Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a significant health issue. For most patients, there are no options for targeted therapy, and existing treatments are limited by toxicity. The HOPE trial (Harnessing Organoids for PErsonalized Therapy) was a pilot feasibility trial aiming to prospectively generate patient-derived organoids (PDO) from patients with PDAC and test their drug sensitivity and correlation with clinical outcomes. Experimental Design: PDOs were established from a heterogeneous population of patients with PDAC including both basal and classical PDAC subtypes. Results: A method for classifying PDOs as sensitive or resistant to chemotherapy regimens was developed to predict the clinical outcome of patients. Drug sensitivity testing on PDOs correlated with clinical responses to treatment in individual patients. Conclusions: These data support the investigation of PDOs to guide treatment in prospective interventional trials in PDAC.

Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring

“…Our own initial findings using monotypic organoid cultures indicate that we may benefit from, including multiple readouts in PDO drug sensitivity and resistance testing. Other groups use a variety of readouts, but the number of organoids and matched patient responses are too low to draw conclusions about the impact of assay parameters on predicting/guiding personalized treatments [51,[53][54][55]64]. Clearly, we must continue to test and validate organoids as a predictive platform for clinical efficacy.…”

“…Similarly, Sharick et al [63] found that drug screening results matched clinical data for all of the patients (7/7 PDOs) in their study. Grossman et al found concordance between the ex vivo responses of at least one anticancer agent and the clinical treatment regimen in 12/12 cases [55]. In a study comparing organoids from patients who were administered FOLFIRINOX in the neoadjuvant setting to organoids derived from treatment-naïve patients, the ex vivo PDO responses to FOLFIRINOX were weak/absent in 5 of 5 cases of the neoadjuvant-treated group and robust in 4/5 of the treatment-naïve cases [64].…”

“…Of these patients, six had a greater PFS than historical controls, and organoids from these patients responded well to at least one of the tested drugs, while two PDOs resistant to all tested drugs mirrored clinical treatment resistance [51]. The Muthuswamy and Hidalgo groups described a 96-well-based PDO DSRT platform in which organoids established from both primary tumor tissue and metastases from 12 PDAC patients were tested for responses to several anticancer agents and compared to clinical responses [55]. The authors documented promising concordance between the most or least active single agents classified in two tiers by dose-response area-under-the-curve (AUC).…”

“…This discrepancy was also evident when inspecting the organoids under microscope (Figure 2D). Organoids are being explored as potential predictive functional assay platforms to guide precision medicine for pancreatic cancer patients [51,[53][54][55]64]. The number of studies assessing clinical responses in both patients and organoids is rising but is still too small to draw conclusions about the robustness and reliability of organoids as predictive tests.…”

Overcome Drug Resistance in Cholangiocarcinoma: New Insight Into Mechanisms and Refining the Preclinical Experiment Models

“…This makes PDO and PDX models become a hot area of research. Several studies have already reported that PDOs can be used to predict responses in cancer patient in the clinic ( 159 , 160 ). The model that uses the PDO model to conduct high-throughput drug screening and further confirm the response to agents in PDX seems to be promising in facilitating personalized medicine.…”