39 In this fashion, it is possible that examination of the molecular characteristics of a tumor, derived from multiple potential sites of disease, might provide a more comprehensive understanding of the heterogeneity of an individ- ual patient’s malignancy, facilitating treatment choice as well as understanding of the time- and therapy-related development of resistance pathways. 40,41 However, the concordance of NGS panel results from differing ctDNA analysis platforms has not yet been widely established, suggesting that additional efforts to standardize this approach will be required before it is widely adopted. 42,43

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PRECLINICAL MODELSTO INFORM PRECISION ONCOLOGY

Although useful for the evaluation of the therapeutic index of new anticancer drugs, mouse tumor xenografts derived by transplanting long-established human tumor cell lines (that have been adapted to cell culture on plastic for decades) into immunocompromised mice do not reproducibly predict the histologically specific efficacy