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Table 3 Precision treatment for targeted therapy using GIC PDOs

From: The pivotal application of patient-derived organoid biobanks for personalized treatment of gastrointestinal cancers

Cancer type

Target

Assay

Key findings

Ref.

CRC

EGFR, AKT, RAS, BRAF, Wnt, PI3K, IGF1R, ERBB

CTG

The activity of cetuximab in KRAS wild-type PDOs was the same as that in corresponding CRC patients. The effectiveness of Nutlin-3a was confirmed in TP53 wild-type PDOs.

[22]

CRC

MEK, mTOR, VEGFR, EGFR

CTG

Linking drug sensitivity patterns and molecular profiles with based on PDOs identify new biomarkers to predict specific drug sensitivity in CRC.

[26]

CRC

EGFR, MEK, CRAF, VEGFR, mTORC1/2, PI3K, RTK

CTG

Drug screening in multiple subpopulations of organoids from the same CRC patient helps to improve the outcome of patients in clinic for its better understanding of intra-tumoral heterogeneity in drug response.

[28]

CRC

MEK

DAPI/PI staining

MEK inhibition increased Wnt activity, and stemness- and cancer relapse- associated gene signatures, revealing a side effect of clinically used MEK inhibitors.

[83]

CRC

Hedgehog, Notch, Wnt

Alamablue

There are synergy effects between Hedgehog signal inhibitors and chemotherapy drugs used in clinic.

[84]

CRC

BTK

CTG

The combination of BTK inhibitors with 5-FU can be a treatment strategy in CRC patients.

[85]

CRC

EGFR, RAS, ERK, PI3K, AKT

CTG

There is a synergistic effect of MEK and pan-HER inhibition on mutant RAS CRC PDOs. However, the treatment induces a cell cycle arrest instead of cell death, leading to the inability of long-term effectiveness of the therapy in mutant RAS CRC patients.

[86]

CRC

MEK, EGFR, IGF1R, HDAC, PI3K, COX-2

CTG

KRAS and TP53 mutations PDOs are resistant to most drugs, except for trametinib. For APC mutation patient, EGFR inhibition is most effective strategy for CRC. The combination of HDAC inhibitors and EGFR inhibitor was more effective than the FOLFOX regimen in PDO and PDX models.

[10]

CRC

EGFR

Organoid size

The CRC PDOs knocked out of all RASGAPs are generated, only loss of NF1 leads to the activation of RAS-ERK signaling and resistance to limited EGF stimulation, suggesting that NF1-deficient CRC patients may not response to anti-EGFR therapy.

[87]

CRC

PFKFB3

Organoid size

KAN0438757, the inhibitor of glycolysis-related gene PFKFB3, may be a promising therapeutical approach for CRC.

[88]

CRC

PDGFRA, PDGFRB, FLT3

CCK-8

Crenolanib suppresses the growth of both KRAS mutation PDOs and KRAS/BRAF wild-type PDOs, suggesting that crenolanib may be applied for CRC patients.

[89]

CRC

MEK

MTS assay

The ribosomal pS6 has great value of predicting the drug response to trametinib (a MEK inhibitor) in RAS/BRAF mutant CRC PDOs.

[90]

CRC

mTOR, MNK

Cell-Titer Blue assay

PDOs with KRAS mutation sustain expression of c-MYC via the MNK/eIF4E pathway in CRC. Patients with activation of h mTORC1 and MNKs may benefit from a c-MYC-dependent co-targeting strategy in clinic.

[91]

CRC

PI3K/mTOR, CDK4/6, VEGFR1, VEGFR2, VEGFR3, PDGFR-β, c-Kit, Smoothened, EGFR, AKT, MEK

CTG

Nineteen out of 25 CRC PDOs show good responses to one or more drugs. However, CRC patients treated with the recommended treatment based on the drug screening pf PDOs do not exhibit good outcome.

[92]

CRC

EGFR, RAF

Organoid size

EGFR activited MAPK signaling in KRAS/BRAF mutant CRC PDOs, providing a mechanism of the effectivity of EGFR inhibition within combination therapies against BRAF/KRAS mutant CRC.

[93]

CRC

ERK

CTG

The molecular signature of human original CRC tissues may represent the drug responses in the CRC PDOs, but is not completely overlapping.

[94]

mCRC

PARP

CTG

The organoids from patients with limited therapeutic options and poor prognosis is sensitive to the PARP inhibitors.

[30]

mCRC

EGFR, MDM2, TP53, CDK, MEK, BRAF, mTOR, AKT

CTG

Three drug response clusters are identified based on the sensitivities to MDM2 and EGFR inhibition. The combination of MEK and mTOR/AKT inhibition may be a potential strategy for CRC patients with the MDR profile and a RAS mutant background.

[67]

RC

EGFR

CTG

KRAS-mutant CRC PDOs are resistant to cetuximab, while the KRAS-wild-type PDOs are sensitive to cetuximab.

[32]

PC

FGFR, MEK, mTOR

CTG

Targeted therapy sensitivities based on the PDO pharmacotyping may improve the personalized medicine for the patients with PC.

[34]

PC

AURKA, PIK3CA, HER2, EGFR, AKT, PRMT5

CTG

Therapeutic response to targeted drugs shows heterogeneity in PC PDOs.

[35]

PDAC

EZH2

CTG

Organoids from different patients with PDAC show distinct responses to the EZH2 inhibitors, which associated with H3K27me3 in PDOs and corresponding patient tumor.

[38]

PDCA

SHP2, MEK

Tumor volume

Synergy effect is observed between SHP2 inhibitor and MEK inhibitor in PDCA PDOs, indicating the dual MEK/SHP2 inhibition may be a promising targeted therapy for KRAS-mutant patients.

[95]

PC

ATR, WEE1

CTG

DDR deficiency and high replication stress are independently of each other, providing therapy strategy for DDR proficient and high replication stress PC patients with by WEE1 or ATR inhibition.

[96]

PDCA

MEK, AKT, EGFR, ERBB

CTG, tumor volume

Dual of MEK/AKT inhibition is synergistic with ERBB inhibition, and the combination of MEK antagonists with a ERBB inhibitor shows the highest activity in PDCA PDOs.

[97]

PDCA

MEK, HSP-90

CTG

The inhibition of HSP-90 increases the anti-cancer activity of MEK inhibition in PDOX model by overcoming the compensatory activation of resistance pathways induced by MEK inhibition.

[98]

PDAC

DCLK1

CTG

DCLK1-IN-1, the first selective probe of the DCLK1 kinase domain, shows anti-cancer activity in PDAC PDOs by modulating cell motility related proteins.

[99]

GC

STAT3, VEGFR, ATR, PARP, SMO, EGFR, ARID1A, CDK4/6, MEK, RAF, PI3K, mTOR, HER2, HGFR, WNT, BCR, CDK, TNF-a, TTK, PLK

CTG

The GC PDOs shows good responses to some new target drugs and some target drugs currently in clinical trials. Besides, drug response heterogeneity is found in different PDOs from the same GC patient.

[44]

GC

HER2, ERBB2, c-KIT, CDK4/6

Annexin V/PI

The mutational features of GC PDOs allow the palbociclib treatment for CDKN2A loss and the trastuzumab treatment for ERBB2 alterations.

[45]

GC

TrxR

Organized size

Ethaselen (a TrxR inhibitor) inhibits the growth of GC PDOs, indicating that the ethaselen could be an effective drug for the treatment of GC.

[100]

GC

PI3K-AKT

Ki-67 staining

The PI3K-AKT pathway protects FOXO3-Cyt GCs from FOXO3-mediated growth suppression and an AKT inhibitor suppresses the proliferation of FOXO3-Cyt GC PDOs, indicating that the targeting the PI3K-AKT pathway may have potential applications for FOXO3-Cyt GC treatment.

[101]

PLC

RTK, MAPK, PI3K, AKT, mTOR

CTG

SCH772984, the ERK inhibitor, may be a promising treatment for PLC based on the PLC-derived organoids.

[25]

HCC

Hedgehog, RAF

CTG

GANT61 (a Hedgehog signaling inhibitor) reverses the resistance of sorafenib in CD44(+) HCC PDOs.

[102]

HCC

FAO

Numbers of organoids

The inhibition of FAO by Eto in HCC PDOs with CPS1-deficiency shows good response.

[103]

HCC

Omacetaxine

CTG

Omacetaxine is found to be one of the most effective drugs in HCC PDOs and the effects were confirmed using a cohort of 40 HCC PDOs.

[104]

EADC

PI3K, IGF1R, EGFR, MDM2, ERK, MEK1/2

CTG

The EADC PDO model serves as a reliable pre-clinical tool for personalized medicine.

[50]

BC

MDM2, EGFR, mTOR

CCK-8

Drug sensitivity is associated with genomic profiles in BC PDOs, and they can complement each other in precision medicine.

[52]

PBC

ILK

AlamarBlue Cell Viability

An ILK inhibitor suppresses the proliferation of PBC PDOs.

[59]

GIC

BRAF, EGFR, AKT, ERBB2, PI3K, mTOR, CDK4/6

CTG

There is high specificity (93%), sensitivity (100%), negative predictive value (100%) and positive predictive value (88%) of GIC PDOs in predicting response to targeted drugs for patients in clinic.

[53]

aGEA

EGFR

NM

In EGFR-amplified aGEA PDOs, the EGFR inhibitors even antagonize the effects of EPI.

[105]

  1. PDOs Patient-derived organoids, Ref Reference, CRC Colorectal cancer, CTG CellTiter-Glo, mCRC Metastatic colorectal cancer, RC Rectal cancer, GC Gastric cancer, FOXO3-Cyt FOXO3 cytoplasmic distributed, PC Pancreatic cancer, PDAC Pancreatic adenocarcinoma, PLC Primary liver cancer, HCC Hepatocellular carcinoma, CPS1 Carbamoyl phosphate synthetase I, FAO Fatty acid β-oxidation, Eto Etomoxir, GBC Gallbladder cancer, YAP1 The Hippo-Yes-associated protein 1, EADC Esophageal adenocarcinoma, BC Biliary cancer, PBC Pancreato-biliary cancers, ILK Integrin-linked kinase, MDR Multi-drug resistance, GIC Gastrointestinal cancer, aGEA Advanced gastro-oesophageal adenocarcinoma, HSP Heat shock protein