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

通过靶向前药纳米疗法克服骨髓中乳腺癌的保护性屏障

• 批准号: 10320444
• 负责人: Gregory M Lanza
• 金额: $ 61.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-12 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320444
• 关键词: Address; Adjuvant; Biological Availability; Biology; Biopsy; Bone Marrow; Bone Pain; Bone neoplasms; Breast; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast cancer metastasis; Camptothecin; Cancer Biology; Cancer Model; Cancer Relapse; Cells; Chemoprotective Agent; Chemoresistance; Clinical; Data; Dependence; Development; Disease; Doctor of Philosophy; Dose; Drug Delivery Systems; Effectiveness; Goals; Hematology; Hepatic; Heterozygote; Human; ITGB3 gene; Image; Implant; In Vitro; Integrin alphaVbeta3; Journals; Lipase; Malignant Bone Neoplasm; Malignant neoplasm of lung; Mammary Neoplasms; Mastectomy; Medical; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Micelles; Micrometastasis; Mus; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Oncogenic; Oncologist; Oncology; Operative Surgical Procedures; Osteoclasts; Osteolytic; Pathological fracture; Patients; Pharmaceutical Preparations; Physicians; Prodrugs; Quality of life; Radiation; Recurrent disease; Relapse; Research; Resistance; Safety; Scientist; Site; Stromal Cells; Surveys; Testing; Therapeutic; Therapeutic Human Experimentation; Topoisomerase; Toxic effect; Transforming Growth Factor beta; Tumor Burden; Tumor-associated macrophages; Up-Regulation; Visceral; Visceral metastasis; Woman; anticancer research; bone; cancer recurrence; cancer stem cell; cancer subtypes; cell type; chemotherapy; clinical investigation; clinically relevant; cytotoxic; docetaxel; dosimetry; hormone therapy; hypoxia inducible factor 1; improved; in vivo; inhibitor; lifetime risk; malignant breast neoplasm; mortality; nanomedicine; nanosystems; nanotherapy; neoplastic cell; novel strategies; programs; relapse risk; response; selective expression; skeletal; spinal cord compression; stem cells; transforming growth factor beta3; treatment response; tumor; tumor progression

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).

妇女患乳腺癌的终生风险中有1个，使其成为其第二高的致癌原因 肺癌背后的死亡率。 I期至III疾病的患者中有30％的患者具有无声的骨髓（BM） 微焦点酶增加了其癌症复发的可能性以及并发症，例如 病理骨折，与疾病的骨质性质有关。甚至早期有限的患者 在主要部位对化学或激素治疗反应良好的疾病可能会在几年后传达 休眠的骨髓微糖浆酶，以前在骨髓小裂中受到保护，饲养。 我们的研究最近揭示了在骨髓间基质存在下的乳腺癌转移 细胞在体外和体内，上调的αVβ3-整合蛋白表达，导致对对 全身化疗。此外，这些数据表明TGF-β3在骨微观状态隔离 利用该骨BC靶标，αVβ3为靶向的混合胶束 （〜15nm）掺入的SN2脂肪酶-Labile多西他赛（DTX）前药（DTX-PD）（αVβ3-DTX-PD MP）为 开发成快速和均匀地渗透到显示的肿瘤中，并将DTX疗法直接传递到 通过一种新颖的方法，该细胞称为“接触促进药物输送”（CFDD）。 αVβ3-DTX-PD MP 明显降低了骨髓BC肿瘤伯恩和骨化损伤，而脱靶效应可忽略不计 剂量高达4倍的全身性DTX对肿瘤进展没有影响，但引起了肝 和血液学毒性。 但是，许多骨BC患者以前可能会接受DTX。从这个角度和 识别乳腺癌骨转移的“干细胞”性质，一种camptothecin（CPT）SN2脂肪酶 - 脂肪 开发前药（CPT-PD）可提供新的患者治疗。 CPT是拓扑异构酶1（TOPO 1） 具有强大缺氧诱导因子1-α（HIF-1α）抑制剂的抑制剂，对癌症干细胞具有细胞毒性。 该提案研究了αVβ3-CPT-PD-MP或αVβ3-DTX-PD MP纳米系统的效率和安全性 针对骨BC肿瘤，微焦糖酶，休眠肿瘤细胞，可为骨提供潜在的治疗和 降低乳腺癌从微转移酶减轻的风险。 该提案解决了卑诗骨骨骼所提出的未满足的治疗挑战和医疗需求 转移。该项目将描述αVβ3-SN2-grodrug胶束的骨BC效率和安全性 阐明钥匙骨微观瘤的影响构成了TGF-β和αVβ3+肿瘤的影响 巨噬细胞（M2 TAM）和αVβ3+破骨细胞在治疗反应上。翻译的总体目标 将更有效地治疗骨骼中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糖浆减少的乳腺癌，持久治愈率 疾病缓解（AIM 3）。

项目成果

VLA4-Targeted Nanoparticles Hijack Cell Adhesion-Mediated Drug Resistance to Target Refractory Myeloma Cells and Prolong Survival.

• DOI: 10.1158/1078-0432.ccr-20-2839
• 发表时间: 2021-04-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Fontana F;Scott MJ;Allen JS;Yang X;Cui G;Pan D;Yanaba N;Fiala MA;O'Neal J;Schmieder-Atteberry AH;Ritchey J;Rettig M;Simons K;Fletcher S;Vij R;DiPersio JF;Lanza GM
• 通讯作者: Lanza GM

Implementation and prospective clinical validation of AI-based planning and shimming techniques in cardiac MRI.

• DOI: 10.1002/mp.15327
• 发表时间: 2022-01
• 期刊: Medical physics
• 影响因子: 3.8

Local Intratracheal Delivery of Perfluorocarbon Nanoparticles to Lung Cancer Demonstrated with Magnetic Resonance Multimodal Imaging.

通过磁共振多模态成像证实全氟化碳纳米粒子局部气管内递送至肺癌

• DOI: 10.7150/thno.21466
• 发表时间: 2018
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Wu L;Wen X;Wang X;Wang C;Sun X;Wang K;Zhang H;Williams T;Stacy AJ;Chen J;Schmieder AH;Lanza GM;Shen B
• 通讯作者: Shen B

Ultrasound Imaging: Something Old or Something New?

• DOI: 10.1097/rli.0000000000000679
• 发表时间: 2020-09
• 期刊: Investigative radiology
• 影响因子: 6.7
• 作者: Lanza GM

Cellular Trafficking of Sn-2 Phosphatidylcholine Prodrugs Studied with Fluorescence Lifetime Imaging and Super-resolution Microscopy.

使用荧光寿命成像和超分辨率显微镜研究 Sn-2 磷脂酰胆碱前药的细胞贩运。

• DOI: 10.33218/prnano1(2).180724.1
• 发表时间: 2018
• 期刊: Precision nanomedicine
• 作者: Maji,Dolonchampa;Lu,Jin;Sarder,Pinaki;Schmieder,AnneH;Cui,Grace;Yang,Xiaoxia;Pan,Dipanjan;Lew,MatthewD;Achilefu,Samuel;Lanza,GregoryM
• 通讯作者: Lanza,GregoryM