Table 1.

Other antiplatelet agents that may affect tumor metastasis and tumorigenesis

CategoryAgentsTargeting receptor–ligand interactionsReported tumor typesCommentsReferences
Targeting direct molecule contacts between platelets and tumor cells 
 αIIbβ3 integrin antagonists Abciximab,* eptifibatide,* tirofiban,* RUC-4; mAb10E5 and XV454, anti-integrin PSI domain mAb Platelet αIIbβ3 integrin– plasma fibrin(ogen) or fibrin–fibronectin complex–tumor αVβ3 integrin Melanoma, cancers of breast and likely prostate, pancreatic, ovarian, cervical; glioblastoma αIIbβ3 is critical for bone metastasis of melanoma; activation of integrin controls metastasis in human breast cancer 79,-81  
 α6β1 integrin antagonists Anti–α6-antibody GoH3 Platelet α6β1integrin– tumor ADAM9 Cancers of breast and colon α6β1 promotes spontaneous and experimental lung metastasis 82  
 GPIbα inhibitors Anfibatide, H6B4, NIT family mAb Platelet GPIbα–tumor VWF, (sub)endothelial VWF or P-selectin, leukocyte αMβ2 Melanoma GPIbα supports experimental lung metastasis; anti-GPIbα inhibits interactions with VWF and thrombin, which may inhibit TCIPA and tumor arrest; anti-GPIbα decreases thrombopoietin generation and may inhibit tumor-induced thrombocytosis 91,93,119  
 TLR4 inhibition Anti-HMGB1 Platelet TLR-4–tumor HMGB1 Melanoma and lung cancer TLR4 mediates tumor-induced platelet activation, tumor-platelet adhesion, and metastasis 89  
 P-selectin inhibitors Anti–P-selectin antibody, anti-CD24 (P-selectin ligand) antibody FL80 Platelet P-selectin–tumor P-selectin ligands Mucin-type ligands bearing sialyl-Lewis X on colon, prostate, small-cell lung cancers, and neuroblastoma; sulfated galactosylceramide-type ligands on colon cancer P-selectin mediates tumor growth, metastasis, and platelet–tumor cell microthrombi 83,,,-87  
 CLEC-2 inhibitors Anti-mouse CLEC-2 mAb 2A2B10 Platelet CLEC-2–tumor podoplanin Melanoma, brain tumors, and likely squamous cell carcinoma of the lung, head, and neck CLEC-2 promotes hematogenous tumor metastasis and prothrombotic state; high podoplanin induces platelet aggregation, correlates with increased risk of venous thromboembolism 71,72,90  
 GPVI antagonists Revacept, losartan, scFv 9012 Platelet GPVI–tumor fibrin(ogen) and/or subendothelial collagen Melanoma and lung cancer GPVI deficiency is associated with a 50% reduction in experimental lung metastasis 238,-240  
 CD36 inhibitors Anti-CD36 neutralizing antibody Platelet CD36–platelet released TSP-1–cancer cell CD36/integrins (?) Oral squamous cell carcinoma, melanoma, breast cancer, etc Anti-CD36 results in an antimetastatic effect; may inhibit CD36-mediated platelet activation and TCIPA 21,74,-76,157  
CategoryAgentsTargeting receptor–ligand interactionsReported tumor typesCommentsReferences
Targeting direct molecule contacts between platelets and tumor cells 
 αIIbβ3 integrin antagonists Abciximab,* eptifibatide,* tirofiban,* RUC-4; mAb10E5 and XV454, anti-integrin PSI domain mAb Platelet αIIbβ3 integrin– plasma fibrin(ogen) or fibrin–fibronectin complex–tumor αVβ3 integrin Melanoma, cancers of breast and likely prostate, pancreatic, ovarian, cervical; glioblastoma αIIbβ3 is critical for bone metastasis of melanoma; activation of integrin controls metastasis in human breast cancer 79,-81  
 α6β1 integrin antagonists Anti–α6-antibody GoH3 Platelet α6β1integrin– tumor ADAM9 Cancers of breast and colon α6β1 promotes spontaneous and experimental lung metastasis 82  
 GPIbα inhibitors Anfibatide, H6B4, NIT family mAb Platelet GPIbα–tumor VWF, (sub)endothelial VWF or P-selectin, leukocyte αMβ2 Melanoma GPIbα supports experimental lung metastasis; anti-GPIbα inhibits interactions with VWF and thrombin, which may inhibit TCIPA and tumor arrest; anti-GPIbα decreases thrombopoietin generation and may inhibit tumor-induced thrombocytosis 91,93,119  
 TLR4 inhibition Anti-HMGB1 Platelet TLR-4–tumor HMGB1 Melanoma and lung cancer TLR4 mediates tumor-induced platelet activation, tumor-platelet adhesion, and metastasis 89  
 P-selectin inhibitors Anti–P-selectin antibody, anti-CD24 (P-selectin ligand) antibody FL80 Platelet P-selectin–tumor P-selectin ligands Mucin-type ligands bearing sialyl-Lewis X on colon, prostate, small-cell lung cancers, and neuroblastoma; sulfated galactosylceramide-type ligands on colon cancer P-selectin mediates tumor growth, metastasis, and platelet–tumor cell microthrombi 83,,,-87  
 CLEC-2 inhibitors Anti-mouse CLEC-2 mAb 2A2B10 Platelet CLEC-2–tumor podoplanin Melanoma, brain tumors, and likely squamous cell carcinoma of the lung, head, and neck CLEC-2 promotes hematogenous tumor metastasis and prothrombotic state; high podoplanin induces platelet aggregation, correlates with increased risk of venous thromboembolism 71,72,90  
 GPVI antagonists Revacept, losartan, scFv 9012 Platelet GPVI–tumor fibrin(ogen) and/or subendothelial collagen Melanoma and lung cancer GPVI deficiency is associated with a 50% reduction in experimental lung metastasis 238,-240  
 CD36 inhibitors Anti-CD36 neutralizing antibody Platelet CD36–platelet released TSP-1–cancer cell CD36/integrins (?) Oral squamous cell carcinoma, melanoma, breast cancer, etc Anti-CD36 results in an antimetastatic effect; may inhibit CD36-mediated platelet activation and TCIPA 21,74,-76,157  
CategoryAgentsCommentsReferences
Targeting platelet activation pathways 
 P2Y12 antagonists Clopidogrel,* prasugrel,* ticagrelor,* cangrelor* Coadministration of clopidogrel with aspirin markedly improves the efficacy of adoptive T-cell therapy of cancer in animal models and prevents chronic hepatitis B–associated hepatocellular carcinoma. P2Y12 deficiency results in >85% reduction in the growth of syngeneic ovarian cancer tumors; ticagrelor reduces tumor growth by 75% compared with placebo 194,225,236  
 PAR1 antagonists Vorapaxar,* atopaxar Targeting PAR-1 is important for thrombin-enhanced metastasis 235  
 EP3 receptor antagonists DG-041 DG-041 inhibits PGE2-dependent platelet activation and aggregation and prevents platelet-mediated induction of EMT in CRC 149,243  
CategoryAgentsCommentsReferences
Targeting platelet activation pathways 
 P2Y12 antagonists Clopidogrel,* prasugrel,* ticagrelor,* cangrelor* Coadministration of clopidogrel with aspirin markedly improves the efficacy of adoptive T-cell therapy of cancer in animal models and prevents chronic hepatitis B–associated hepatocellular carcinoma. P2Y12 deficiency results in >85% reduction in the growth of syngeneic ovarian cancer tumors; ticagrelor reduces tumor growth by 75% compared with placebo 194,225,236  
 PAR1 antagonists Vorapaxar,* atopaxar Targeting PAR-1 is important for thrombin-enhanced metastasis 235  
 EP3 receptor antagonists DG-041 DG-041 inhibits PGE2-dependent platelet activation and aggregation and prevents platelet-mediated induction of EMT in CRC 149,243  

mAb, monoclonal antibody; PGE, prostaglandin E2; PSI, plexin-semaphorin-integrin.

*

US Food and Drug Administration approved.

Preclinical stage of development.

Phase 2.

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