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Ref Type Journal Article
PMID (32376656)
Authors Narasimhan V, Wright JA, Churchill M, Wang T, Rosati R, Lannagan TRM, Vrbanac L, Richardson AB, Kobayashi H, Price T, Tye GXY, Marker J, Hewett PJ, Flood MP, Pereira S, Whitney GA, Michael M, Tie J, Mukherjee S, Grandori C, Heriot AG, Worthley DL, Ramsay RG, Woods SL
Title Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy.
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PTEN Y174H missense unknown PTEN Y174H lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). Y174H has been identified in the scientific literature (PMID: 32376656), but has not been biochemically characterized and therefore, its effect on Pten protein function is unknown (PubMed, Dec 2023).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA N1044K colorectal cancer predicted - sensitive Alpelisib Preclinical - Patient cell culture Actionable In a preclinical study, Piqray (alpelisib) inhibited cell proliferation in a patient-derived colorectal cancer organoid harboring PIK3CA N1044K, along with KRAS G12D, in culture (PMID: 32376656). 32376656
PIK3CA N1068Kfs*5 PTEN Y174H PTEN K263* colorectal cancer predicted - sensitive Alpelisib Preclinical - Patient cell culture Actionable In a preclinical study, Piqray (alpelisib) inhibited cell proliferation in a patient-derived colorectal cancer organoid harboring PIK3CA N1068Kfs*5, PTEN Y174H, and PTEN K263* in culture (PMID: 32376656). 32376656
PTEN Y174H PTEN K263* colorectal cancer predicted - sensitive Rucaparib Preclinical - Patient cell culture Actionable In a preclinical study, Rubraca (rucaparib) inhibited cell proliferation in a patient-derived colorectal cancer organoids harboring PTEN Y174H and K263*, along with PIK3CA N1068fs, in culture (PMID: 32376656). 32376656
PIK3CA N1044K colorectal cancer predicted - sensitive Taselisib Preclinical - Patient cell culture Actionable In a preclinical study, Taselisib (GDC-0032) inhibited cell proliferation in a patient-derived colorectal cancer organoid harboring PIK3CA N1044K, along with KRAS G12D, in culture (PMID: 32376656). 32376656
PIK3CA N1044K colorectal cancer predicted - sensitive MK2206 Preclinical - Patient cell culture Actionable In a preclinical study, MK2206 inhibited cell proliferation in a patient-derived colorectal cancer organoid harboring PIK3CA N1044K, along with KRAS G12D, in culture (PMID: 32376656). 32376656
PTEN Y174H PTEN K263* colorectal cancer predicted - sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, Lynparza (olaparib) inhibited cell proliferation in a patient-derived colorectal cancer organoid harboring PTEN Y174H and K263*, along with PIK3CA N1068fs, in culture (PMID: 32376656). 32376656
PIK3CA N1068Kfs*5 PTEN Y174H PTEN K263* colorectal cancer predicted - sensitive Taselisib Preclinical - Patient cell culture Actionable In a preclinical study, Taselisib (GDC-0032) inhibited cell proliferation in a patient-derived colorectal cancer organoid harboring PIK3CA N1068Kfs*5, PTEN Y174H, and PTEN K263* in culture (PMID: 32376656). 32376656