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: 8911802
• 负责人: Charalambos Andreadis
• 金额: $ 7.93万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911802
• 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; Health; 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; 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（由申请人提供）：急性髓系白血病（AML）是一种侵袭性恶性肿瘤，长期预后不良。所有来者的生存率仍低于 50%。患有复发或难治性疾病的患者可以对二线治疗产生反应，但五年生存率仅为 10%。因此，AML 是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预后。最近，多项研究表明，c-Met/肝细胞生长因子 (HGF) 通路在介导耐药性和促进从上皮性肿瘤到血液恶性肿瘤等不同肿瘤类型的肿瘤生长中的重要性 13,25,30。在 AML 中，高血清HGF 水平与更具侵袭性的病程以及缩短的生存期相关 10、11、14、28。最近，使用抗 HGF 进行 HGF 基因耗竭c-Met 抗体或小分子抑制剂在体外和体内有效抑制表达 HGF 的 AML 母细胞的生长和存活 13。基于这些数据以及 c-Met 抑制剂在胃腺癌和肺癌 II 期研究中的成功，我们推测，将高剂量阿糖胞苷 (HIDAC) 与 ficlatuzumab（一种抗 HGF 抗体）相结合将通过以下方式改善复发/难治性 AML 患者的临床结果：下游 c-Met 信号通路的废除，导致白血病克隆的存活率降低。我们建议使用 3+3 设计进行 Ib 期研究，以发现这些药物组合的最大耐受剂量 (MTD)，并描述该方案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 和生活质量的变化。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 下游靶标（p-ERK、p-AKT 和 p-STAT3）。此外，将通过免疫组织化学 (IHC) 与骨髓活检标本上的基质和干细胞标记物共染色来评估 c-Met 和 HGF 表达，以探索造血生态位旁分泌信号传导的作用。 如果成功的话，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、毒性更小的治疗选择的公司。