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

描述(由申请人提供)：有一个尚未满足的需求，开发新的化疗药物，以提高选择性和特异性，以靶向化疗耐药肿瘤。特别是，缺乏攻击化疗不敏感的癌症干细胞/肿瘤启动细胞(TICs)的新策略。这项建议的目的是了解TIC在向侵袭和转移的转变过程中与其微环境之间的相互作用，以及开发一种新的治疗试剂来在临床前环境中特异性地诱导侵袭性TIC死亡。我们的中心假设是，一种细胞表面锚定的蛋白酶，基质金属蛋白酶-14(MMP14)，是一个关键分子，能够在上皮抽动中执行从静止细胞到侵袭细胞的切换，从而控制转移。利用基质金属蛋白酶-14结合肽开发选择性和特异性靶向侵袭性抽搐的试剂将有助于预防癌症扩散。这个项目的基本原理是，开发一种携带抑制肽和细胞毒性药物的特定肿瘤归巢载体将使我们不仅能够阻止癌症的侵袭，而且还可以诱导癌细胞死亡。此外，这项研究将促进我们对微环境如何影响静止性抽动从而引起转移的理解。我们计划通过追求以下三个具体目标来验证我们的假设：1)阐明在低氧条件下静止的抽搐转化为侵袭细胞的作用和机制；2)确定MMP-14归宿多肽的作用机制；以及3)开发一种专门针对癌症侵袭性并诱导癌细胞死亡的双功能试剂。就预期结果而言，本申请中提出的工作可能会导致双功能试剂的开发 能够将一种有效的化疗药物输送给侵袭性抽搐。这个项目是创新的，因为它利用针对基质金属蛋白酶-14的新型多肽来选择性地靶向侵袭性抽搐。这项拟议的研究将对未来产生重大影响，因为它有望在垂直方向上推进我们对静止的抽动如何在低氧环境中重新编程为侵袭性抽动的理解。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，并最终可能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.