Targeting MET overexpression in colon and pancreatic cancers as identified through a novel PAThway-based RNA and DNA Integration with Tumor Organoid Testing (PATRIOT™) Platform
Background: The PATRIOT™ platform greatly advances precision medicine for cancer treatment. The PATRIOT™ platform analyzes unique mutational profiles using RNA DE and NGS pathway analysis. This approach progresses traditional methods by matching each patient's tumor characteristics with tailored therapeutic strategies. Patient tumor samples are grown into organoids and replicate tumors' heterogeneity and complexity to assess therapeutic responses. Drug screenings on these organoids give comprehensive examples of preclinical testing of selected therapies and how they would affect the patients. To assess PATRIOT™ workflow, we are testing the platform on MET-overexpressing colon and pancreatic cancers. Methods: Before PATRIOT™ analysis, patients received FOLFOX/FOLFIRINOX chemotherapy in clinic but developed resistance to these treatments. To verify organoid model viability, FOLFOX/FOLFIRINOX were tested on cultured organoids to confirm resistance. To validate predictive measures of PATRIOT™, two patients predicted with different levels of TACSTD2 were screened with TROP2 ADC. Western blots were performed to verify presence of MET in patient samples. 72-hour, 4-fold dilution drug screening is conducted on cultured organoids; high-quality control for all screenings. Crizotinib was tested in three replicates with a Cisplatin control. A combination drug screen of Crizotinib and Gemcitabine was assessed for pancreatic cancer patients. Cytotoxicity and Bliss Synergy were assessed using Combenefit and GraphPad Prism. Results: PATRIOT™ suggested Crizotinib as the drug for patients with MET overexpression. Our hypothesis was verified when the organoid models showed strong sensitivity towards Crizotinib This study demonstrates that PATRIOT™ is an excellent tool for identifying pathway-based therapeutic options, as shown through organoid testing.
