| Lung cancer,
rare in women in the early 1900s has reached epidemic
proportions accounting for nearly 29% of all cancer
deaths in females in the United States. Although
lung tumors are classified into many different
subtypes, the predominant risk factor for all
tumor types is cigarette smoking. However, bronchio,alveolar
carcinoma (BAC), a unique subtype of non-small
cell lung cancer (NSCLC), is increasing in incidence,
and it is most prevalent in females who have never
smoked. Unfortunately, no optimal therapy has
been established. Oral inhibitors targeting proteins
on the cell surface, specifically the epidermal
growth factor receptor (EGFR), have proven to
be ineffective as the sole chemotherapy agent,
resulting in regrowth of the tumor and death of
the patient. Only those lung tumors that contain
a specific mutation in the EGFR are sensitive
to drugs, such as gefitinib or erlotinib. Emerging
evidence indicates that the relative risk of BAC
between men and women and the response to therapy
may not be the same. One type of molecule expressed
on the cell that activates growth pathways in
the lung is the gastrin releasing peptide receptor
(GRPR). These receptors have a role in normal
lung development, but also stimulate cells to
grow enabling tumor formation. The gene for GRPR
is located on the X-chromosome, the chromosome
that designates the female sex (XX chromosomes),
allowing for women to have two actively transcribed
copies of the gene, while men (XY chromosomes)
have only one active copy. Our laboratory has
shown that GRPR expression is greater in nonsmoking
females than nonsmoking males (55% vs 0%). More
recent unpublished data shows that activation
of the GRPR pathway causes the release of molecules
that can activate EGFR, causing this pathway to
continue to produce growth signals despite the
presence of a specific inhibitor. We have created
a mouse model in which the human gene for GRPR
is expressed in the airway epithelial cells that
may give rise to BAC. Initial studies show that
these mice have an increased growth in their airway
cells and an increased susceptibility to lung
cancer when treated with a tobacco carcinogen.
We propose to test the effects of GRPR antagonists
alone or in combination with EGFR inhibitors to
demonstrate that inhibiting both pathways is more
effective in preventing tumor growth than either
one alone. Therefore, this combined mode of treatment
may have therapeutic potential in non-smoking
females with adenocarcinoma where high GRPR expression
is observed.
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