Targeting the c-Met/HGF Axis in Acute Myeloid Leukemia

靶向急性髓系白血病中的 c-Met/HGF 轴

• 批准号: 8768686
• 负责人: Charalambos Andreadis
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768686
• 关键词: Acute Myelocytic Leukemia; Aftercare; Antibodies; Biological Markers; Biopsy Specimen; Blast Cell; Bone Marrow; Bone marrow biopsy; Clinical; Clinical Data; Cytarabine; Data; Disease; Dose; Drug resistance; Epithelial; Gastric Adenocarcinoma; Gene Expression; Gene Targeting; Genetic; Growth; Hematologic Neoplasms; Hematopoietic; Hepatocyte Growth Factor; Immunohistochemistry; In Vitro; Institution; Malignant Neoplasms; Malignant neoplasm of lung; Maximum Tolerated Dose; Mediating; Outcome; Paracrine Communication; Pathway interactions; Patients; Phase; Population; Proto-Oncogene Proteins c-akt; Quality of life; Recombinants; Recurrent disease; Refractory; Refractory Disease; Regimen; Relapse; Role; STAT3 gene; Safety; Serum; Signal Pathway; Solid; Staining method; Stains; Stem cells; Stromal Cells; Survival Rate; Tissues; Toxic effect; Tumor Tissue; base; cohort; design; high risk; high standard; humanized monoclonal antibodies; improved; in vivo; inhibitor/antagonist; leukemia; meetings; novel; outcome forecast; phase 2 study; pre-clinical; public health relevance; resistance mechanism; small molecule; success; treatment response; tumor; tumor growth

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is an aggressive malignancy with a poor long-term prognosis. Survival rate for all comers remains less than 50%. Patients with either relapsed or refractory disease can respond to second-line therapy but only achieve a five-year survival of 10%. Thus, AML represents a disease with an unmet clinical need, and novel agents are urgently needed to improve outcomes. Recently, several studies have shown the importance of the c-Met/hepatocyte growth factor (HGF) pathway in mediating drug resistance and fueling tumor growth across distinct tumor types ranging from epithelial to hematological malignancies 13, 25, 30. In AML, high serum HGF levels have correlated with a more aggressive disease course as well as shortened survival 10, 11, 14, 28. More recently, genetic depletion of HGF using anti-HGF antibodies or a small molecule inhibitor of c-Met potently suppressed the growth and survival of HGF expressing AML blasts in vitro and in vivo 13. Based on these data and the success of c-Met inhibitors in phase II studies for gastric adenocarcinomas and lung cancer, we surmise that combining high-dose cytarabine (HIDAC) with ficlatuzumab (an anti-HGF antibody) will improve clinical outcomes in patients with relapsed/refractory AML through abrogation of the downstream c-Met signaling pathway, resulting in decreased survival of the leukemia clones. We propose a phase Ib study using the 3+3 design to discover the maximally tolerated dose (MTD) of these agents in combination and describe the preliminary activity and effect on quality of life afforded by this regimen. The primary endpoint is the safety/tolerability of the combination. Secondary endpoints consist of CR rate, OS, PFS, and changes in quality of life. Planned correlatives include: serum HGF levels, blast counts, and downstream targets of c-Met (p-ERK, p-AKT, and p-STAT3) pre- and post-treatment. In addition, c-Met and HGF expression will be assessed by immunohistochemistry (IHC) co-staining with stromal and stem cell markers on bone marrow biopsy specimen to explore the role of paracrine signaling by the hematopoietic niche. If successful, this study will be the first to offer a more potent and less toxic treatment option for this high-risk population utilizing a rationally selected antibody.

描述(申请人提供)：急性髓系白血病(AML)是一种侵袭性的恶性肿瘤，长期预后较差。所有来者的存活率仍然不到50%。复发或难治性疾病的患者可以对二线治疗有反应，但只有10%的五年存活率。因此，AML代表了一种临床需求未得到满足的疾病，迫切需要新的药物来改善结果。最近，一些研究表明c-Met/肝细胞生长因子(HGF)通路在介导耐药和促进肿瘤生长中的重要性，涉及从上皮性恶性肿瘤到血液系统恶性肿瘤13、25、30等不同类型的肿瘤。在急性髓细胞白血病中，高水平的血清HGF水平与更具侵袭性的病程以及10、11、14、28岁的生存期缩短相关。最近，用抗HGF抗体或c-Met的小分子抑制剂基因缺失HGF可以有效地抑制体外和体内表达HGF的AML细胞的生长和存活。基于这些数据和c-Met抑制剂在胃腺癌和肺癌II期研究中的成功，我们推测，大剂量阿糖胞苷(HIDAC)联合抗HGF单抗(抗HGF抗体)将通过取消下游c-Met信号通路而改善复发/难治性AML患者的临床预后，从而降低白血病克隆的存活率。我们建议采用3+3设计进行Ib期研究，以发现这些药物联合使用的最大耐受量(MTD)，并描述该方案提供的初步活性和对生活质量的影响。主要终点是组合的安全性/耐受性。次要终点包括CR率、OS、PFS和生活质量变化。计划的相关性包括：治疗前和治疗后的血清HGF水平、原始细胞计数和c-Met下游靶点(p-ERK、p-AKT和p-STAT3)。此外，c-Met和HGF的表达将通过免疫组织化学(IHC)与基质和干细胞标记物在骨髓活检标本上的共同染色来评估，以探讨旁分泌信号在造血生态位中的作用。如果成功，这项研究将 成为第一个利用合理选择的抗体为这一高危人群提供更有效和毒性更低的治疗选择的公司。