The role of protein kinase C-alpha in malignancies of the nervous system and implications for the clinical development of the specific PKC-alpha inhibitor aprinocarsen (Review).
Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to specifically inhibit the intracellular signal transduction protein, protein kinase C-alpha (PKC-alpha). The clinical development of such specific or "new targeted" agents in cancer requires a comprehensive understanding of the target protein. This understanding is expected to improve the identification of patients who most likely will benefit from treatment with a specific inhibitor, such as aprinocarsen. In order to better understand the role of PKC-alpha in nervous system malignancies we here review the published literature on PKC-alpha expression in nervous system tumors, including glioblastoma multiforme. In pre-clinical experiments aprinocarsen had demonstrated anti-tumor activity, in particular in animal models of glioblastoma. Thus, clinical study CS10 with aprinocarsen was undertaken in patients with central nervous system (CNS) malignancies. The results of this study and considerations for future clinical studies in CNS tumors are reviewed.
Lahn
Michael M
MM
Eli Lilly and Company, Oncology Product Development, Lilly Corporate Center, Indianapolis, IN 46285, USA. mlahn@lilly.com
Sundell
Karen L
KL
Paterson
Blake M
BM
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009423:Nervous System Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051571:Protein Kinase C-alpha
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; C488084:aprinocarsen