在癌症中過量表現的C-X-C chemokine receptor type 4 (CXCR4)及其配體–　stromal cell-derived factor 1 (SDF-1 ) 或是CXCL12，在腫瘤生長和轉移中具有關鍵作用，此外CXCL12 / CXCR4的作用途徑，亦與腫瘤微環境中免疫細胞的分佈和浸潤有著高度的相關性。目前已證明幾種CXCR4拮抗劑是很有潛力的抗癌藥物，其結合化療和免疫治療，在動物模型中具有良好抑制腫瘤生長的效果，但目前美國FDA批准的CXCR4拮抗劑–AMD3100的藥代動力學 (pharmacokinetics) 較差，阻斷CXCR4下游途徑的效果亦較低。在我們的研究中，我們旨在開發新型CXCR4拮抗劑，結合抗血管生成療法和免疫療法，可用於治療肝細胞癌(HCC)，在原位肝細胞癌模型中，CXCR4拮抗劑–BPRCX807顯著抑制了原發性腫瘤的生長和遠端癌細胞轉移；此外，我們利用BPRCX807和索拉非尼(sorafenib) 的合併治療，顯著地使腫瘤相關的巨噬細胞(tumor-associated macrophage)在腫瘤的浸潤減少, 並趨向M1表型，促進了細胞毒性T細胞和輔助T細胞在腫瘤的浸潤；更進一步與PD-1免疫檢查點抑制劑合併治療後，證實使用BPRCX807能夠阻礙CXCL12 / CXCR4的作用途經，可以增強抗癌免疫反應。因此我們證實BPRCX807可以防止HCC腫瘤中免疫細胞功能的抑制、增強腫瘤中免疫細胞的滲透和活化、減少遠端癌細胞轉移並最終延遲HCC的進展.

The C-X-C chemokine receptor type 4 (CXCR4) and its ligand, stromal cell-derived factor 1 (SDF-1) or CXCL12 overexpressed in a variety of cancer types play crucial roles in tumor growth, invasion, angiogenesis, cell survival and metastasis. Furthermore, the CXCL12/CXCR4 axis is highly related to immune cells redistribution and infiltration in tumor microenvironment. Hence, several CXCR4 antagonists have been demonstrated to be promising anti-cancer drugs that have the clinical potential in combination of chemotherapy and immunotherapy to treat solid tumors. However, poor pharmacokinetics of AMD3100, a FDA-approved CXCR4 antagonist, make the efficacy of CXCR4-blocking approach lower. In this proposal, we aim to develop the novel CXCR4 antagonists for the potential treatment of Hepatocellular carcinoma in combination of anti-angiogenic therapy and immunotherapy. In orthotopic Hepatocellular carcinoma model, CXCR4 antagonists- BPRCX807 significantly suppressed primary tumor growth and distal metastasis. Furthermore, the combination of CX807 and sorafenib significantly primed tumor-associated macrophages toward M1-like phenotype and promoted the tumor infiltration of cytotoxic T cell and T helper cell. Its further combination with PD-1 check point blockade demonstrated that antitumor immune responses can be boosted by disrupting the CXCL12/CXCR4 axis by using BPRCX807.
BPRCX807 prevents suppression of immune cell function in HCC tumors, enhances immune cell tumor penetration and activation, reduce metastasis and ultimately delays HCC progression.

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