Multidrug Analyses In Cancer Patients Via Intratumoral Microdosing With Civo: A Functional Approach To Precision Oncology

Abstract The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intra-tumor heterogeneity, interpatient diversity, and complex interactions between tumor cells and the surrounding microenvironment. Attempts to model this complexity through the use of ex vivo systems have failed to accurately represent tumor biology, and resulting predictions of clinical drug efficacy have met with limited success. The era of genomics, highlighted by remarkable advances in high-throughput next generation sequencing technology, has sparked hope that this issue can be solved through a precision medicine approach to cancer treatment: matching the right drugs to the right patients. However, despite a few noteworthy successes pairing targeted agents with oncogenic driver mutations, genome-based precision medicine has been limited by an incomplete understanding of the relationship between cancer mutations and drug responsiveness. To overcome these issues, we developed CIVO (Comparative In Vivo Oncology), an arrayed microinjection technology that evaluates tumor responsiveness to microdoses of multiple drugs simultaneously and directly in a patient's tumor. CIVO consists of a multidrug injection device, fluorescent tracking microspheres which accurately denote the position of each drug injection site, and automated image analysis tools capable of quantifying both tumor cell and microenvironmental biomarkers of response to local drug exposure. Here we present preliminary data on the first 4 patients from our clinical feasibility study in soft tissue sarcoma. No unexpected adverse events related to microdose injection were observed. Consistent with historical clinical data, front line agent doxorubicin induced localized increases in markers for DNA damage, tumor cell apoptosis, and macrophage infiltration, whereas gemcitabine did not induce any observable local responses. Doxorubicin also induced tumor cell responses that suggest potential mechanisms of resistance to single agent therapy, including upregulation of PDGFαR and ERK phosphorylation. Multidrug investigation via intratumoral microinjection with CIVO in patients with soft tissue sarcoma appears safe and feasible. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors across a diverse immune competent patient population provides an innovative and exciting functional approach to complement current precision oncology strategies and enables deep characterization of cancer biology in early drug development. Citation Format: Matthew J. Thompson, Darin J. Davidson, Jessica A. Bertout, Kimberly H. Sottero, Marc O. Grenley, Emily Beirne, Richard A. Klinghoffer, Seth M. Pollack. Multidrug analyses in cancer patients via intratumoral microdosing with CIVO: A functional approach to precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT142.