Use Of Fine Needle Aspirate Biopsy (Fnab) In Evaluating Drug Responses In Tumor Models: Better Data With Less Animal Use?.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC It is now accepted that the coordinated application of pharmacokinetics (PK) and pharmacodynamics (PD) provides a rational, efficient and informative approach to preclinical and clinical drug development. In clinical studies, core or aspirate biopsies are used normally for PK/PD evaluation. In contrast in the majority of preclinical studies whole tumor samples are collected for PK/PD studies requiring killing of animals at each time point and hence the use of large numbers of animals for such studies. For example to perform a single dose PK/PD experiment in this manner typically uses 20 animals (4 animals at each of 5 time points). In the present study we evaluated the use of FNAB for performing PK/PD studies in tumor bearing mice and rats. The technique involved collecting biopsies from tumors using a fine needle (21 or 25 G) and applying a negative pressure through use of a syringe attached to a Camego gun. The use of a fine needle allowed sampling of serial biopsies from mid-size (400 mm3) tumors. The biopsies contained enough tissue for analysis of biomarkers using one of several techniques (IHC, in situ hybridization, immunoassays or by RTPCR). Depending on the technique used for biomarker analysis compound levels could also be determined in the same biopsies using LC-MS/MS. PK evaluation in small blood samples (20 μL) collected from the tail vein at the same time as the biopsies also allowed determination of PK/PD relationship. Sampling of serial biopsies from mid-sized tumors using FNA allowed determination PK/PD using just 4 animals instead of the 20 typically used when whole tumors were collected for such studies. The data obtained using the two techniques were comparable for a number of different targets (e.g. PI3K and MEK inhibitors) in different tumor types. Potentially the use of FNAB instead of whole tumor sampling could increase the quality of the data since tissue from the same tumor is analyzed at different time points. Studies using a number of different tumors also showed that several biopsies can be collected through the course of an efficacy study (starting at about 200 mm3) without influencing the growth of tumors thus enabling longitudinal analysis of biomarkers/changes in tumors during such studies and potentially providing better PK/PD and efficacy relationship. In conclusion, use of FNAB technique to determine PK/PD responses can reduce animal use by up to 80% compared to a previous method. In addition the technique opens up the possibilities of more readily determining changes which are transient and performing longitudinal studies to evaluate changes leading to development of drug resistance or tumor heterogeneity without using large numbers of animals. Citation Format: Christian R. Schnell, Prakash Mistry, Julien Perdoux, Robert Cozens, Matthew Meyer, Tinya Abrams. Use of fine needle aspirate biopsy (FNAB) in evaluating drug responses in tumor models: Better data with less animal use? . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3370. doi:10.1158/1538-7445.AM2013-3370