A Novel Therapeutic Approach for Primary and Metastatic Prostate Cancer

描述(由申请人提供)：这个项目的主要目标是进行与前列腺癌治疗的蛋白激酶CK2(以前的酪蛋白激酶2或II)相关的临床前研究，以实现癌症的根除。CK2已成为细胞功能的“主要调节者”，具有决定细胞命运的深刻能力。CK2在所有已被检查的癌症中都表达上调。由于细胞增殖和死亡的解除调控是癌细胞表型的标志，CK2不仅是细胞生长和增殖的促进剂，而且是强大的细胞凋亡抑制因子，这一事实突显了CK2在癌细胞中的重要性。我们在前列腺细胞病理生物学中对CK2功能的研究表明，CK2的下调可以在体内有效地诱导细胞凋亡。在我们最初提出的靶向CK2信号用于前列腺癌治疗的基础上，我们开发了通过使用针对CK2a和CK2a‘催化亚单位的反义ODN来实现CK2分子下调的策略，称为双特异性反义CK2或bs-as-CK2。此外，我们还设计了一种尺寸小于50 nm的新型Tenfigen纳米胶囊(亚50 nm Tenfigen纳米胶囊或S50 TbG纳米胶囊)，它可以将其bs-as-CK2货物特异性地运送到肿瘤细胞，克服了非特异性药物输送的重要问题。因此，我们的中心假设是，在肿瘤细胞特异性靶向的纳米胶囊递送载体中，使用bs-as-CK2的催化CK2a和CK2a‘亚单位的分子下调将导致体内广泛的细胞死亡，从而不仅可以稳定疾病，还可以根除原发和转移的前列腺癌。建议的策略有很大的成功潜力，因为(A)CK2的下调应该影响前列腺癌细胞的增殖和凋亡活性，以及(B)CK2的缺失不能被细胞中的另一种信号所取代。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未来这一治疗前列腺癌和转移性前列腺癌的新方法的推广至关重要。

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.