2016 Fiscal Year Annual Research Report
血小板内在性ＶＥＧＦ－Ａを分子標的とする新規大腸癌治療の臨床及び分子生物学的研究
| Project/Area Number |
16F16420
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| Research Institution | Kagoshima University |
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Principal Investigator |
井本 浩 鹿児島大学, 医歯学域医学系, 教授 (60274461)
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| Co-Investigator(Kenkyū-buntansha) |
ARYAL BIBEK 鹿児島大学, 医歯学域医学系, 外国人特別研究員
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| Project Period (FY) |
2016-11-07 – 2018-03-31
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| Keywords | Platelet / VEGF-A / Bevacizumab / Pegaptinib / Sunitinib / Colorectal Cancer / Angiogenesis |
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| Outline of Annual Research Achievements |
As proposed in our research plan, in our first phase, we have identified the optimal dosing and condition for platelet incubation with bevacizumab. Under this optimal condition, we performed ex vivo and in vitro experiments to examine the drug incorporation inside the platelets. Unlike the current belief that bevacizumab incorporate inside the platelets and neutralize the intra-platelet VEGF-A, we have now evidences using two different models to support our proposed hypothesis that bevacizumab doesn't have effect on the concentration of intra-platelet VEGF-A. We are now working to set up our protocol for labeling bevacizumab and observe if its bind to the platelet membrane or still incorporates to some extent to inside platelets. Meantime, to determine the effect of bevacizumab on intra-platelet VEGF-A in clinical settings, we are now recruiting colorectal cancer patients with bevacizumab containing chemotherapy regimen.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
Through our optimal ex vivo and in vitro model experiments, we are a step closer to prove that bevacizumab less likely incorporates inside the platelet and have dismal effects on intra-platelet VEGF-A. If we establish with one more robust model, it will break the current belief that has been rooted in angiogenesis world that bevacizumab incorporates inside the platelets.
So far, the purpose and the plan we submitted for the grant is going in an appropriate direction.
Besides, we have also completed a study demonstrating how platelet growth factors exhaustion in cancer patients is able to predict the cancer recurrence in a small but homogenous cohort. The manuscript has been completed and has just been submitted.
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| Strategy for Future Research Activity |
Electron microscopy : We will validate our result with electron micrscopy data to establish that bevacizumab doesn't penetrate inside the platelet granules to neutralize the intra-platelet VEGF-A.
Examining the effect with other anti-VEGF-A agents: We have now selected two more agents that are clinically used. Recently it was shown that Sunitinib (oral Tyrosine kinase inhibitor) incorporates inside the platelets, but its interaction with intra-platelet VEGF-A is unknown. The next agent we are using is Pegaptinib (an aptamer, that's blocks the effect of VEGF-A).We will proceed the same ex vivo, in vitro and electron microscopy experiments with these additional agents.
Establish the effect in a fairly homogenous cohort of colorectal cancer patient : Patients recruitment has started and we will soon start the blood collection and finally, identify a mechanism how intra-platelet VEGF-A can be neutralized in cancer patients.
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