OVERCOMING THE PROTECTIVE BARRIERS OF BREAST CANCER IN BONE MARROW WITH TARGETED PRODRUG NANOTHERAPY

女性一生中患乳腺癌的风险为1/8，使其成为第二大致癌原因。 死亡率低于肺癌。30%的I至III期疾病患者骨髓无症状（BM） 微转移，这增加了癌症复发的可能性以及并发症，如 病理性骨折，并与溶骨性疾病的性质。即使是早期阶段的患者 在原发部位对化疗或激素治疗反应良好的患者，可能在多年后复发， 先前在骨髓小生境内受到保护的休眠骨髓微转移复发。 我们最近的研究表明，乳腺癌转移在骨髓基质细胞存在的情况下， 细胞，在体外和体内，上调αvβ3-整合素表达，导致显着降低敏感性， 全身化疗此外，这些数据表明，TGF-β3在骨微基质中被隔离 释放以诱导αvβ3-整联蛋白上调。利用这种骨BC靶向，αvβ3靶向混合胶束 （~ 15 nm）的掺入Sn 2脂肪酶不稳定的多西他赛（DTX）前药（DTX-PD）（αvβ3-DTX-PD MP）。 开发了快速和均匀地渗透到所示的肿瘤中，并将DTX治疗直接递送到 通过一种新的方法，称为“接触促进药物输送”（CFDD）。αvβ3-DTX-PD MP 显著降低骨髓BC肿瘤负荷和溶骨性损伤，脱靶效应可忽略不计， 而高达4倍高剂量的全身性DTX对肿瘤进展没有影响，但引起肝细胞凋亡。 和血液毒性。 然而，许多骨BC患者可能以前接受过DTX。从这个角度来看， 认识到乳腺癌骨转移的“干细胞”性质， 开发了CPT-PD前药以提供新的患者初始治疗。CPT是拓扑异构酶1（TOPO 1） 抑制剂与对癌症干细胞具有细胞毒性的强效缺氧诱导因子1-α（HIF-1α）抑制剂。 本提案研究了αvβ3-CPT-PD-MP或αvβ3-DTX-PD MP纳米系统的有效性和安全性 针对骨BC肿瘤、微转移、休眠肿瘤细胞提供有效的骨治疗， 降低乳腺癌微转移复发的风险。 该提案解决了BC骨带来的未满足的治疗挑战和医疗需求 转移该项目将描述αvβ3-Sn 2-前药胶束的骨BC有效性和安全性， 阐明关键的骨微基质成分如TGF-β和αvβ3+肿瘤相关的影响， 巨噬细胞（M2 TAMS）和αvβ3+破骨细胞对治疗反应的影响。翻译的总体目标 更有效地治疗骨中的4期乳腺癌患者（目标1和2），并增加 通过治疗隐匿性乳腺癌微转移以减少1 - 3期BC患者的持久治愈率 疾病复发（目标3）。

Women have a 1 in 8 lifetime risk of breast cancer making it their second highest oncogenic cause of mortality behind lung cancer. Thirty percent of patients with stage I to III disease have silent bone marrow (BM) micro-metastases, which increase their likelihood of cancer recurrence as well as complications, such as pathological fractures, and related to the osteolytic nature of the disease. Even patients with limited early-stage disease, who responded well to chemo- or hormonal therapy at the primary site, may relapse years later when dormant bone marrow micro-metastases, previously protected within the bone marrow niche, recrudesce. Our research has recently revealed that breast cancer metastasis in the presence of bone marrow stromal cells, in vitro and in vivo, up-regulated αvβ3-integrin expression, leading to marked diminished sensitivity to systemic chemotherapy. Moreover, these data indicated that TGF-β3 sequestered in the bone microstroma was liberated to induce αvβ3-integrin up-regulation. Utilizing this bone BC target, αvβ3-targeted mixed micelles (~15nm) incorporating Sn2 lipase-labile docetaxel (DTX) prodrug (DTX-PD) (αvβ3-DTX-PD MP) were developed to rapidly and homogeneously penetrate into the tumor shown and deliver DTX therapy directly into the cell through a novel approach, termed "Contact Facilitated Drug Delivery" (CFDD). αvβ3-DTX-PD MP markedly reduced bone marrow BC tumor burden and osteolytic damage with negligible off-target effects, whereas systemic DTX at up to 4-fold higher doses had no impact on tumor progression yet elicited hepatic and hematologic toxicity. However, many patients with bone BC likely will have previously received DTX. From this perspective and recognizing the "stem cell" nature of breast cancer bone metastases, a camptothecin (CPT) Sn2 lipase-labile prodrug (CPT-PD) was developed to offer a new patient-naive treatment. CPT is a topoisomerase 1 (TOPO 1) inhibitor with powerful hypoxia-inducible factor 1-alpha (HIF-1α) inhibitor that is cytotoxic to cancer stem cells. This proposal investigates the efficacy and safety the αvβ3-CPT-PD-MP or αvβ3-DTX-PD MP nanosystems against the bone BC tumors, micro-metastases, dormant tumor cells to provide potent therapy to bone and to reduce the risk of breast cancer relapse from micrometastases. This proposal addresses the unmet therapeutic challenge and medical need posed by BC bone metastases. This project will delineate the bone BC efficacy and safety of αvβ3-Sn2-prodrug micelles and also elucidate the impact of key bone microstroma constituents such as TGF-β and αvβ3+ tumor associated macrophages (M2 TAMS) and αvβ3+ osteoclasts on treatment responses. The translational overarching goals are to more effectively treat patients with Stage 4 breast cancer in bone (Aims 1& 2), and to increase the enduring cure rate for Stage 1 to 3 BC patients by treating occult breast cancer micro-metastases to diminish disease relapse (Aim 3).