Diacylglycerol Signaling

23 Atypical PKCs as Targets for Cancer Therapy
be useful in identifying lung cancer patients most likely to respond to ATM therapy.
A phase I clinical trial is currently accruing at Mayo Clinic to determine an appropriate
dosing regimen for ATM, and to assess antitumor activity.
23.10 Conclusions
The aPKCs (PKCi and PKCz) have been implicated in several aspects of transformation,
and the roles of the aPKCs in human cancer appear to be nonredundant.
In most of the carcinogenesis models investigated, PKCz either plays no
demonstrable role or inhibits transformation; PKCi on the other hand, promotes
transformed growth, invasion, resistance to chemotherapeutics, and tumor cell
survival in a growing number of tumor types. PKCi is the first PKC isozyme to be
identified as a human oncogene. Specifically, PKCi is frequently overexpressed
and is a target of tumor-specific gene amplification in multiple human tumor
types. PKCi overexpression is prognostic of poor clinical outcome in several
human cancers and also shows promise as a means of identifying patients with
early stage lung cancer at elevated risk of relapse. The PB1-PB1 domain interaction
formed between PKCi and Par6 is important for oncogenic PKCi signaling and
has been successfully targeted using ATM, a novel mechanism-based therapy that
disrupts this interaction. ATM is actively being evaluated in the clinic for the
treatment of NSCLC and other tumor types. PRKCI amplification and PKCi overexpression
is a frequent event in squamous carcinomas of the head and neck
(Snaddon et al. 2001), esophagus (Imoto et al. 2001; Pimkhaokham et al. 2000),
ovary (Eder et al. 2005; Weichert et al. 2003; Zhang et al. 2006), and cervix
(Sugita et al. 2000). These findings suggest that therapies designed to target PKCi
signaling in NSCLC may also be effective therapeutic approaches in these tumors.
ATM holds promise as a novel, mechanism-based agent for the effective treatment
of multiple human cancers.
Acknowledgments The authors wish to thank the members of the Fields laboratory for their key
contributions to the data described in this chapter. The authors also wish to apologize to any of
our colleagues whose important contributions to this area have been inadvertently omitted in our
citations. Though we attempted to cite as much relevant literature as possible, space limitations
made comprehensive citation impossible. Work from the Fields laboratory discussed in this article
was supported by grants to A.P.F. from the National Institutes of Health, the American Lung
Association, The V Foundation for Cancer Research, The James and Esther King Biomedical
Research Program, and the Mayo Foundation.
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