Developing targeted therapy with prostate cancer specific nanomedicine

开发前列腺癌特异性纳米药物的靶向治疗

• 批准号: 9325475
• 负责人: Jer-Tsong Hsieh
• 金额: $ 31.49万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325475
• 关键词: Ablation; Address; Adverse effects; Affinity; Age; Aging; American; Androgens; Animal Model; Antineoplastic Agents; Area; Biocompatible Materials; Cancer Patient; Castration; Cell Death; Cell model; Cells; Clinical; DNA Damage; Detection; Development; Disease; Drug Delivery Systems; Drug Monitoring; Drug resistance; Engineering; FDA approved; Goals; Image; Investigational Therapies; Kidney; Knowledge; Left; Legal patent; Liver; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Metastatic/Recurrent; Modeling; Monitor; Mus; Mutagens; Nanotechnology; Neoplasm Metastasis; Outcome; Outcome Study; Patients; Peptides; Permeability; Phenotype; Polymers; Population; Property; Prostatic Neoplasms; Quality of life; Radiation; Recurrence; Regimen; Reporting; Research; Resistance; Solid Neoplasm; Specificity; Spleen; Stem cells; Structure of base of prostate; System; Technology; Therapeutic; Therapeutic Agents; Time; Treatment Efficacy; androgen sensitive; base; biodegradable polymer; biomaterial compatibility; cancer cell; cancer initiation; cancer prevention; cancer recurrence; cancer stem cell; cancer therapy; castration resistant prostate cancer; cell type; chemotherapeutic agent; chemotherapy; clinically relevant; combat; cytolethal distending toxin; deprivation; design; early onset; effective therapy; fluorescence imaging; imaging capabilities; improved; in vivo; innovation; intravenous injection; killings; men; metastasis prevention; molecular imaging; mortality; nanomedicine; nanoparticle; neoplastic cell; novel therapeutic intervention; personalized medicine; poly(lactide); pre-clinical; prevent; prostate cancer cell; public health relevance; response; self-renewal; targeted agent; targeted treatment; theories; therapy development; therapy resistant; tumor; tumor heterogeneity; tumor progression; uptake

DESCRIPTION (provided by applicant): Prostate cancer (PCa) has surpassed lung cancer as the leading cancer among American men. The majority of patients have already developed metastatic lesions at initial clinical presentation and androgen ablation has become a standard therapy because PCa is an androgen-dependent (AD) disease. Inevitably, the recurrence of castration resistant PCa (CRPC) will result in mortality of patients since CRPC cells are resistant to conventional chemotherapy. Moreover, because of high age, PCa patients often do not have favorable physical conditions to tolerate undesirable side effects of chemotherapy. Thus, developing a new, safe and effective therapy becomes a high priority. Although PCa patient survival with newly developed therapeutic regimens has been significantly improved, PCa remains incurable. One of the possible theories to explain the recurrence and ineffectiveness of cancer treatment is the cancer stem cell (CSC) model in which a subset of tumor cells is responsible for cancer initiation and progression as well as cancer recurrence. These CSCs share with normal stem cells the properties of self-renewal, immortal and differentiation into a variety of cell types including heterogeneous lineages of cancer cells. Also CSC can re-grow from a few cells left behind after therapy, it will be important to develop therapies that are more specifically directed against CSCs. Thus, targeting cancer stem cell is now becomes an active research area of cancer therapy to achieve the ultimate cure. In order to target PCa specifically, we are developing a new biodegradable and biocompatible nanoparticle that can target PCa specifically with imaging capabilities. Using this unique delivery system, we propose to engineer a unique genotoxin that can preferentially kill PCa cells expressing stem cell properties then evaluate the therapeutic efficacy of PCa monitored by molecular imaging in pre-clinical animal models. We expect be able to monitor the drug delivery and/or response of cancer cells in a real-time manner. This experimental therapy could become a better regimen for treating CRPC because this agent has a PCa specificity, which is expected to be less toxic than chemotherapeutic agents. Most importantly, this proposal is to explore a new avenue of tailored therapy in contrast to conventional therapeutic strategy; we expect that the outcome of this study should have an immediate clinical impact on CRPC therapy.

描述（由申请人提供）：前列腺癌（PCa）已超过肺癌，成为美国男性的头号癌症。大多数患者在最初的临床表现时就已经出现转移性病变，并且雄激素消融已成为标准治疗方法，因为 PCa 是一种雄激素依赖性 (AD) 疾病。由于去势抵抗性PCa（CRPC）细胞对常规化疗具有抵抗力，其复发将不可避免地导致患者死亡。此外，由于PCa患者年龄较大，身体状况往往较差，无法耐受化疗带来的不良副作用。因此，开发一种新的、安全且有效的疗法成为当务之急。 尽管新开发的治疗方案使 PCa 患者的生存率得到显着改善，但 PCa 仍然无法治愈。解释癌症治疗复发和无效的可能理论之一是癌症干细胞（CSC）模型，其中肿瘤细胞的子集负责癌症的发生和进展以及癌症复发。这些CSC与正常干细胞一样具有自我更新、永生和分化成多种细胞类型（包括异质癌细胞谱系）的特性。此外，CSC 可以从治疗后留下的一些细胞中重新生长，因此开发更专门针对 CSC 的疗法非常重要。因此，靶向癌症干细胞现已成为癌症治疗的一个活跃研究领域，以实现最终治愈。为了专门针对前列腺癌，我们正在开发一种新型可生物降解且具有生物相容性的纳米颗粒，它可以专门针对前列腺癌，并具有成像能力。利用这种独特的递送系统，我们建议设计一种独特的基因毒素，可以优先杀死表达干细胞特性的 PCa 细胞，然后评估临床前动物模型中通过分子成像监测的 PCa 的治疗效果。我们期望能够实时监测癌细胞的药物输送和/或反应。这种实验性疗法可能成为治疗 CRPC 的更好方案，因为该药物具有 PCa 特异性，预计其毒性低于化疗药物。最重要的是，该提案旨在探索一种与传统治疗策略不同的定制治疗新途径；我们预计这项研究的结果会对 CRPC 治疗产生直接的临床影响。

项目成果

Sensitization of radio-resistant prostate cancer cells with a unique cytolethal distending toxin.

• DOI: 10.18632/oncotarget.2133
• 发表时间: 2014-07-30
• 期刊: Oncotarget
• 作者: Lai CH;Chang CS;Liu HH;Tsai YS;Hsu FM;Yu YL;Lai CK;Gandee L;Pong RC;Hsu HW;Yu L;Saha D;Hsieh JT
• 通讯作者: Hsieh JT

Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy.

• DOI: 10.3389/fcimb.2017.00223
• 发表时间: 2017
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Lin HJ;Liu HH;Lin CD;Kao MC;Chen YA;Chiang-Ni C;Jiang ZP;Huang MZ;Lin CJ;Lo UG;Lin LC;Lai CK;Lin H;Hsieh JT;Chiu CH;Lai CH
• 通讯作者: Lai CH

Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer.

• DOI: 10.1158/1078-0432.ccr-15-0190
• 发表时间: 2016-02-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Yun EJ;Zhou J;Lin CJ;Hernandez E;Fazli L;Gleave M;Hsieh JT
• 通讯作者: Hsieh JT