Synstatin Therapy for Multiple Myeloma

多发性骨髓瘤的合成他汀治疗

基本信息

  • 批准号:
    8010929
  • 负责人:
  • 金额:
    $ 38.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-01-01 至 2014-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma is the second most prevalent hematologic malignancy and accounts for over 10% of all hematologic cancers in the United States. It is estimated that over 16,500 new cases of myeloma are diagnosed and over 11,000 die from this disease each year. Although progress has been made in treatment over the last decade, the overall outlook for patients is grim. Multiple myeloma is a disease in which malignant plasma cells invade to populate and form tumors within the bone marrow. Their interactions with the tumor microenvironment lead to the release of cytokines that support myeloma cell proliferation, stimulate angiogenesis that supports myeloma cell growth and metastasis, and trigger bone lytic disease by over-stimulating differentiation of osteoclasts and their ensuing destruction of the bone. We have discovered a central mechanism in all of these processes that involves four effectors, each known to have a role in myeloma formation and progression - namely, the matrix receptor syndecan-1 (Sdc1), the av¿3 and av¿3 integrins, the insulin-like growth factor-1 receptor, and heparanase. The central mechanism is activation of a signaling complex comprised of Sdc1, the two integrins and the IGF1R when Sdc1 is activated by cleavage of its heparan sulfate chains by heparanase. Importantly, this mechanism is blocked by a peptide (called synstatin (SSTN)) that targets the active site on syndecan-1. This proposal will examine the mechanism by which Sdc1 is activated by heparanase on the myeloma cells, leading to tumorigenesis of the myeloma and heightened activation of vascular endothelial cells and osteoclast progenitors in the tumor microenvironment. Next, we will test the efficacy of SSTN as an inhibitor of this mechanism on the tumor cells and the cells in their microenvironment. The benefit of this work is likely to be new and effective treatments for multiple myeloma and other cancers. PUBLIC HEALTH RELEVANCE: Multiple myeloma is the second most prevalent hematologic malignancy. A novel mechanism, based on the matrix receptor syndecan-1 that is highly expressed in multiple myeloma, will be targeted by a new therapeutic called synstatin. Synstatin will be tested for its efficacy on the myeloma tumor and on the tumor microenvironment.
描述(由申请人提供):多发性骨髓瘤是第二常见的血液系统恶性肿瘤,占美国所有血液系统癌症的10%以上。据估计,每年有超过16,500例新的骨髓瘤病例被诊断出来,超过11,000人死于这种疾病。虽然在过去十年中治疗取得了进展,但患者的总体前景是严峻的。多发性骨髓瘤是一种恶性浆细胞侵入骨髓并在骨髓内形成肿瘤的疾病。它们与肿瘤微环境的相互作用导致支持骨髓瘤细胞增殖的细胞因子的释放,刺激支持骨髓瘤细胞生长和转移的血管生成,并通过过度刺激破骨细胞的分化及其随后的骨破坏引发骨溶解性疾病。我们已经发现了所有这些过程中涉及四种效应物的中心机制,每种效应物已知在骨髓瘤形成和进展中起作用-即基质受体多配体蛋白聚糖-1(Sdc 1)、av <$3和av <$3整联蛋白、胰岛素样生长因子-1受体和乙酰肝素酶。中心机制是当Sdc 1通过乙酰肝素酶切割其硫酸乙酰肝素链而激活时,由Sdc 1、两种整合素和IGF 1 R组成的信号传导复合物的激活。重要的是,这种机制被一种靶向多配体蛋白聚糖-1上活性位点的肽(称为合成抑素(Synstatin))阻断。该提案将研究Sdc 1被骨髓瘤细胞上的乙酰肝素酶激活的机制,从而导致骨髓瘤的肿瘤发生以及肿瘤微环境中血管内皮细胞和破骨细胞祖细胞的活化增强。接下来,我们将测试Sodium作为该机制的抑制剂对肿瘤细胞及其微环境中的细胞的功效。这项工作的好处可能是多发性骨髓瘤和其他癌症的新的有效治疗方法。 公共卫生相关性:多发性骨髓瘤是第二常见的血液系统恶性肿瘤。一种新的机制,基于基质受体syndecan-1,在多发性骨髓瘤中高度表达,将被一种新的治疗称为synstatin的目标。将检测合成他汀对骨髓瘤肿瘤和肿瘤微环境的疗效。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(10)

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ALAN C RAPRAEGER其他文献

ALAN C RAPRAEGER的其他文献

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{{ truncateString('ALAN C RAPRAEGER', 18)}}的其他基金

A kinase-independent role for EGFR in p38MAPK suppression and S-phase progression in head and neck cancer
EGFR 在头颈癌 p38MAPK 抑制和 S 期进展中的激酶独立作用
  • 批准号:
    9885259
  • 财政年份:
    2020
  • 资助金额:
    $ 38.91万
  • 项目类别:
A kinase-independent role for EGFR in p38MAPK suppression and S-phase progression in head and neck cancer
EGFR 在头颈癌 p38MAPK 抑制和 S 期进展中的激酶独立作用
  • 批准号:
    10392360
  • 财政年份:
    2020
  • 资助金额:
    $ 38.91万
  • 项目类别:
Syndecan-1 (CD138) and its synstatins: targeting invasion, survival and angiogenesis in myeloma
Syndecan-1 (CD138) 及其 Synstatins:靶向骨髓瘤的侵袭、存活和血管生成
  • 批准号:
    9383657
  • 财政年份:
    2017
  • 资助金额:
    $ 38.91万
  • 项目类别:
Syndecan-1 (CD138) and its synstatins: targeting invasion, survival and angiogenesis in myeloma
Syndecan-1 (CD138) 及其 Synstatins:靶向骨髓瘤的侵袭、存活和血管生成
  • 批准号:
    10208798
  • 财政年份:
    2017
  • 资助金额:
    $ 38.91万
  • 项目类别:
Signaling role of syndecans in HER2+ and triple negative breast cancer
Syndecans 在 HER2 和三阴性乳腺癌中的信号作用
  • 批准号:
    8777946
  • 财政年份:
    2013
  • 资助金额:
    $ 38.91万
  • 项目类别:
Signaling role of syndecans in HER2+ and triple negative breast cancer
Syndecans 在 HER2 和三阴性乳腺癌中的信号作用
  • 批准号:
    8439629
  • 财政年份:
    2013
  • 资助金额:
    $ 38.91万
  • 项目类别:
Signaling role of syndecans in HER2+ and triple negative breast cancer
Syndecans 在 HER2 和三阴性乳腺癌中的信号作用
  • 批准号:
    8987547
  • 财政年份:
    2013
  • 资助金额:
    $ 38.91万
  • 项目类别:
Signaling role of syndecans in HER2+ and triple negative breast cancer
Syndecans 在 HER2 和三阴性乳腺癌中的信号作用
  • 批准号:
    8601294
  • 财政年份:
    2013
  • 资助金额:
    $ 38.91万
  • 项目类别:
Synstatin Therapy for Multiple Myeloma
多发性骨髓瘤的合成他汀治疗
  • 批准号:
    8403534
  • 财政年份:
    2010
  • 资助金额:
    $ 38.91万
  • 项目类别:
Synstatin Therapy for Multiple Myeloma
多发性骨髓瘤的合成他汀治疗
  • 批准号:
    8190334
  • 财政年份:
    2010
  • 资助金额:
    $ 38.91万
  • 项目类别:

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