Table 3.
Precision treatment for targeted therapy using GIC PDOs
| 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] |
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