Lung Cancer.pdf

296 W.N. Hittelman, J.M. Kurie, and S.G. Swisher
Other Investigational Approaches to Lung Cancer Treatment
As more is understood about the molecular events associated with the development,
growth, and metastasis of human lung tumors, the number of
potentially targetable gene products increases. For example, since loss of
functional activity of the lung cancer tumor suppressor genes is associated
with hypermethylation of their promoters, one approach being explored
is the use of agents such as azacitidine analogues to reverse the hypermethylation
patterns in proliferating cells. Similarly, since an important component
of tumor establishment and growth is the ability to develop a vasculature
(angiogenesis), molecules that interfere with vessel initiation and
development are being explored as therapeutic agents in patients with
lung cancer. Current trials ongoing at M.D. Anderson are exploring several
potential antiangiogenic agents, including thalidomide, TNP-470, endostatin,
an antibody to vascular endothelial growth factor receptor, interleukin-12,
neovastat, and marimastat. These agents are thought to
interfere with different components of the angiogenic pathway, including
endothelial invasion, matrix remodeling, adhesion, and—by blocking
growth factors and their receptors—proliferation.
Another important component of metastatic development is the ability
of circulating lung tumor cells to find a suitable organ environment in
which to attach and become established. This process has been shown to
have some specificity with regard to “addressing” the tumor cell to a particular
site and initiating interactive tumor/stromal/endothelial signaling.
As the specificities of these interactions are better defined, small peptides
will be developed that will serve to interfere with these interactions
and thus decrease the risk of metastasis.
Chemoprevention Approaches
Common molecular pathways operate throughout the process of lung tumorigenesis.
Thus, strategies used in the therapeutic management of lung
cancer should also be applicable in the premalignant setting provided that
the treatment is not unduly toxic. We and other investigators have identified
various approaches that target molecular pathways important for
lung tumor development and apparently have few ill effects on normal
tissue. For example, in phase I and II clinical trials of the EGFR kinase inhibitor
ZD1839, little normal tissue damage was identified. As a result,
clinical trials using ZD1839 are being initiated that will examine the activity
of this agent in the chemopreventive setting in chronic smokers. Similarly,
since lung tumors are frequently found to exhibit increased cyclooxygenase-2
activity and since chronic administration of the
cyclooxygenase-2 inhibitor celecoxib (Celebrex) has been shown to be well
tolerated in patients with arthritis, chemoprevention trials at M.D. Anderson
are being initiated that will explore the use of cyclooxygenase-2 inhibitors
for chemoprevention.