Targeting CD44 in the bone marrow microenvironment of MM

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最终复发会导致较差的临床结果。我们实验室最近发现了一种含有d-氨基酸的多肽HYD1，它可以阻断骨髓瘤细胞与细胞外基质的黏附，并诱导坏死细胞死亡。重要的是，体外HYD1显示，与新诊断的相比，从复发患者获得的MM细胞的效力增强，表明这类新的化合物可能是治疗复发骨髓瘤患者的有效策略。我们最近环化了线状HYD1多肽，我们称之为cHYD1结合。CHYD1结合于重组CD44的胞外区，其Kd值为5 nM。此外，生物素偶联多肽使用从MM细胞系获得的膜提取物来下拉含有CD44/VLA-4的复合体。已知CD44调节整合素介导的黏附、白细胞的运输、存活和分化。我们认为，阻断基质介导的细胞黏附和诱导细胞死亡的双重功能为cHYD1是一类有吸引力的新型抗癌药物提供了证据。此外，我们根据目标的生物学假设，cHYD1将扰乱MM生态位。众所周知，MM利基对疾病进展和耐药性的出现至关重要，需要破坏该利基的药物来改进标准治疗。这项提案的具体目标1的目标将是利用体内免疫活性模型确定cHYD1与Bortezomib联合使用的疗效。具体目标2的目标将是确定cHYD1对破坏MM生态位的特定成分的影响。 公共卫生相关性：临床结果强烈支持制定治疗这一致命疾病的新战略的必要性。为此，这项提议将决定被称为cHYD1的环化肽是否是一种与骨髓瘤标准治疗相结合的有吸引力的策略。

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.