Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Background: Mammalian models of cancer have been instrumental in the development of many targeted therapies. It is, however, difficult to establish these models, such as patient-derived cell cultures (PDCC) and xenografts (PDX). As a result, most cancer types have only a limited number of models available, which do not accurately reflect the diversity of human cancer in real life. Innovation: The majority of the patient-derived models were developed using untreated primary samples with plenty of tumor tissue. The next challenge in tumor modeling will require much more difficult samples, such as minute residual tumor foci in a patient with a partial chemotherapy response. Even though cancer is a disease of unchecked cell growth in the body, normal cells paradoxically proliferate faster than malignant cells in cell culture. As a result, in the majority of PDCC models, the cancer cells eventually disappear. To address the issue of normal cell overgrowth, we are creating a tumor-specific medium (TSM) that suppresses normal cell proliferation. Preliminary data: As a proof-of-concept, we published twenty-five new ovarian cancer cell (OvCa) lines that retained the molecular, histologic, and outcome features of the patient tumors. Objectives: Our goal is to create innovative and simple culture methods that enable the creation of patient- derived cell cultures and PDX models and develop best practices for validating these models. Specific Aims: We are working on five major solid tumor types (lung, breast, prostate, kidney, and ovary) and a liquid tumor (leukemia) to illustrate that our system can be adapted to culture the full spectrum of tumor types. Aim 1: Patient-Derived Culture of Solid Tumors: We will establish patient-derived lung, breast, prostate, kidney, and ovary adenocarcinoma cultures and compare their molecular profiles with the original patient tumor. Aim 2) Patient-Derived Culture of Solid Tumors: We will establish patient-derived AML cultures and compare their molecular and phenotypic profiles with the original patient tumor. Research Strategy: We will compare the genome, transcriptome, and proteome of each cell line with the original patient tumor, existing cell lines, and tumor datasets. Innovation: By suppressing the expansion of normal stromal cells and normal epithelium, the TSM culture system can maintain cancer cell lines long-term without feeder layers, drugs, or extracts. Impact: Predicting drug activity in the clinic has always been difficult using traditional cultural models. Therefore, having access to biologically relevant lung, breast, prostate, kidney, ovary, and AML cell lines could revolutionize cancer drug development.
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