Ex vivo drug testing with patient derived tumor cells for translational research.

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Cancer patients have benefited from both genetic screening and the development of targeted therapies. However, there is a clear need for more accurate tumor models and clinically useful assays to help identify potential treatment options for patients who fail standard therapies and/or who lack actionable biomarkers. Patient-derived tumor cells cultured as organoids or tumor slices can help fill the gap between molecular understanding of cancer and the identification of patient specific therapies because they share most genomic and biologic features of the tumors from which they were derived and can be subjected to functional assays, including drug sensitivity testing. We have developed a CLIA (Clinical Laboratory Improvement Amendments)- approved assay, termed PARIS (Personalized, Aimed, Robotic, Informatics, Sequenced), that can prescreen up to 120 FDA approved oncology drugs or drug combinations directly on patient derived tumor organoids (PDTOs) to rank drugs from lowest to highest efficacy. The PARIS assay is highly actionable and, in a clinically relevant time frame, can identify at least one drug with exceptional tumor cell killing activity in >85% of patient samples tested to date. Because many anticancer drugs also act through the tumor microenvironment, we have also developed a tumor slice culture (TSC) platform that preserves tumor tissue architecture and allows the study of the impact of the tumor microenvironment, including immune and stromal cells, on drug response. Combined use of PDTOs and TSCs will reveal both tumor cell intrinsic and microenvironmental contributions to drug sensitivity. Our objective in this project to Enhance Applicability of Mammalian Models for Translational Research (PAR-24-306) is to use these patient derived tumor models to understand drug resistance and identify strategies to treat drug resistant disease. We will focus on pancreatic ductal adenocarcinoma (PDAC) and metastatic colorectal cancer (mCRC) because these are common cancers with limited treatment options and poor prognosis and fresh tumor tissue can be readily accessed during surgical resection. In Aim 1 we will use PDTOs to study patient specific mechanisms of drug resistance and identify novel therapeutic strategies. In Aim 2 will use TSCs from the same patients to determine the role of the TME on drug response and identify drug combination strategies to treat drug resistant disease.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE The outcome for patients with pancreatic cancer and metastatic colorectal cancer remains poor. We propose that testing drugs directly on patient’s tumor cells cultured outside the body will improve the ability to match the right drug to the right patient. We will obtain tumors from surgical resections and keep them alive as individual tumor cells and as tumor slices and test approved and experimental oncology drugs in order to understand and overcome drug resistant disease.