Microorganospheres as a novel precision oncology platform in colorectal cancer.

Abstract

149 Background: Patient-derived organoids (PDO) have been shown to have a high degree of similarity to the original patient tumors. PDO have also been used to perform high throughput drug screens and shown to correlate with patient response to therapy. Unfortunately, PDO require too much tissue, take too long to establish and are too inefficient and costly for adoption into the clinic. The ideal assay for clinical use would be one that could be performed in less than14 days from a core biopsy to minimize delay in therapy. We have now circumvented these barriers by leveraging recent technological advances in emulsion microfluidics and droplet generators to develop MicroOrganoSpheres (MOS) that can be established and used to predict drug sensitivity within 14 days of obtaining a biopsy. Methods: 18-gauge core biopsy specimens from patients with colorectal cancer liver metastasis who subsequently received an oxaliplatin based therapy were first obtained. Biopsy specimens were minced, enzymatically digested and mixed with components necessary to generate MOS. The mixture was then processed through a custom fabricated flow-focusing droplet microfluidic chip in our MOS Generator Device to generate MOS. After culturing for 8-10 days, MOS were then used to perform drug screen with oxaliplatin. Results: A total of twelve CRC biopsies from liver metastasis were obtained and processed to generate MOS with a success rate of 12/12 (100%). Furthermore, drug screens with oxaliplatin were performed on all twelve samples with an average time to drug screen of 10.1 days. We next wanted to determine if there was a correlation between MOS drug sensitivity and patient clinical outcome (ie. time on treatment). For the first eight patients, MOS was used to predict sensitivity to oxaliplatin and using a drug sensitivity cut-off of 1 uM, four patients were predicted to be sensitive to oxaliplatin and four patients were predicted to be resistant. Three of the four patients predicted to be sensitive to oxaliplatin continue to be on treatment (> 6 months), whereas 3 of the four patients predicted to be resistant to oxaliplatin progressed on oxaliplatin based therapy within 8 weeks (sensitivity = 80%, specificity = 100%, positive predictive value = 100%, negative predictive value = 75%). Conclusions: MOS can be generated from core biopsies and correlates to time on treatment. Although further studies will need to be conducted, the ability to generate MOS and perform a drug screen in < 14 days will allow for the development of a precision oncology platform that can be rapidly used in the clinic to guide therapy.