The time is ripe for the application of cAMP-elevating drugs to cancer therapeutics. PDEs have been implicated in carcinogenesis and tumor progression for a variety of tumor types including: prostate cancer 50
, brain tumors 5, 11, 19
, hematological malignancies 51, 52
, colon cancer 53
, melanoma 54
, as well as in the enhancement of drug delivery 55
. Finally, various PDE inhibitors have been or are being actively clinically evaluated ().
However, several important issues must be addressed prior to the successful incorporation of PDE inhibition into cancer therapeutic regimens. First, the development of PDE inhibitors, especially PDE4 inhibitors, has been powerfully guided by the desire to reduce the gastrointestinal side effects of the catalytic site directed competitive antagonists. Overcoming these toxicities may require refinement in this class of inhibitors or advancement of alternative inhibitors such as allosteric or isoform-specific inhibitors 20, 34, 48
Regardless, in cancer therapeutics, nausea and vomiting are common, anticipated, and well controlled through the use of myriad established and potent anti-emetics. The risk-benefit analysis for the use of effective, yet emetogenic agents, is overwhelmingly in favor of their use. Emetogenicity should not limit the advancement of effective agents as anti-cancer medications. In this regard, broad screening of any PDE inhibitor for which expression data supports its use is warranted, with a focus on anti-tumor activity alone.
Although isoform-specific inhibition could be appropriate for some cancers, there are data to implicate multiple cAMP-specific PDEs in the promotion of neoplastic growth. We showed that PDE4A1 can stimulate gliomagenesis; it is possible that other PDE4 isoenzymes, or even other cAMP PDEs could do the same 11, 19
. PDE4D has been demonstrated to be important for prostate carcinogenesis 50
and PDE7 appears to be required for leukemic cell growth in vitro 52
. Thus, while there is a rationale for evaluating isoform-specific inhibitors as cancer therapeutics, broad PDE inhibition could be required for maximal anti-tumor effects. The feasibility of pan-PDE4 inhibition was demonstrated in clinical trials of rolipram for depression 56
In addition, it is important to consider the multiple potential cellular and intracellular targets for PDE inhibition in cancer therapeutics. Although data indicate that tumor cells are sensitive to cAMP elevation, cAMP also regulates endothelial cell activity 57
and CNS inflammatory responses 58
, both potentially powerful modulators of brain tumor growth. It may also be necessary to consider how precise genetic profiles of cancer cells impact on PDE inhibitor effects. For example, astrocytomas commonly possess genetic alterations that activate the MAPK pathway, a driver of their growth 59, 60
. These oncogenetic events include: amplification or mutational activation of cell surface receptors like the EGF and PDGF receptors, mutational activation of K-RAS, B-RAF, or loss of neurofibromin. Cyclic AMP regulates the MAPK pathway at multiple levels between the cell surface and the nucleus 34, 61
(). Thus, the tumor-specific profile of genetic alterations could impact on the efficacy of cAMP elevation. In addition, the regulation of PDE4 activity by the ERK and PKA pathways must also be considered 20, 34
. Inhibition and stimulation of PDE4 activity by ERK and PKA are different for long and short forms. Therefore the integrated response of the full cellular complement of PDE4 to any inhibitor may be difficult to predict. Any clinical trial of PDE4 inhibitors should include efforts to profile not only the known oncogenetic events but also the PDE complement.
Growth targets of cAMP Signaling
Finally, the lessons learned from comparing the activity of aminophylline and theophylline to specific PDE4 inhibitors in the treatment of asthma suggests that the combination of PDE inhibition with other target modulation might be most effective 47, 62
. Theophylline and aminophylline have been in clinical use for nearly a century. Their mechanism of action is incompletely understood but they are known to be weak pan-PDE inhibitors as well as adenosine receptor antagonists 63
. The potential importance of this combined activity was recently rediscovered in a high throughput drug screen for anti-leukemic cell activity. In this study the combination of PDE7 inhibition and adenosine receptor A2 antagonism was identified as possessing superior anti-tumor effect 64
. It is possible that newer generation agents with these combined properties could maintain or enhance their activity and reduce their toxicity.
In sum, we have made enormous strides in understanding the complexity of cAMP regulation of growth and the role that PDE4 plays in specifying cAMP activity. Multiple PDE4 inhibitors, with defined activity, have been evaluated in preclinical and clinical studies. The rationale and the tools for cancer application are available, and the desire is strong to usher in this new era with reasonable hopes for breakthroughs.