Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	26	14	2020 07 15	3662-3670	Clin Cancer Res

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
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 N1068Kfs5 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 N1068Kfs5, PTEN Y174H, and PTEN K263 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
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 N1068Kfs5 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 N1068Kfs5, PTEN Y174H, and PTEN K263 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