ABSTRACT
Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established â¼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
Subject(s)
Antineoplastic Agents/therapeutic use , High-Throughput Screening Assays/methods , Neoplasms/drug therapy , Xenograft Model Antitumor Assays/methods , Animals , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Pancreatic Ductal/drug therapy , Colorectal Neoplasms/drug therapy , Disease Models, Animal , Female , Humans , Lung Neoplasms/drug therapy , Melanoma/drug therapy , Mice , Neoplasm Transplantation , Pancreatic Neoplasms/drug therapy , Reproducibility of Results , Skin Neoplasms/drug therapy , Stomach Neoplasms/drug therapyABSTRACT
Efficient tissue-specific delivery is a crucial factor in the successful development of therapeutic oligonucleotides. Screening for novel delivery methods with unique tissue-homing properties requires a rapid, sensitive, flexible and unbiased technique able to visualize the in vivo biodistribution of these oligonucleotides. Here, we present whole body scanning PCR, a platform that relies on the local extraction of tissues from a mouse whole body section followed by the conversion of target-specific qPCR signals into an image. This platform was designed to be compatible with a novel RT-qPCR assay for the detection of siRNAs and with an assay suitable for the detection of heavily chemically modified oligonucleotides, which we termed Chemical-Ligation qPCR (CL-qPCR). In addition to this, the platform can also be used to investigate the global expression of endogenous mRNAs and non-coding RNAs. Incorporation of other detection systems, such as aptamers, could even further expand the use of this technology.
