A Novel Therapeutic Approach for 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蛋白激酶CK2（以前称为酪蛋白激酶2或II）靶向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深刻能力。CK2在所有研究过的癌症中都是上调的。由于细胞增殖和死亡的失调是癌细胞表型的标志，CK2在癌细胞中的重要性被CK2不仅是细胞生长和增殖的促进因子，也是细胞凋亡的有效抑制因子这一事实所强调。我们对前列腺细胞病理生物学中CK2功能的研究表明，体内CK2的下调可有效诱导细胞凋亡。基于我们最初提出的靶向CK2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，我们还设计了一种小于50纳米尺寸的新型tenfibgen纳米胶囊（低于50纳米的tenfibgen纳米胶囊或50 TBG纳米胶囊），它可以将bs-As-CK2特异性地递送到肿瘤细胞中，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，在肿瘤细胞特异性靶向的纳米胶囊递送载体中使用bs-As-CK2对催化CK2a和CK2a'亚基的分子下调将导致体内广泛的细胞死亡，不仅导致疾病稳定，而且导致原发性和转移性前列腺肿瘤的根除。所提出的策略具有强大的成功潜力，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，(b)细胞中CK2的丢失不能被另一个信号所取代。在小鼠模型中进行的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这种治疗原发性和转移性前列腺癌的新方法的未来翻译至关重要。

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.