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.
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.
|Trembley, Janeen H; Unger, Gretchen M; Korman, Vicci L et al. (2014) Tenfibgen ligand nanoencapsulation delivers bi-functional anti-CK2 RNAi oligomer to key sites for prostate cancer targeting using human xenograft tumors in mice. PLoS One 9:e109970|
|Qaiser, Fatima; Trembley, Janeen H; Kren, Betsy T et al. (2014) Protein kinase CK2 inhibition induces cell death via early impact on mitochondrial function. J Cell Biochem 115:2103-15|
|Unger, Gretchen M; Kren, Betsy T; Korman, Vicci L et al. (2014) Mechanism and efficacy of sub-50-nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma. Mol Cancer Ther 13:2018-29|
|Trembley, Janeen H; Unger, Gretchen M; Korman, Vicci L et al. (2012) Nanoencapsulated anti-CK2 small molecule drug or siRNA specifically targets malignant cancer but not benign cells. Cancer Lett 315:48-58|
|Trembley, Janeen H; Unger, Gretchen M; Tobolt, Diane K et al. (2011) Systemic administration of antisense oligonucleotides simultaneously targeting CK2ýý and ýý' subunits reduces orthotopic xenograft prostate tumors in mice. Mol Cell Biochem 356:21-35|