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Targeting CD44 in the bone marrow microenvironment of MM

靶向 MM 骨髓微环境中的 CD44

基本信息

批准号：
8453303
负责人：
Lori A Hazlehurst
金额：
$ 21.88万
依托单位：
MODULATION THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2013-09-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453303
关键词：
Adhesions Amino Acids Antigen-Presenting Cells Antineoplastic Agents Award Binding Biological Biology Biotin Bone Marrow Bone Marrow Neoplasms Bortezomib CD44 gene Caspase Cell Adhesion Cell Adhesion Molecules Cell Death Cell Line Cells Clinical Clinical Trials Collaborations Complex Cyclization Data Development Disease Disease Progression Drug resistance Extracellular Domain Extracellular Matrix Florida Future Goals Grant Home environment Homing Immune In Vitro Integrin alpha4beta1 Integrins Laboratories Lead Leukocyte Trafficking MSX1 gene Malignant neoplasm of lung Mediating Membrane Modeling Multi-Drug Resistance Multiple Myeloma Mus Myelogenous Necrosis Neoplasm Metastasis Newly Diagnosed Osteoblasts Osteoclasts Outcome Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Reagent Recombinants Recurrent disease Refractory Relapse Reporting Resistance Solid Neoplasm Suppressor-Effector T-Lymphocytes Technology Technology Transfer Therapeutic Translations base bone cell killing chemotherapy design drug candidate effective therapy improved in vivo in vivo Model inhibitor/antagonist innovation neoplastic cell novel novel strategies novel therapeutics promoter small molecule treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): The majority of multiple myeloma (MM) patients will initially respond to standard chemotherapy. However, eventually relapse of the disease, associated with a multi-drug resistant phenotype, contributes to poor clinical outcomes. Our laboratory has recently discovered that a d-amino acid containing peptide, HYD1, blocks adhesion of myeloma cells to extracellular matrices and induces necrotic cell death. Importantly, ex-vivo HYD1 demonstrates increased potency in MM cells obtained from relapsed patients compared to newly diagnosed, indicating that this novel class of compounds may be an effective strategy for the treatment of relapsed myeloma patients. We have recently cyclized the linear HYD1 peptide which we refer to as cHYD1 binds. cHYD1 binds to the extracellular domain of recombinant CD44 with a KD value of 5 nM. Furthermore, biotin conjugated peptide pulls down a CD44/VLA-4 containing complex using membrane extracts obtained from MM cell lines. CD44 is known to regulate integrin mediated adhesion, trafficking of leukocytes, survival, and differentiation. We propose that the dual function of blocking matrix mediated cell adhesion and inducing cell death provides evidence that cHYD1 is an attractive novel class of anti-cancer agents. Furthermore, we hypothesize, based on the biology of the target, that cHYD1 will disrupt the MM niche. It is well known that the MM niche is critical for disease progression and emergence of drug resistance and agents that disrupt the niche are needed to improve standard therapy. The goal of specific aim 1 of this proposal will be to determine the efficacy of cHYD1 in combination with bortezomib, using immune competent in vivo models. The goal of specific aim 2 will be to determine the effect of cHYD1 on disrupting specific components of the MM niche. PUBLIC HEALTH RELEVANCE: Clinical outcomes strongly support the need for the development of novel strategies for the treatment of this deadly disease. To this end this proposal will determine whether the cyclized peptide referred to as cHYD1 is an attractive strategy to combine with standard therapy for the treatment of myeloma.

描述（由申请人提供）：大多数多发性骨髓瘤（MM）患者最初对标准化疗有反应。然而，与多药耐药表型相关的疾病的最终复发导致不良的临床结果。我们的实验室最近发现，含有d-氨基酸的肽HYD 1，阻断骨髓瘤细胞与细胞外基质的粘附，并诱导坏死性细胞死亡。重要的是，与新诊断的患者相比，离体HYD 1在从复发患者获得的MM细胞中表现出增加的效力，表明这类新型化合物可能是治疗复发性骨髓瘤患者的有效策略。我们最近环化了线性HYD 1肽，我们称之为cHYD 1结合。cHYD 1与重组CD 44的胞外结构域结合，KD值为5 nM。此外，使用从MM细胞系获得的膜提取物，生物素缀合的肽拉下含CD 44/VLA-4的复合物。已知CD 44调节整联蛋白介导的粘附、白细胞的运输、存活和分化。我们提出，阻断基质介导的细胞粘附和诱导细胞死亡的双重功能提供了证据表明，cHYD 1是一种有吸引力的新型抗癌剂。此外，基于靶点的生物学，我们假设cHYD 1将破坏MM生态位。众所周知，MM生态位对于疾病进展和耐药性的出现至关重要，需要破坏该生态位的药物来改善标准治疗。本提案的具体目标1的目标是使用免疫活性体内模型确定cHYD 1与硼替佐米联合治疗的疗效。具体目标2的目标是确定cHYD 1对破坏MM生态位特定组分的影响。公共卫生相关性：临床结果强烈支持开发治疗这种致命疾病的新策略的必要性。为此，该提议将确定称为cHYD 1的环化肽是否是与标准疗法组合联合收割机用于治疗骨髓瘤的有吸引力的策略。