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Molecular Modalities in the Treatment of Lung Cancer

Molecular Modalities in the Treatment of Lung Cancer

ABSTRACT: Despite recent advances in the treatment of lung cancer, long-term survival remains rare. As more information pertaining to the biology of lung cancer is understood, it is hoped that improvements in outcome can be realized with the use of molecularly based therapies. The identification of gene mutations in lung cancer has led to the development of inhibitory therapies, including antisense oligonucleotides and direct injection of tumor-suppressor genes, such as wild-type p53. Other therapeutic approaches are targeted at inhibiting angiogenesis by blocking endogenous growth factors with antibodies or administering natural antiangiogenic substances. Recognition of the dendritic cell as one of the primary cells responsible for antitumor immunity has encouraged studies of immunotherapy for patients with lung cancer. In addition, studies have shown that dendritic cell function is defective in tumor-bearing animals. Research continues to explore the effect of tumor on immune cell function and ways to overcome such defects. Rationally derived therapies based on these biological findings may advance the treatment, as well as early detection and prevention, of lung cancer, thereby improving patient outcomes. [ONCOLOGY 13(Suppl 5):142-147, 1999]


Introduction

In spite of many complex and aggressive
approaches to therapy and great strides in understanding the biology
and etiology of lung cancer, corresponding improvements in outcome
are not yet apparent. It is hoped that in the future, advances in our
knowledge of the molecular biology of lung cancer will provide the
foundation for real improvement in outcomes. Emerging molecularly
based modalities that may soon be combined with chemotherapy,
radiation therapy, and surgery to improve the effectiveness of lung
cancer treatment are discussed.

Knowledge of Lung Cancer Precursors May Allow
Prevention or Early Detection

It is quite clear that lung cancer is caused by an accumulation of
genetic damage in the bronchial epithelium. Exposure to inhaled
carcinogens, such as the polycyclic aromatic hydrocarbons and the
nitrosamines from cigarette smoke, can directly damage the DNA of
bronchial epithelial cells. These agents covalently modify DNA,
causing misreplication and mutation or loss of genetic material. The
bound carcinogens can be directly detected in the DNA of smokers,
and, disturbingly, also in the DNA of infants born to smoking
mothers.[1] Using modern molecular detection techniques, loss of
genetic material from large regions of chromosomes or point mutations
in dominant or recessive oncogenes can be found in the bronchial
epithelium of smokers, even those without microscopically visible
histological changes.[2] Prolonged exposure results in visible
hyperplasia and metaplasia, which often, but not always, precede
frank malignancy. It is likely that detectable genetic abnormalities
always precede the development of invasive cancer. New molecular
markers of loss of growth control, such as loss of expression of the
retinoic acid receptor beta (RAR-b), have
been found to be strongly associated with malignant progression and
are being tested as molecular intermediate markers in chemoprevention
and early detection studies. These genetic premalignant changes are
widespread throughout the respiratory epithelium, suggesting that a
field effect is induced by the carcinogens,[3] explaining the high
incidence of second malignancies in those cured of lung cancer or
head and neck cancer.

Lung Cancer Biology: Gene Therapy and
Receptor-Targeted Therapeutics

It is clinically useful to categorize bronchogenic cancers into two
groups that reflect their biology and management: small-cell lung
cancer and non–small-cell lung cancer. Small-cell lung cancer is
highly responsive to chemotherapy, but only very infrequently
curable, as it rapidly relapses and metastasizes. Non–small-cell
lung cancer is often less dramatically responsive to chemotherapy,
but is more often cured by surgery or combined-modality therapy. Each
of these categories is divided into subtypes, but as mentioned above,
in reality, these categories often blend into each other or coexist
with each other. Data on cellular and molecular biology, as well as
ultrastructural studies, can help refine these groupings, and more
importantly, perhaps guide therapy in the future.

Small-cell lung cancer tumors and a subset of non–small-cell
lung cancer tumors express many neuroendocrine markers.
Neuroendocrine cells are present in small numbers in many tissues and
share many properties with neural cells, hence the term. The primary
function of these neuroendocrine cells is to produce, package, and
secrete small peptide or amine hormones. Lung tumors, especially
small-cell lung cancer, may secrete factors that stimulate their own
growth (autocrine secretion). Individual tumors may secrete up to 10
discrete hormones, which may contribute to the paraneoplastic
syndromes often associated with small-cell lung cancer.
Cross-reactive antigens, such as the HuD gene, may also lead to
autoimmune paraneoplastic syndromes.

Small-cell lung cancer is strongly associated with cigarette smoking,
and nearly always demonstrates loss of genetic material on
chromosomes,[4] including the gene for RAR-b
and FHIT (fragile histidine triad), but the important genes are not
fully identified. Mutations in the ras oncogene are rare, but
mutations in p53 and overexpression of bcl-2 are nearly universal.
These abnormalities form the basis for several new therapeutic
approaches. One of these is the inhibition of expression of bcl-2 in
small-cell lung cancer using antisense oligonucleotides[4] or other
approaches. The antisense oligonucleotides have been found to be
highly effective in cell lines, and if nontoxic methods can be
developed to inhibit bcl-2 expression in patients, this will be a
promising new modality.

Non–small-cell lung cancer is a morphologically diverse group
that includes the squamous (epidermoid) carcinoma, adenocarcinoma,
and large-cell carcinoma. The squamous phenotype used to be the
predominant form of lung cancer worldwide, although its relative and
absolute incidence in the United States (and other parts of the world
such as East Asia) has dramatically declined within the last two
decades.[5] Squamous carcinomas are strongly associated with
cigarette smoking, and this explains their frequent association with
metaplastic and dysplastic changes in adjacent epithelium.
Adenocarcinomas have become the most common form of lung cancer in
the United States. In general, they tend to arise in the peripheral
airways and may possess distinctive intracellular mucin granules as
part of their acinar/glandular differentiation.

Mutations in p53 are observed in about half of non–small-cell
lung cancers,[6] occurring somewhat more frequently in squamous cell
carcinomas, whereas ras mutations are found in about 20% of
adenocarcinomas[7] and less frequently in squamous carcinomas.
Several approaches are being clinically tested that are based on the
tumor-suppressive properties of p53. One of these is the delivery of
a normal p53 in a recombinant adenovirus to cause high-level
expression of this tumor-suppressor gene. Overexpression of p53 has
been found to be selectively toxic to tumor cells and not normal
ones. The normal p53 is delivered by direct injection into tumor
masses either alone or in combination with radiation or
chemotherapy.[8] It is hoped that this combination will allow
improved local control and palliation of unresectable tumors. An
Eastern Cooperative Oncology Group study is evaluating adenovirus-p53
delivered by bronchoalveolar lavage directly to entire lobes of the
lung with bronchoalveolar carcinoma. This approach should allow
excellent access of the gene therapeutic vector to the tumor cells
that cause the main respiratory symptoms of this disease; that is,
those lining and involving the alveoli and small airways.

Overexpression of several growth factor receptors, such as
insulin-like growth factor 1 receptor (IGF-1r) and epidermal growth
factor receptor (EGFr), as well as HER-2/neu, has also been observed
and may be correlated with the biology of lung cancer, and, thus,
important therapeutic targets. Several companies are developing
small-molecule antagonists of tyrosine kinase receptors, such as EGFr
and IGF-1r, for clinical application. Gene-based therapeutic
approaches to block these receptors have been effective in animal
models.[9] Similarly, antibodies against HER-2/neu, found to be
useful in breast cancer, are now being tested in non–small-cell
lung cancer.

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