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Bioengineered Lung Tumor Organoids For Development Of Personalized Medicine

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? DESCRIPTION (provided by applicant):Lung cancer affects a large number of people in the U.S. with very poor long-term prognosis. Non-small cell carcinoma of the lung (NSCLC) is no longer a single disease, but a constellation of cancer types pathologically classified by histology which respond differently to drugs. As a consequence, personalized/precision oncology is proposed as a standard clinical practice for NSCLC and other cancers treatment. This practice, whereby tumor DNA is sequenced to identify actionable gene mutations, is dependent on the availability of sufficient amounts of intact tumor cell DNA, and creates a need to develop a high fidelity process of tissue biopsy retrieval, processing and analysis. However, there are no uniform methods to address this need and very small and low-purity tumors, such as microscopic metastases of the lung and fine-needle aspirate (FNA) biopsies, present an inherent challenge in obtaining cancer cell-specific DNA, and thus may preclude patients from the benefits of precision medicine. Alternatively, expansion of biopsy-derived cells could address this problem. This proposal is motivated by the critical need to understand to what extent the process of cell expansion from tumor biopsy may negatively influence downstream molecular and cellular analyses - influences that, at best, are difficult to detect and remove. Cancer research in general, and specifically expansion of primary cancer cells, still relies on standard cell culture techniques that use plastic dishes; thus, presenting the cells with artificia culture conditions that impose a selective pressure on the cells that could substantially alter their original molecular properties. We hypothesize that by recapitulating the in vivo lung microenvironment we will be able to successfully expand a small number of freshly isolated lung cancer cells in vitro, while preserving their cellular and genetic phenotype, including their mutational profile. To test this hypothesis we propose to bioprint bioengineered lung organoids (BLOs), consisting of lung endothelial and fibroblastic cells, embedded inside lung-specific extracellular matrix (ECM), and expand lung tumor cells inside lung tumor organoids (BLTOs). Future developments may include patient-specific BLTOs as surrogates for testing the efficiency of the personalized treatments and BLTOs may also be used to elucidate new/novel mechanisms of tumor growth and invasion and identify new therapeutic targets.
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