Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy

Abstract

Purpose: Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.Experimental Design: CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.Results: Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.Conclusions: Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Patient-Derived Cancer Organoids as Predictors of Treatment Response

“…One patient received vandetanib (pan-tyrosine-kinase inhibitor) which strongly reduced organoid viability, however no clinical response was observed. For another patient, gemcitabine showed an initial partial clinical response but after two additional months of treatment, disease progression was again observed ( 26 ). Peritoneal CRC-metastases organoids were also treated for efficacy towards mitomycin C and oxaliplatin (commonly used in HIPEC; intra-peritoneal chemotherapy treatment) and showed a general resistance, corresponding with the high recurrence rates observed in clinic ( 19 ).…”

Patient-derived organoids as a predictive biomarker for treatment response in cancer patients

“…The AUC of a DRC, which combines the potency and efficacy of a drug, is a robust parameter when aiming to compare one agent across multiple tissue lines exposed to the same concentration range and may be more accurate than IC 50 (50% inhibitory concentration) 24,25 . Lastly, for combination treatment two approaches were used to define in vitro response: analysing each agent separately for a combined response classification 19,21,23,26,27 or analysing the response to combination treatment directly in vitro 17,20,21,[26][27][28][29][30][31][32] . The CinClare trial and de Witte et al report evidence of synergism for combination treatment 26,32 .…”

“…The studies were heterogeneous, varying in study design, patient population and treatments (Table 1). All studies were observational, with the exception of the APOLLO trial which was the first study to offer patients assay-guided treatment 28 . The results encompassed a variety of tumour types and stages of disease.…”

“…Colorectal cancer (CRC) studies were the most frequent among the publications (5/17) and also the largest in patient cohort size 21,22,26,28,29 . Many studies (7/17) derived PDOs from patients with metastatic disease 11,14,18,20,21,28,30 . Lastly, the treatments examined included systemic chemotherapy, targeted therapy, (chemo)radiation and immunotherapy.…”

A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

“…Another study in pancreatic cancer supported this notion and showed that organoids, although primarily clonal, maintain distinct patient phenotypes and respond differently to drug combinations 9 . Patient-derived pancreatic cancer or colorectal cancer organoids are now being used to predict therapeutic responses, and facilitate precision medicine for patients 10, 11 . PDO or PDX-derived organoids (PDxO) have also been described for hepatocellular carcinoma 12 , hepatoblastoma 13 and glioblastoma 14 , as well as prostate 15, 16 ; bladder 17 ; ovarian 18–19 ; breast 20 ; gastric 21 ; lung 22, 23 ; esophageal 24 ; kidney 25 ; and head and neck 26, 27 cancers.…”