Overcoming tumor cell resistance to apoptosis with a natural product, GCS-100

描述（由申请人提供）：本提案的目的是研究从柑橘果胶中提取的天然产物在克服半乳糖凝集素-3介导的淋巴瘤细胞凋亡抗性中的作用机制，并了解这种天然产物与传统癌症药物的相互作用。半乳糖凝集素-3是哺乳动物凝集素家族的一员，可促进细胞存活，因此半乳糖凝集素-3过表达可促进肿瘤细胞抵抗凋亡，从而对许多常规化疗药物产生耐药性。半乳糖凝集素-3在弥漫性大B细胞淋巴瘤（DLBCL）中高度过表达，并促进DLBCL细胞的凋亡抵抗。然而，半乳糖凝集素-3表达促进细胞凋亡抵抗的机制尚不清楚。一种修饰的柑橘果胶选择性地抑制半乳糖凝集素-3介导的细胞-细胞相互作用，在各种转移性癌症动物模型中已经被开发为一种新的治疗化合物，称为GCS-100，目前正在血液系统恶性肿瘤的临床试验中。然而，关于这种果胶衍生的多糖抑制半乳糖凝集素-3的机制，或这种天然产物与传统癌症治疗的相互作用的信息很少。该R21申请的目的是开展临床前研究，以推进我们对GCS-100对淋巴瘤细胞的作用机制的了解，使用人类淋巴瘤细胞系和原发患者样本。具体而言，我们将1)确定半乳糖凝集素-3在B淋巴瘤细胞中的亚细胞定位，并确定GCS-100对这些细胞中半乳糖凝集素-3的数量和分布的影响；2)明确半乳糖凝集素-3介导B淋巴瘤细胞凋亡抵抗的机制，确定GCS-100如何拮抗半乳糖凝集素-3的抗凋亡作用；3)研究半乳糖凝集素-3在原发性DLBCL患者样本中细胞存活和疾病进展中的作用，以表征可能受益于GCS-100的患者群体。了解GCS-100如何拮抗半乳糖凝集素-3的促生存功能也将有助于阐明半乳糖凝集素-3的表达如何使肿瘤细胞抵抗凋亡。因此，该R21应用程序对PA-06-400“癌症治疗补充方法的发展项目”具有高度响应。公共卫生相关性：一组被称为淋巴瘤的癌症需要新的治疗方法，因为许多患有这种疾病的患者对传统的癌症治疗没有反应。我们将研究一种从柑橘果胶中提取的天然治疗产品，它能使淋巴瘤细胞对常规癌症疗法的影响变得敏感，从而有可能提高淋巴瘤患者对治疗的反应和生存率。

DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the mechanism of action of a natural product derived from citrus pectin in overcoming galectin-3 mediated resistance to apoptosis in lymphoma, and to understand the interaction of this natural product with conventional cancer agents. Galectin-3, a member of the galectin family of mammalian lectins, promotes cell survival, so that galectin-3 overexpression promotes tumor cell resistance to apoptosis and thus resistance to many conventional chemotherapeutic agents. Galectin-3 is highly overexpressed in a specific type of lymphoma, termed diffuse large B cell lymphoma (DLBCL) and promotes apoptosis resistance in DLBCL cells. However, the mechanism by which galectin-3 expression promotes apoptosis resistance is unknown. A modified citrus pectin that selectively inhibits galectin-3 mediated cell-cell interactions in various animal models of metastatic cancer has been developed as a novel therapeutic compound, termed GCS-100, that is currently in clinical trials for hematologic malignancies. However, there is little information on the mechanism by which this pectin-derived polysaccharide inhibits galectin-3, or the interaction of this natural product with conventional cancer therapies. The goal of this R21 application is to perform preclinical studies to advance our knowledge of the mechanism of action of GCS-100 on lymphoma cells, using both human lymphoma cell lines and primary patient samples. Specifically, we will 1) Identify the subcellular localization of galectin-3 in B lymphoma cells, and determine the effect of GCS-100 on the amount and distribution of galectin-3 in these cells; 2) Characterize the mechanism of galectin-3 mediated apoptosis resistance in B lymphoma cells and determine how GCS-100 antagonizes the anti-apoptotic action of galectin-3; 3) Investigate the role of galectin-3 in cell survival and disease progression in primary DLBCL patient samples, to characterize patient populations that could benefit from GCS-100. Understanding how GCS-100 antagonizes pro-survival functions of galectin-3 will also help to elucidate how galectin-3 expression makes tumor cells resistant to apoptosis. This R21 application is thus highly responsive to PA-06-400, "Developmental Projects in Complementary Approaches to Cancer Care". PUBLIC HEALTH RELEVANCE: Novel therapies are needed for a group of cancers termed lymphomas, as many patients with this disease fail to respond to conventional cancer therapies. We will investigate a natural product therapeutic, derived from citrus pectin, for the ability to sensitize lymphoma cells to the effects of conventional cancer therapies and thus potentially enhance the response to treatment and survival of lymphoma patients.