This Synergistic IDEA project seeks to develop a novel strategy to effectively target ErbB2-overexpressing breast cancer with anti-ErbB2 antibody coated nanogels carrying potent chemotherapeutics in combination with HSP90 inhibitors to enhance the endocytosis of ErbB2-receptor bound nanogel cargo. A successful outcome of our studies will provide a new therapeutic approach against a particularly difficult form of breast cancer and may provide a template for therapeutic targeting of other forms of breast cancer and other cancers. Success in preclinical models would also provide strong rationale for clinical translation of this technology with the ultimate goals of selective delivery of imaging and therapeutic modalities to tumors. Robust procedures for the synthesis of nanogels were developed, key structural parameters of block copolymers governing the physicochemical properties of the nanogels were identified, nanogels loaded with combination of anticancer therapeutics and methods for the preparation of ErbB2-targeted nanogels were developed, Mannose functionalized BICs provided a safe and stable platform for gene delivery to macrophages, doxorubicin-nanogels showed an efficient systemic drug delivery to human tumor xenografts.

关键词：医药；治疗技术；乳腺癌；纳米丰胸癌症治疗；临床医学

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关键词：医药；治疗技术；PTEN基因；前列腺癌

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Dissemination and metastasis of tumor cells are major causes of morbidity and mortality in breast cancer patients. Therefore it is of vital importance to identify druggable targets to inhibit breast tumor invasion and metastasis. A critical component in the invasive growth, dissemination, and metastasis of cancer is acquisition of motility by tumor cells. Our preliminary studies suggest a novel role for the thromboxane A2 receptor (TP) in controlling breast tumor cell motility via regulating cytoskeleton reorganization. The objective of this proposal is to define the function of TP in tumor cell motility and to validate TP as a target for anti-metastasis therapy of breast cancer. In the first aim, the role of TP in breast tumor cell motility will be determined in the presence or absence of TP activation or inhibition. The isoform(s) of TP involved in tumor cell contraction and motility will be identified in the second specific aim. In the third aim, an orthotopic mouse model will be used to assess whether TP can be targeted to reduce breast cancer metastasis. The proposed studies will be highly significant toward the goals of developing mechanism-based interventions for cancers.

关键词：医药；治疗技术；乳腺癌；抗转移治疗；G蛋白偶联受体

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The goal of this research is to firmly establish the mechanism of androgen receptor (AR)-JunD heterodimer induction of the SSAT gene leading to oxidative stress that contributes to the development and progression of prostate cancer (PCa), and to identify small molecules that specifically inhibit this AR-JunD interaction and prevent development/progression of PCa in pre-clinical models. Data from this research will identify the most efficacious drug to be further developed in preclinical toxicity testing and clinical trials for PCa that fall beyond the scope of this proposal. Significant findings during Year 2 of the research include: identification of two non- antiandrogenic AR-JunD inhibitors that significantly inhibit ROS production and androgen-dependent and -independent growth in PCa cells; and determination that the lead compound is orally bioavailable and therefore a promising clinical drug candidate to be further tested for efficacy against preclinical animal models of PCa as proposed.

关键词：医药；治疗技术；前列腺癌；临床试验；基因；抑制剂

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Xavier University of Louisiana is in the unique position of developing capability in drug discovery especially in the areas of cancer and health disparities. A significant proportion of the funded research on Xavier s campus including collaborative projects involving Tulane University are related to cancer, drug design, synthesis, and drug delivery. This project expands the partnership between Xavier University and Tulane Cancer Center to develop and validate drugs for breast cancer therapy. The Drug Design Team at Xavier consists of experts in computer aided drug design methods and synthesis and has formed a productive partnership with the Cancer Drug Validation Team at the Tulane Cancer Center. This inter-university collaboration involves training Xavier researchers, including undergraduate students, to carryout the experiments necessary to determine if new compounds would be suitable as new drugs to treat breast cancer. Three separate studies are ongoing as subprojects: (1) Design and synthesis of novel ceramide analogs that potentially reverse chemotherapy drug resistance, (2) Design and synthesis of small molecule inhibitors of HER2 tyrosine kinase to suppress tumorigenesis, and (3) Identification of compounds with the potential for estrogen receptor activity.

关键词：医药；治疗技术；乳腺癌；医学研究；磷转移

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Bone is the most common site of metastasis for human breast cancer (BCa), which results in significant morbidity and mortality in patients with advanced disease. A vicious cycle, arising due to the interaction of BCa cells and cells in the bone microenvironment results in the activation of osteoclasts and increased osteolytic bone destruction. The major treatment to reduce the burden of bone metastasis in BCa patients is bisphosphonate therapy. Despite significant efforts to improve the potency of bisphosphonates, the complications are only retarded but not prevented. Thus, development of newer therapies that can both ameliorate the threshold of bone destruction and increase survival of patients with metastatic breast disease will be highly beneficial. The central hypothesis of the proposed work is bone-targeted delivery of genetically-engineered MSC, over-expressing OPG, will prevent osteolytic bone damage and restore skeletal remodeling. Further, based on the requirement of angiogenesis for tumor growth in primary and metastatic sites, in combination with a systemically stable anti-angiogenic therapy, long-term survival will significantly increase. These hypotheses will be tested in this proposal using an immnocompetent, preclinical mouse model of BCa dissemination to all major bones as in human patients.

关键词：医药；治疗技术；乳腺癌；骨溶解；临床医学

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The project is intended to determine whether a specific nitric oxide- mediated tumor stress response pathway that is initiated following a cytotoxic injury (1) is observed in prostate cancer xenografts and (2) can be inhibited by the administration of dietary glycine supplementation. The rationale is based upon prior preclinical studies establishing, for other solid tumor types, that upregulation of inducible nitric oxide synthase (iNOS) in activated macrophages recruited to the site of cytotoxic injury from radiation or chemotherapy leads to the production of NO that stabilizes hypoxia-inducible factor 1-alpha, which in turns leads to increased expression of vascular endothelial growth factor (VEGF). As a result of this signaling process, tumor angiogenesis is supported, leading to recovery from the initial cytotoxic injury. It is believed that inhibiting this NO-mediated process of angiogenesis can enhance the cytotoxicity of radiation or chemotherapy, and it is believed that glycine might be an effective.

关键词：医药；治疗技术；前列腺癌；甘氨酸；放射疗法

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There are several new emerging monitoring technologies for combat casualty care that can be used as platforms for decision assist (D-A) and closed loop resuscitation (CLR) algorithms. It is our goal to evaluate these and other novel technologies with algorithms for fluid resuscitation in hemorrhaged human volunteers and patient studies.

关键词：医药；治疗技术；流体输送系统；决策辅助；闭环系统

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关键词：医药；治疗技术；乳腺癌；卡尔曼滤波；放疗

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Underlying mechanisms that account for the increased risk of aggressive, metastatic disease associated with basal type breast cancers compared to the more differentiated, luminal tumor subtype have not been well established. Our work demonstrates that the transcription factor GATA3, essential for luminal differentiation during mammary gland development, is sufficient to promote global changes in basal triple-negative breast cancer (BTNBC) cells resulting in both (1) reduced metastasis via LOX downregulation and (2) acquisition of luminal features, thus offering a direct link between these two processes. GATA3 promoted global alterations of the transcriptome of BTNBC cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase (LOX) expression, a metastasis promoting matrix remodeling protein, via epigenetic changes. MDA-MB-231 breast cancer cells overexpressing GATA3 showed increased methylation at the LOX promoter compared to control cells. Expression of LOX and GATA3 in breast cancer cells were inversely correlated. Most importantly, elevated LOX and reduced GATA3 expression levels predicted poor survival in breast cancer patients. Thus, altering transcription factor expression that promotes differentiation may be an important approach to mitigate aggressive tumor characteristics and to identify therapeutic targets such as LOX for the prevention or treatment of metastatic disease.

关键词：医药；治疗技术；乳腺癌；预防医学；分化治疗

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