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).

女性一生中患乳腺癌的风险为八分之一，使其成为第二大致癌原因

项目成果

Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer.

放射性核素将化学治疗剂转化为光疗法，以精确治疗传播癌症。

• DOI: 10.1038/s41467-017-02758-9
• 发表时间: 2018-01-18
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Kotagiri N;Cooper ML;Rettig M;Egbulefu C;Prior J;Cui G;Karmakar P;Zhou M;Yang X;Sudlow G;Marsala L;Chanswangphuwana C;Lu L;Habimana-Griffin L;Shokeen M;Xu X;Weilbaecher K;Tomasson M;Lanza G;DiPersio JF;Achilefu S
• 通讯作者: Achilefu S

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

Loss of Consciousness in a 34 Yo Male Related to Marijuana.

一名 34 岁男性因吸食大麻而失去意识。

• DOI: 10.29011/2574-7754.101468
• 发表时间: 2023
• 期刊: Annals of case reports
• 作者: Merchant,Azim;Singareddy,Aashray;McCabe,Leighton;Raghupathy,Rachana;Wang,Qianli;Hwang,Daniel;Zajarias,Alan;Lanza,GregoryM
• 通讯作者: Lanza,GregoryM

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

心脏MRI中基于AI的计划和光滑技术的实施和前瞻性临床验证。

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

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