Personalized Chemotherapy Profiling Using Cancer Cell Lines from Selectable Mice

Abstract

Purpose High-throughput chemosensitivity testing of low-passage cancer cell lines can be used to prioritize agents for personalized chemotherapy. However, generating cell lines from primary cancers is difficult, because contaminating stromal cells overgrow the malignant cells. Experimental Design We produced a series of hypoxanthine phosphoribosyl transferase (hprt)-null immunodeficient mice. During growth of human cancers in these mice, hprt-null murine stromal cells replace their human counterparts. Results Pancreatic and ovarian cancers explanted from these mice were grown in selection media to produce pure human cancer cell lines. We screened one cell line with a 3,131-drug panel and identified seventy-seven FDA approved drugs with activity, including two novel drugs to which the cell line was uniquely sensitive. Xenografts of this carcinoma were selectively responsive to both drugs. Conclusion Chemotherapy can be personalized using patient-specific cell lines derived in biochemically selectable mice.

Ovarian and cervical cancer patient derived xenografts: The past, present, and future

“…There is interest in personalizing chemotherapy for ovarian cancer patients through the creation of cell lines from PDX tumors for ex vivo modeling [66]. Improvement in dissociation techniques can make these ex vivo models more reliable because the current mechanical and enzymatic methods may sensitize the cells to apoptosis and may destroy the cell surface molecules [10,67].…”

The genetic classification of pancreatic neoplasia

“…In addition, PDAs with microsatellite instability, on the basis of experience with colorectal cancers with microsatellite instability, are less likely to be sensitive to 5-fluorouracil than are microsatellite-stable pancreatic cancers [67]. Primary tumor xenografts may help to test the effect of multiple therapeutic agents on a patient's tumor in order to individualize the drug regimen for that patient, thereby avoiding unnecessary side effects from ineffective drugs administered [68].…”

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

“…Despite tremendous advancements in our understanding of the initiation and progression of pancreatic cancer from premalignant precursor lesions to fully invasive and systemically metastatic disease states on the molecular level, progress in identifying and clinically exploiting novel targets for therapeutic intervention has been hampered by the sheer complexity (with each pancreatic cancer cell carrying on average more than 60 mutations) and intra- as well as interindividual variability in the patterns of genetic alterations underlying pancreatic carcinogenesis [1,6,7]. Another boost in target discovery and translational research came from recent advancements in relevant preclinical in vitro and in vivo model systems of pancreatic cancer, including advanced xenografts models, genetically engineered murine model systems as well as low-passage cell lines, three-dimensional cell cultures, and ex vivo and organoid models [8,9,10,11,12,13,14,15,16,17,18,19,20,21]. …”