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八分之一，这是她们患乳腺癌的第二大致癌原因 肺癌背后的死亡率。30%的I-III期患者有无症状的骨髓(BM) 微转移，增加癌症复发的可能性以及并发症，如 病理性骨折，与疾病的溶骨性质有关。即使是早期有限的患者 在原发部位对化疗或激素治疗反应良好的疾病，可能在几年后复发，当 潜伏性的骨髓微转移，以前在骨髓龛内受到保护，复发。 我们的研究最近发现，乳腺癌存在骨髓间质转移 在体外和体内，细胞上调αvβ3-整合素的表达，导致对 全身化疗。此外，这些数据表明，转化生长因子-β-3隔离在骨微基质中。 被释放后诱导αvβ3整合素上调。利用这一骨BC靶点，αvβ3靶向混合胶束 (~15 nm)掺入SN2脂肪酶不稳定多西紫杉醇前药(DTX-PD)(αvβ3-DTX-PD MP) 被开发成快速和均匀地渗透到所示的肿瘤中，并将DTX疗法直接输送到 通过一种新的方法，称为“接触促进药物传递”(CFDD)。αvβ3-dtx-pd MP 显著降低骨髓BC肿瘤负荷和骨溶解损伤，靶外影响可忽略不计， 而全身剂量高达4倍的DTX对肿瘤的进展没有影响，但却引发了肝脏 和血液毒性。 然而，许多骨性BC患者可能以前接受过DTX治疗。从这个角度来看， 认识到乳腺癌骨转移的“干细胞”性质，喜树碱(CPT)SN2脂肪酶不稳定 前药(CPT-PD)是为了给患者提供一种新的治疗方法而开发的。CPT是一种拓扑异构酶1(Topo 1) 含有强大的缺氧诱导因子1-α(HIF-1α)抑制剂的抑制剂，对肿瘤干细胞具有细胞毒性。 该方案研究了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、潜伏的肿瘤细胞提供有力的骨和去骨治疗 降低乳腺癌微转移复发的风险。 这项建议解决了bc bone尚未满足的治疗挑战和医疗需求。 转移瘤。该项目将描述αvβ3-Sn2-前体药物胶束的骨BC有效性和安全性，并 阐明关键的骨微基质成分如转化生长因子-β和αvβ3+肿瘤相关的影响 巨噬细胞(M2 TAM)和αvβ3+破骨细胞对治疗反应的影响。翻译的首要目标 是更有效地治疗骨癌4期患者(目标1和2)，并增加 减少隐匿性乳腺癌微转移对1~3BC期患者持久治愈率的影响 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).