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）患者最初将对标准化疗反应。然而，最终与多药耐药表型有关的疾病复发导致临床结果不良。我们的实验室最近发现，含有肽HYD1的D-氨基酸阻断骨髓瘤细胞对细胞外基质的粘附并诱导坏死细胞死亡。重要的是，与新诊断的复发患者获得的MM细胞的效力相比表明，与新诊断的MM细胞相比，这表明这种新型化合物可能是治疗复发性骨髓瘤患者的有效策略。我们最近已将线性hyd1肽循环起来，我们称之为CHYD1结合。 CHYD1与重组CD44的细胞外域结合，KD值为5 nm。此外，使用从MM细胞系获得的膜提取物，生物素共轭肽将含有复合物的CD44/VLA-4拉下。已知CD44可以调节整联蛋白介导的粘附，白细胞的运输，生存和分化。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是一种有吸引力的新型抗癌药。此外，我们基于目标的生物学假设CHYD1会破坏MM的利基市场。众所周知，MM利基对于疾病进展和耐药性的出现至关重要，并且需要破坏利基市场以改善标准疗法。该提案的特定目标1的目的是使用免疫在体内模型中确定CHYD1与硼替佐米结合使用的功效。特定目标2的目的是确定CHYD1对破坏MM利基市场特定组件的影响。公共卫生相关性：临床结果强烈支持开发这种致命疾病的新型策略的需求。为此，该提案将确定被称为CHYD1的环化肽是否是将骨髓瘤治疗的标准疗法结合使用的有吸引力的策略。