Targeting the tumor microenvironment in B-cell malignancies

针对 B 细胞恶性肿瘤中的肿瘤微环境

• 批准号: 8702866
• 负责人: Sherine F. Elsawa
• 金额: $ 7.35万
• 依托单位: NORTHERN ILLINOIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702866
• 关键词: Address; Adverse effects; Affect; Apoptosis; B lymphoid malignancy; B-Cell Activation; B-Lymphocytes; Binding; Biology; Blood; Bone Marrow; CCL2 gene; CCL7 gene; CCR3 Signaling Pathway; CD40 Ligand; Cancer Biology; Cancer Patient; Cell physiology; Cells; Chemotaxis; Chronic Lymphocytic Leukemia; Combined Modality Therapy; Communication; Complex; Data; Development; Disease; Disease Progression; Drug resistance; Event; Flare; Foundations; GLI2 gene; Goals; Immunoglobulin M; Interleukin-6; Investigation; Knowledge; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant Stromal Cell; Malignant lymphoid neoplasm; Modeling; Molecular; Monoclonal Antibodies; Multiple Myeloma; Non-Malignant; Oncogenic; Pathogenesis; Pathway interactions; Patients; Play; Property; Proto-Oncogene Proteins c-akt; Publishing; RANTES; Role; Signal Pathway; Signal Transduction; Staging; Stromal Cells; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Waldenstrom Macroglobulinemia; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; cytokine; cytotoxic; cytotoxicity; efficacy testing; improved; in vivo; in vivo Model; interest; malignant phenotype; mouse model; novel; novel therapeutic intervention; outcome forecast; partial response; preclinical efficacy; preclinical study; promoter; public health relevance; response; rituximab; therapeutic target; treatment strategy; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): The tumor microenvironment (TME) plays an important role in the development, persistence and disease progression in cancer. Lymphoid malignancies, in particular B-cell malignancies residing in the bone marrow, are an example of malignancies depending on the microenvironment. These malignancies are serious and often fatal. Although significant advances have been made in our understanding of the biology of these cancers, most remain incurable and clearly, new therapies are needed. Because the TME plays an integral role in malignant B-cell functions, it is difficult to dissociate it from cancer ells. There is compelling evidence to suggest that the crosstalk between malignant B cells and bone marrow stromal cells favors disease progression. Therefore, disrupting the crosstalk between cancer cells and stromal cells is an attractive therapeutic strategy for the treatment of these lymphoid malignancies. In addition, combining therapies that target the TME and malignant cells will inhibit the crosstalk between these two compartments and lead to improved survival of cancer patients. Therefore, a better understanding of the signaling mechanisms modulating the TME in B-cell malignancies is necessary for the development of novel targeted therapies for these devastating diseases and the appropriate choice of therapy must be derived from a detailed knowledge of the signaling network controlling this cellular crosstalk. Cytokines play a key role in regulating the crosstalk between malignant cells and non-malignant cells in the TME. Although this phenomenon is well established, the molecular mechanisms regulating this cellular event in the TME remain elusive. We identified a novel CCR3-PI3K-AKT-GLI2 pathway in stromal cells that is initiated by the cytokine CCL5, leading to increased IL-6 secretion by stromal cells. IL-6 secretion from the TME, in turn, promotes immunoglobulin M (IgM) secretion by malignant B cells. Therefore, disrupting the CCR3-PI3K-AKT-GLI2-IL-6 signaling pathway in the TME alone or in combination with rituximab therapy may provide therapeutic efficacy by targeting 2 components of malignant phenotype; the malignant cells (Rituximab therapy) and stromal cell signaling (CCR3 and/or IL-6 blockade). We have recently identified novel target molecules of CCR3-PI3K-AKT-GLI2 pathway including CCL2, CCL7 and CD40L. A better understanding of the molecular mechanisms regulated by these cytokines may facilitate the development of novel therapies. In this application we propose to expand on these findings and address the CENTRAL HYPOTHESIS that the CCR3-PI3K-AKT-GLI2 pathway contributes to the maintenance of an active TME in B-cell malignancies and thus represents a viable therapeutic target. To address this hypothesis, we propose two specific aims: AIM 1: To determine the translational implications of the combined targeting of CCR3 and/or IL-6 in combination with rituximab therapy in a B-cell malignancy mouse model and AIM 2: To characterize the role of CCR3-PI3K- AKT-GLI2 axis in the TME.

描述（由申请人提供）：肿瘤微环境（TME）在癌症的发生、持续和疾病进展中发挥着重要作用。淋巴恶性肿瘤，特别是存在于骨髓中的 B 细胞恶性肿瘤，是依赖于微环境的恶性肿瘤的一个例子。这些恶性肿瘤很严重并且往往是致命的。尽管我们对这些癌症生物学的理解已经取得了重大进展，但大多数癌症仍然无法治愈，显然需要新的疗法。由于 TME 在恶性 B 细胞功能中发挥着不可或缺的作用，因此很难将其与癌细胞分开。有令人信服的证据表明恶性 B 细胞和骨髓基质细胞之间的串扰有利于疾病进展。因此，破坏癌细胞和基质细胞之间的串扰是治疗这些淋巴恶性肿瘤的一种有吸引力的治疗策略。此外，针对 TME 和恶性细胞的联合疗法将抑制这两个区室之间的串扰，从而提高癌症患者的生存率。因此，更好地了解 B 细胞恶性肿瘤中调节 TME 的信号传导机制对于开发针对这些破坏性疾病的新型靶向疗法是必要的，并且必须从控制这种细胞的信号传导网络的详细知识中得出适当的治疗选择。相声。 细胞因子在调节 TME 中恶性细胞和非恶性细胞之间的串扰中发挥着关键作用。尽管这种现象已得到充分证实，但调节 TME 中这种细胞事件的分子机制仍然难以捉摸。我们在基质细胞中发现了一种新的 CCR3-PI3K-AKT-GLI2 通路，该通路由细胞因子 CCL5 启动，导致基质细胞分泌 IL-6 增加。 TME 分泌的 IL-6 反过来又促进恶性 B 细胞分泌免疫球蛋白 M (IgM)。因此，单独或与利妥昔单抗治疗联合破坏 TME 中的 CCR3-PI3K-AKT-GLI2-IL-6 信号通路可能会通过靶向恶性表型的 2 个组成部分来提供治疗效果；恶性细胞（利妥昔单抗治疗）和基质细胞信号传导（CCR3 和/或 IL-6 阻断）。我们最近发现了CCR3-PI3K-AKT-GLI2通路的新靶分子，包括CCL2、CCL7和CD40L。更好地了解这些细胞因子调节的分子机制可能有助于新疗法的开发。 在本申请中，我们建议扩展这些发现并解决中心假设，即 CCR3-PI3K-AKT-GLI2 通路有助于维持 B 细胞恶性肿瘤中的活性 TME，因此代表了一个可行的治疗靶点。为了解决这一假设，我们提出了两个具体目标：AIM 1：确定 CCR3 和/或 IL-6 联合靶向联合利妥昔单抗治疗在 B 细胞恶性肿瘤小鼠模型中的翻译意义；AIM 2：表征CCR3-PI3K-AKT-GLI2 轴在 TME 中的作用。