Are Integrins Still Practicable Targets for Anti-Cancer Therapy?
Abstract
:1. Introduction
2. Integrin Adhesion Receptors, a Class of Its Own
3. Integrin Adhesome as a Signaling Complex
4. Cancer Cell Integrins
4.1. Epithelial-to-Mesenchymal Transition (EMT) and Cancer Invasion
4.2. Anoikis
4.3. Metabolism
4.4. Stemness and Resistance to Therapy
4.5. Metastatic Niche
4.6. Metastatic Dormancy
5. Tumor Stroma
5.1. Fibroblasts and the Extracellular Matrix
5.2. Endothelial Cell
6. Targeting Integrins in Cancer
6.1. Inhibiting Integrin Function
6.2. Targeting Drug to the Tumor
6.3. Tumor Imaging
7. Open Questions and Challenges Ahead
7.1. Did We Target the Wrong Integrin(s)?
7.2. Did We Use the Wrong Inhibitor(s)?
7.3. Did We Target the Wrong Biological Process(es)?
7.4. Did We Use the Wrong Preclinical Models?
7.5. Did We Perform the Wrong Clinical Trials?
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Integrin Heterodimer | Arg-Gly-Asp Ligand Binding Dependency | Integrin Expression Patterns | |||
---|---|---|---|---|---|
Cancer Cells | Vascular Cells | CAF, MyF | Immune Cells | ||
α1β1 | + | ++ | ++ | ++ | |
α2β1 | +++ | ++ | ++ | ++ | |
α3β1 | +++ | ++ | ++ | ||
α4β1 | +++ | ++ | +++ | ||
α5β1 | + | +++ | +++ | ++ | ++ |
α6β1 | +++ | ++ | ++ | ||
α7β1 | ++ | ||||
α8β1 | + | + | ++ | ||
α9β1 | ++ | ++ | ++ | ||
α10β1 | ++ | ||||
α11β1 | ++ | ||||
αVβ1 | + | ++ | ++ | ++ | |
αLβ2 | +++ | ||||
αMβ2 | +++ | ||||
αXβ2 | +++ | ||||
αDβ2 | +++ | ||||
αVβ3 | + | +++ | +++ | ++ | +++ |
αiibβ3 | + | Platelets | |||
α6β4 | +++ | ++ | |||
αVβ5 | + | +++ | +++ | ++ | |
αVβ6 | + | +++ | ++ | ||
α4β7 | + | +++ | |||
αEβ7 | +++ | ||||
αVβ8 | + | ++ | +++ | ++ | ++ |
Study Name and Description | Indication | Phase/N pts | Design | Endpoints | Outcome and Remarks | References |
---|---|---|---|---|---|---|
Abituzumab (EMD 525797, anti-αV integrin antibody) (Merck-Serono): total no. of trials 3 | ||||||
POSSEIDON: SofC ± abituzumab (two doses) | Colon Ca (KRAS WT) | II 216 | dose finding/randomized | 1o: PFS 2o: OS | No diff in PFS, superior surv. of both abituzumab arms vs. SoC. | [213] |
AMELION: Cetuximab/FOLFIRI ± Abituzumab, high αVβ6 expr. | Colon Ca | II 230 | Randomized | 1o: PFS 2o: OS, RR | Start planned for 2nd quarter 2019 | NA |
Intetumumab (CNTO95, anti-αV integrin antibody) (Centocor, Johnson &Johnson): total no. of trials: 3 | ||||||
Intetuzumab ± DTIC vs. DTIC | Melanoma | II 129 | randomized (4-arms) | 1o: PFS: 2o: OS, RR | Trend for improved OS with high-dose intetumumab | [214] |
Docetaxel ± intetumumab | Prostate Ca | II 131 | Randomized | 1o: PFS 2o: RR | Outcome favors placebo (!) | [215] |
Cilengitide (EMD 121974, anti-αVβ3/αVβ5 integrin cyclic peptide) (Merck-Serono): total no. of trials: 21 (+ 8 terminated) | ||||||
ADVANTAGE: CDDP/5-FU/Cetuximab ± cil weekly vs. 2×/wk vs. control | Rec/metast. H&NCa | II 184 | 3-arms | 1o: PFS: 2o: OS, RR | No difference in 1o or 2o endpoints | [216] |
CERTO: CDDP-based regimen ± cilengitide weekly or 2×/week | NSCLC | II 169 | Randomized/dose-finding | 1o: PFS 2o: OS | Inconsistent results | [217] |
NABTT:0306: Cil 500 vs. 2000 mg + TMZ/RT→TMZ | nd GBM | II 112 | Randomized | OS | Both arms improved over historical controls | [218] |
Cil 500 vs. 2000 mg | Rec GBM | II 81 | Randomized | PFS6mo | Responses at all doses | [219] |
Cil 2000 mg | Prostate | II 16 | Uncontrolled, 2-stage design | PSA response | No activity | [220] |
010: Cil (500 mg) + TMZ/RT →TMZ | nd GBM | II 52 | Pilot study, uncontrolled | 1o: PFS6mo 2o: OS | Comparison to historical control | [221] |
CENTRIC: TMZ/RT→ TMZ ± Cil | Methyl. MGMT GBM | III 545 | Pivotal international EORTC trial. | OS | No activity | [6] |
CORE: Cil 5d/week vs. 2d/wk vs. control + TMZ/RT | Unmethyl. MGMT GBM | II 265 | 3-arms | OS 2: PFS | No differences | [222] |
Etaracizumab (MEDI-522, anti-αVβ3 integrin antibody) (MedImmune, Astra Zeneca): total trial 9 (+1 discontinued early) | ||||||
Etatacizumab ± DTIC | Melanoma | II 112 | Randomized | RR, OS | No responses with etatcizumab alone. No further evaluation recommended. | [165] |
Volociximab (MEDI-522, anti α5β1 integrin antibody) (AbbVie): total trials 7 (+ 3 discontinued early) | ||||||
Numerous uncontrolled phase II studies against lung, pancreatic and ovarian cancer | ||||||
SoC; standard of care. FOLFIRI; 5FU, leucovorin, irinotecan. DTCI; dacarbazine. CDDP; cisplatin. TMZ; temozolomide. RT; radiotherapy. Cil; cilengitide. PFS; progression-free survival. OS; overall survival. RR; response rate. 1o; primary endpoint. 2o, secondary endpoint. Rec, recurrent; nd, newly diagnosed |
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Alday-Parejo, B.; Stupp, R.; Rüegg, C. Are Integrins Still Practicable Targets for Anti-Cancer Therapy? Cancers 2019, 11, 978. https://doi.org/10.3390/cancers11070978
Alday-Parejo B, Stupp R, Rüegg C. Are Integrins Still Practicable Targets for Anti-Cancer Therapy? Cancers. 2019; 11(7):978. https://doi.org/10.3390/cancers11070978
Chicago/Turabian StyleAlday-Parejo, Begoña, Roger Stupp, and Curzio Rüegg. 2019. "Are Integrins Still Practicable Targets for Anti-Cancer Therapy?" Cancers 11, no. 7: 978. https://doi.org/10.3390/cancers11070978