Diacylglycerol Signaling

392 L. Xiao
Contrary to its tumor suppressor function demonstrated in oncogenic Ras-induced
lung tumorigenesis (Galvez et al. 2009), PKCz appears important for the chemotaxis
of NSCLC cells in vitro. Liu et al. (2009) recently showed that PKCz is involved in
the regulation of epidermal growth factor (EGF)-induced chemotaxis of NSCLC
cells. PKCz is activated in response to EGF stimulation in a phosphatidylinositol 3
kinase (PI3K)/Akt-dependent manner. Specific inhibition of PKCz, but not other
PKC isoforms, blocks EGF-induced chemotataxis and cell adhesion to fibronectin
accompanied with a reduction in actin polymerization. It is possible that the function
of PKCz may be cell-context dependent. Some early studies indicated that PMAsensitive
PKCs (cPKCs and nPKCs) may also contribute to invasion and metastasis
through regulating integrin-mediated adhesion and production of proteinase in
human lung cancer cells (Jakowlew et al. 1997; Quigley et al. 1998).
19.4 Therapeutics: Targeting PKC Isoforms
19.4.1 PKCa Inhibitor: Aprinocarsen (LY900003; ISIS3521)
Aprinocarsen is a 20-mer antisense oligonucleotide that specifically inhibits the
transcription of PKCa (Dean et al. 1994). In preclinical studies, aprinocarsen has
shown antitumor effects in a range of tumor cell lines and xenograft models with
selective inhibition of PKCa mRNA and protein expression (Dean et al. 1996).
Aprinocarsen was the first PKC isoform-specific agent that has gone on phase I–III
studies in patients with advanced NSCLC (Lynch et al. 2003; Villalona-Calero
et al. 2004; Ritch et al. 2006). However, in two randomized phase III studies, aprinocarsen
failed to show additional survival benefit when applied in conjunction
with chemotherapy regiments (Lynch et al. 2003; Paz-Ares et al. 2006). These disappointing
results led to the early termination of the studies. A couple of issues may
be related to the unsuccessful clinical development of aprinocarsen: there is no validated
biomarker(s) for evaluating the effectiveness of aprinocarsen (e.g., it is
unclear whether aprinocarsen is able to accumulate in tumor tissues); and patients
were not screened for PKCa expression. PKCa expression is not significantly
altered in NSCLC and