Molecular Modalities in the Treatment of Lung Cancer

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.