Multi-modal inhibition by an integrin-targeting Type IV Collagen-derived peptide

项目总结/摘要 该项目的目标是表征多方面的抑制和肿瘤靶向特性， SP2043，一种IV型胶原蛋白衍生肽，在三阴性乳腺癌（TNBC）模型中的应用。TNBC是一种 特别是由于转移倾向高和治疗选择有限的致命癌症。试图 使用抗血管生成剂限制TNBC的转移进展还不是很成功，部分地 因为淋巴扩散然而，使用广谱抑制剂阻断淋巴管生成的尝试 有明显的毒性。肽抑制剂提供了一个独特的机会，设计有效的抑制剂， 毒性发现SP2043及其早期类似物抑制多种生长因子受体的活化， 包括许多与血管生成和淋巴管生成（即，VEGFR 2和VEGFR 3）。作为一个可能 为了解释这种多模式抑制，发现这些肽与几种整联蛋白相互作用。 整合素在肿瘤及其脉管系统中高度表达，并与转移性肿瘤的进展相关。 疾病除了它们在粘附和迁移中的作用之外，整联蛋白还可以通过粘附和迁移促进转移。 通过将生长因子受体聚集成大的功能性蛋白质复合物或通过改变 他们的细胞内交易这些过程的破坏可以对受体稳定性产生深远的影响， 信号传导谱，强调了SP2043作为治疗剂的开发的潜在益处。在这里， 我们还打算通过与整合素的相互作用来研究SP2043的抑制机制 作为通过它们结合到肿瘤中来抵消它们的主要缺点之一，即它们在体内的半衰期短 目标纳米颗粒。特异性目标1将使用基于生物物理学和细胞的方法来确定 SP2043特异性整合素对，并研究该肽对整合素生长稳定性的影响 因子受体信号复合物。具体目标2将研究SP2043 影响细胞对生长因子信号的反应，包括特定生长因子分布的变化。 因子受体和血管稳定性和渗透性相关的过程。最后，在具体目标3中， 用于SP2043包被的纳米颗粒的抗血管生成活性的制剂将使用小鼠来研究 MDA-MB-231 TNBC细胞系的异种移植模型，以提高生物利用度并测试其功效 这些化合物。总之，这些实验将允许SP2043的更好的表征 因此，它具有多模式抑制作用，并为其作为治疗TNBC的靶向疗法的发展铺平了道路。

PROJECT SUMMARY/ABSTRACT The goal of this project is to characterize the multifaceted inhibitory and tumor-targeting properties of SP2043, a type IV collagen-derived peptide, in triple negative breast cancer (TNBC) models. TNBC is a particularly lethal cancer owing to a high propensity for metastasis and limited treatment options. Attempts to limit the metastatic progression of TNBC using anti-angiogenic agents have not been very successful, in part due to lymphatic dissemination. However, attempts to block lymphangiogenesis using broad-range inhibitors was met with significant toxicity. Peptide inhibitors offer a unique opportunity to design potent inhibitors with low toxicity. SP2043 and its early analogs were found inhibit the activation of multiple growth factor receptors, including many related to both angiogenesis and lymphangiogensis (ie. VEGFR2 and VEGFR3). As a possible explanation for this multimodal inhibition, these peptides were found to interact with several species of integrins. Integrins are highly expressed in tumors and their vasculature and associated with the progression of metastatic disease. In addition to their roles in adhesion and migration, integrins can contribute to metastasis through the regulation of growth factor receptors by clustering them into large, functional protein complexes or by altering their intra-cellular trafficking. Disruption of these processes can have profound effects on receptor stability and signaling profiles, emphasizing the potential benefit for development of SP2043 as a therapeutic agent. Here, we propose to investigate the inhibitory mechanisms of SP2043 through their interactions with integrins as well as offset one of their major disadvantages, their short half-life in vivo, through their incorporation into tumor target-nanoparticles. Specific Aim 1 will use biophysical and cellular based methods to determine the affinity of SP2043 for specific integrin pairs and investigate the effects of this peptide on the stability of integrin-growth factor receptor signaling complexes. Specific Aim 2 will investigate the mechanism through which SP2043 influences cellular responses to growth factor signaling, including changes in the distribution of specific growth factor receptors and processes involved in vessel stability and permeability . Finally, in Specific Aim 3, optimal formulations for the anti-angiogenic activity of SP2043-coated nanoparticles will be investigated using mouse xenograft models of the MDA-MB-231 TNBC cell line in order to improve the bioavailability and test the efficacy of these compounds. Together, these experiments will allow for the better characterization of SP2043’s multimodal inhibition and pave the way for its development as a targeted therapy for the treatment of TNBC.