A Novel Therapeutic Approach for Primary and Metastatic Prostate Cancer

描述（由申请人提供）：本项目的主要目标是进行与靶向蛋白激酶CK 2（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，从而实现癌症的根除。CK 2已经成为细胞功能的“主调节器”，具有决定细胞命运的深刻能力。CK 2在所有检查过的癌症中均上调。由于细胞增殖和死亡的失调是癌细胞表型的标志，因此CK 2在癌细胞中的重要性通过以下事实来强调：CK 2不仅是细胞生长和增殖的促进剂，而且是细胞凋亡的有效抑制剂。我们对前列腺细胞病理学中CK 2功能的研究表明，CK 2的下调导致体内细胞凋亡的有效诱导。基于我们最初提出的靶向CK 2信号用于前列腺癌治疗的建议，我们已经开发了通过使用针对催化亚基CK 2a和CK 2a '的反义ODN（称为双特异性反义CK 2或bs-As-CK 2）来实现CK 2的分子下调的策略。此外，我们还设计了一种新的小于50 nm尺寸的替诺根纳米胶囊（亚50 nm替诺根纳米胶囊或s50 TBG纳米胶囊），其将其bs-As-CK 2货物特异性地递送至肿瘤细胞，克服了非特异性药物递送的重要问题。因此，我们的中心假设是，在用于肿瘤细胞特异性靶向的纳米胶囊递送载体中采用bs-As-CK 2的催化性CK 2a和CK 2a '亚基的分子下调将导致诱导体内广泛的细胞死亡，不仅导致疾病稳定，而且还导致原发性和转移性前列腺肿瘤的根除。所提出的策略具有很强的成功潜力，因为（a）CK 2的下调应该影响前列腺癌细胞中的增殖和凋亡活性，并且（B）CK 2的损失不能被细胞中的另一种信号替代。在小鼠模型中进行的拟议实验评价了短期和长期研究中的剂量反应，并纳入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这种新型治疗方法在原发性和转移性前列腺癌的未来转化至关重要。 公共卫生相关性：前列腺癌是美国男性癌症相关死亡的第二大常见原因。目前的疗法仅实现部分疾病稳定，并且没有真正的治愈方法可用于致命的去势抵抗性前列腺癌。这项研究与公共卫生有关，因为它的目标是通过靶向癌细胞中不可或缺的信号，产生一种治疗方法，从而导致癌症治疗的范式转变。

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. PUBLIC HEALTH RELEVANCE: Prostate cancer is the second most common cause of cancer related deaths in men in the U.S.A. Current therapies achieve only partial disease stabilization, and no truly curative approaches are available for the lethal castration resistant prostate cancer. The proposed research is relevant to public health because its goal is to generate a therapeutic approach that could lead to a paradigm shift in cancer therapy by targeting an indispensible signal specifically in cancer cells.