A Patient-Centric Approach to Advance Functional Precision Oncology

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT The development of drug resistance is a major cause of cancer treatment failure and mortality. Although much is known about the mechanisms by which tumor cells can become resistant to a given drug, translating this into effective therapeutic solutions remains an unmet clinical need. Here we propose to pioneer the use of patient derived tumor organoids (PDTOs) as a platform to identify and validate novel targets and effective drugs to overcome drug resistance in ovarian cancer, pancreatic cancer, and other tumor types. In our preliminary studies, we show that PDTOs genetically and phenotypically match the tumor from which they were derived and can be used to study the phenotypic consequences of tumor heterogeneity, tumor evolution, and drug resistance. Using a Clinical Laboratory Improvement Amendments (CLIA) approved high complexity assay, we show that PDTO drug sensitivities are highly concordant with known genetic biomarkers, retrospective treatment history and prospective patient responses. Tumor organoids derived from patients who developed in situ drug resistance demonstrate ex vivo resistance to those same drugs but also demonstrate sensitivity to other alternative oncology drugs. Additional preliminary studies show stable disease or tumor regression in patients treated with drugs identified from organoid drug screens. Here, we propose to combine drug screening and molecular profiling of PDTOs derived from a given patient from different anatomic tumor sites and before and after therapy to elucidate the mechanistic basis for drug sensitivity or resistance and to identify novel targets and effective drugs to treat metastatic, drug resistant cancers. Accompanying computational prediction models that integrate large public datasets as well as innovative methods of mechanistic target validation including CRISPR, targeted protein degradation technologies, and epigenetic profiling, will be used to prioritize and advance targets and associated biomarkers with greatest clinical potential. The rationale behind our approach is that identifying targets and effective drugs directly in patient derived samples with known clinical history and outcomes will significantly enhance translation of our findings. This proposal is significant because it will demonstrate the utility of PDTOs as both a research tool for target discovery and validation but also as a clinically useful platform to guide functional precision medicine. The findings and methods developed can be readily applied to other cancer types and clinical challenges, will accelerate preclinical drug and drug target development, and will translate to clinical studies. The models, approaches, and expected outcomes of this proposal are highly responsive to the requirements of PAR-21-274.