A Novel Therapeutic Approach for Primary and Metastatic Prostate Cancer

原发性和转移性前列腺癌的新治疗方法

基本信息

批准号：
8613312
负责人：
Khalil Ahmed
金额：
$ 28.36万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-04 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8613312
关键词：
Abbreviations Ablation Acute Address Advanced Malignant Neoplasm Androgen Receptor Androgens Apoptosis Apoptotic Biodistribution Cancer Etiology Castration Catalytic Domain Cell Death Cell Death Induction Cell Proliferation Cell physiology Cells Cessation of life Characteristics Data Disease Disseminated Malignant Neoplasm Distant Metastasis Dose Down-Regulation Drug Delivery Systems Drug Kinetics Evaluation Future Goals Human Induction of Apoptosis Interruption Investigation Lead Longitudinal Studies Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Modeling Molecular Mus Names Nature Normal Cell Normal tissue morphology Nucleic Acids Oligonucleotides Organ Outcome Phenotype Prostate Prostate Cancer therapy Prostate-Specific Antigen Prostatic Public Health Publishing Research Resistance Signal Transduction Specificity System Therapeutic Therapeutic Agents Toxic effect Translations Work Xenograft Model Xenograft procedure acronyms base bone cancer cell cancer therapy casein kinase II castration resistant prostate cancer cell growth design design and construction in vivo innovation lymph nodes men mortality mouse model nanocapsule nanoencapsulated nanoscale neoplastic cell novel novel therapeutic intervention phosphorothioate preclinical study promoter prostate cancer cell prostate cancer model public health relevance red fluorescent protein research study response success therapeutic target tumor uptake

项目摘要

DESCRIPTION (provided by applicant): The primary goal of this project is to undertake preclinical studies relating to targeting of protein kinase CK2 (formerly casein kinase 2 or II) for prostate cancer therapy so that an eradication of cancer is achieved. CK2 has emerged as a "master regulator" of cell function with a profound ability to determine cell fate. CK2 is upregulated in all cancers that have been examined. Since deregulation of cell proliferation and death are hallmarks of the cancer cell phenotype, the importance of CK2 in cancer cells is underscored by the fact that CK2 is not only a promoter of cell growth and proliferation but also a potent suppressor of apoptosis. Our studies on CK2 function in prostate cell pathobiology have demonstrated that downregulation of CK2 results in potent induction of apoptosis in vivo. Building on our original proposal to target CK2 signal for prostate cancer therapy, we have developed strategies to achieve molecular downregulation of CK2 by using antisense ODN directed towards both catalytic subunits, CK2a and CK2a', called bispecific antisense CK2 or bs-As-CK2. Further, we have also devised a novel tenfibgen nanocapsule which is less than 50 nm size (sub-50 nm tenfibgen nanocapsule or s50 TBG nanocapsule) that delivers its bs-As-CK2 cargo specifically to the tumor cells overcoming the important issue of non-specific drug delivery. Thus, our central hypothesis is that molecular downregulation of the catalytic CK2a and CK2a' subunits employing bs-As-CK2 in a nanocapsule delivery vehicle for tumor cell-specific targeting will lead to induction of extensive cell death in vivo resulting in not just disease stabilization but rather eradication of primary and metastatic prostatic tumors. The proposed strategies have the strong potential of success because (a) downregulation of CK2 should impact both the proliferative and apoptotic activity in prostate cancer cells, and (b) loss of CK2 cannot be replaced by another signal in the cell. The proposed experiments in mouse models evaluate dose response in short and long term studies, and incorporate biodistribution and pharmacokinetic aspects of the tumor targeting agent. These preclinical studies are essential for future translation of this novel therapeutic approach for both primary and metastatic prostate cancer.

描述（由申请人提供）：该项目的主要目标是进行与靶向蛋白激酶 CK2（以前称为酪蛋白激酶 2 或 II）用于前列腺癌治疗相关的临床前研究，从而实现根除癌症。 CK2 已成为细胞功能的“主调节器”，具有决定细胞命运的强大能力。 CK2 在所有已检查的癌症中均上调。由于细胞增殖和死亡的失调是癌细胞表型的标志，因此 CK2 不仅是细胞生长和增殖的促进剂，而且还是细胞凋亡的有效抑制剂，这一事实强调了 CK2 在癌细胞中的重要性。我们对前列腺细胞病理学中 CK2 功能的研究表明，CK2 的下调可有效诱导体内细胞凋亡。基于我们最初提出的针对前列腺癌治疗的 CK2 信号目标，我们开发了通过使用针对两个催化亚基 CK2a 和 CK2a' 的反义 ODN（称为双特异性反义 CK2 或 bs-As-CK2）来实现 CK2 分子下调的策略。此外，我们还设计了一种尺寸小于 50 nm 的新型 tenfibgen 纳米胶囊（亚 50 nm tenfibgen 纳米胶囊或 s50 TBG 纳米胶囊），可将其 bs-As-CK2 货物特异性递送至肿瘤细胞，从而克服了非肿瘤细胞的重要问题。特定的药物输送。因此，我们的中心假设是，在纳米胶囊递送载体中使用 bs-As-CK2 进行肿瘤细胞特异性靶向的催化 CK2a 和 CK2a' 亚基的分子下调将导致诱导体内广泛的细胞死亡，从而不仅导致疾病稳定而是根除原发性和转移性前列腺肿瘤。所提出的策略具有巨大的成功潜力，因为（a）CK2 的下调会影响前列腺癌细胞的增殖和凋亡活性，（b）CK2 的丢失不能被细胞中的其他信号替代。拟议的小鼠模型实验评估了短期和长期研究中的剂量反应，并结合了肿瘤靶向剂的生物分布和药代动力学方面。这些临床前研究对于未来将这种新的治疗方法转化为原发性和转移性前列腺癌至关重要。