Integrating Anti-invasive and Anti-growth Therapies Targeting Cancer Metastasis

描述（由申请人提供）：存在开发新型化疗药物的未满足的需求，所述新型化疗药物增强靶向耐药肿瘤的选择性和特异性。特别是，缺乏攻击化疗不敏感的癌症干细胞/肿瘤起始细胞（TICs）的新策略。该提案的目标是了解在向侵袭和转移过渡期间TIC与其微环境之间的相互作用，以及开发一种新型治疗试剂，以在临床前环境中特异性诱导侵袭性TIC死亡。我们的中心假设是，细胞表面锚定的蛋白酶，基质金属蛋白酶-14（MMP-14），是一个关键的分子，能够执行开关上皮TIC从静止到侵袭性细胞，从而控制转移。开发利用MMP-14结合肽选择性和特异性靶向侵袭性TIC的试剂将有助于预防癌症扩散。该项目的基本原理是，开发一种携带抑制肽和细胞毒性药物的特异性肿瘤归巢载体将使我们不仅能够阻断癌症侵袭，而且还能诱导癌细胞死亡。此外，这项研究将促进我们对微环境如何影响静止TIC引起转移的理解。我们计划通过追求以下三个具体目标来测试我们的假设：1）阐明MMP-14在缺氧条件下将静止TIC转化为侵袭性细胞中的作用和机制; 2）定义MMP-14归巢肽的作用机制;和3）开发特异性靶向癌症侵袭并诱导癌细胞死亡的双功能试剂。关于预期的结果，本申请中提出的工作将潜在地导致双功能试剂的开发 能够将有效的化疗药物递送至侵袭性TIC。该项目具有创新性，因为它利用了MMP-14特异性的新型肽来选择性靶向侵袭性TIC。这项研究将对未来产生重大影响，因为它有望垂直推进我们对静止TIC如何在缺氧环境中重编程为侵入性TIC的理解。开发的双功能试剂将对未来的癌症预防/治疗产生积极影响，并最终改善癌症患者的预后。

DESCRIPTION (provided by applicant): There is an unmet need to develop novel chemotherapeutics that enhance selectivity and specificity for targeting chemo-resistant tumors. In particular, new strategies that attack chemotherapy-insensitive cancer stem cells/tumor initiating cells (TICs) are lacking. The goal of this proposal is to understand the interplay between TICs and their microenvironment during the transition to invasion and metastasis, as well as to develop a novel treatment reagent to specifically induce invasive TIC death in a preclinical setting. Our central hypothesis is that a cell surface-anchored protease, matrix metalloproteinase-14 (MMP-14), is a key molecule capable of executing the switch in epithelial TICs from quiescent to invasive cells, thereby controlling metastasis. Development of reagents to selectively and specifically target invasive TICs utilizing an MMP-14 binding peptide will facilitate prevention of cancer dissemination. The rationale for this project is that the development of a specific tumor-homing vehicle that carries inhibitory peptide and cytotoxic drug will allow us to not only block cancer invasion but to also induce cancer cell death. Furthermore, this study will advance our understanding of how the microenvironment influences quiescent TICs to give rise to metastases. We plan to test our hypothesis by pursuing the following three specific aims:1) Elucidate the role and mechanism of MMP-14 in conversion of quiescent TICs to invasive cells under hypoxic conditions; 2) Define the mechanism of action of an MMP-14 homing peptide; and 3) Develop a bi-functional reagent that specifically targets cancer invasiveness and induces cancer cell death. With respect to the expected outcomes, the work proposed in this application will potentially result in development of a bi-functional reagent capable of delivering a potent chemotherapeutic drug to invasive TICs. This project is innovative because it utilizes novel peptides specific for MMP-14 to selectively target invasive TICs. The proposed research will have significant future implications because it is expected to vertically advance our understanding of how quiescent TICs become reprogrammed into invasive TICs in a hypoxic environment. The developed bi-functional reagent will have a positive impact on future cancer prevention/treatment and could eventually improve the outcome of patients with cancer.