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) 患者最初会对标准化疗产生反应。然而，与多重耐药表型相关的疾病最终复发会导致临床结果不佳。我们的实验室最近发现，含有 d-氨基酸的肽 HYD1 可以阻断骨髓瘤细胞与细胞外基质的粘附并诱导坏死细胞死亡。重要的是，与新诊断的患者相比，体外 HYD1 在从复发患者获得的 MM 细胞中表现出更强的效力，表明此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 HYD1 肽，我们将其称为 cHYD1 结合。 cHYD1 与重组 CD44 的胞外结构域结合，KD 值为 5 nM。此外，生物素缀合肽使用从 MM 细胞系获得的膜提取物拉下含有 CD44/VLA-4 的复合物。已知 CD44 可以调节整合素介导的粘附、白细胞运输、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，证明 cHYD1 是一类有吸引力的新型抗癌药物。此外，根据靶标的生物学特性，我们假设 cHYD1 会破坏 MM 生态位。众所周知，多发性骨髓瘤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进标准治疗。该提案的具体目标 1 的目标是使用免疫活性体内模型确定 cHYD1 与硼替佐米组合的功效。具体目标 2 的目标是确定 cHYD1 对破坏 MM 生态位特定成分的影响。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，该提案将确定称为 cHYD1 的环化肽是否是与标准疗法结合治疗骨髓瘤的有吸引力的策略。