Novel Therapeutics

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The discussion below provides information on molecular alterations that occur frequently in lung cancer (see above for in depth discussion) and to give some examples of therapeutic agents that target them. There may be additional targeted therapeutics that have not been described below. For a more complete listing of drugs in development and ongoing clinical trials please use the following link:
Cancer.gov Clinical Trials

Treatment approaches for lung cancer depend upon the stage of disease at the time of diagnosis. For patients diagnosed with early stage lung cancer (Stage I and II) surgery is the treatment of choice. More often patients are diagnosed with advanced stage disease in which the cancer has spread to the mediastinal lymph nodes (Stage III) or to distant organs (Stage IV). In such cases patients are treated with a combination of radiotherapy and chemotherapy (Stage III) or with chemotherapy alone (Stage IV). However, approximately 90% of patients diagnosed with advanced disease succumb to a recurrence of chemotherapy resistant, metastatic disease (80). Over the past twenty years efforts to lengthen the median survival time for patients diagnosed with lung cancer have focused largely on the use of new combinations of cytotoxic agents, and have resulted in only minimal improvements in survival time. Recent advances in our understanding of the molecular alterations underlying the biology of lung cancer have led to the development of rationally targeted therapies as a new approach to the treatment of lung cancer.

Peptide growth factor autocrine loops are commonly found in NSCLCs. The cells of these tumors often inappropriately express high levels of receptor tyrosine kinases (RTKs) which drive cell proliferation upon binding of their ligands. The epidermal growth factor receptor (EGFR), also known as the ERBB1 receptor, is expressed by approximately 30% of NSCLCs, and has thus been the target of many rationally designed therapeutics. Iressa (ZD1839) is an orally available, quinazolone compound that selectively inhibits ligand induced EGFR autophosphorylation by competitive inhibition of ATP binding. Phase I clinical trials showed Iressa to be well tolerated at doses that inhibited EGFR function in biomarker studies (51). Iressa is currently in Phase II and III studies for the treatment of lung, head and neck, colon and breast cancer. C225 represents an alternative approach to EGFR inhibition. It is a monoclonal antibody directed against the extracellular domain of EGFR. It was shown to be well tolerated and to have anti-cancer activity in Phase I trials (82), and is currently in Phase II trials for the treatment of NSCLC, head and neck and colon cancer . OSI-774 is an orally available small molecule inhibitor of EFGR that has also shown promising results in Phase I and II trials, with Phase III trials being planned (82).

Neovascularization is required for tumors to grow beyond 3 mm in diameter, and for metastasis. Several inhibitors of angiogenesis are currently being studied for effectiveness in the treatment of lung cancer. A recombinant humanized monoclonal antibody to VEGF (Bevacizumab) has been developed by Genentech, Inc. Efficacy has been evaluated in NSCLC patients in Phase II trials accompanying chemotherapeutic treatment and showed an increased response rate and median survival (82). Phase III studies are currently under development. SU5416, produced by Sugen, is a synthetic antagonist of the VEGF receptor, Flk-1. Phase I studies are currently underway to evaluate toxicity when SU5416 is given with paclitaxel and carboplatin. Additional small molecule inhibitors of angiogenesis are currently in early development for lung cancer treatment including SU6668, an orally administered small molecular inhibitor of RTKs including Flk-1, PDGF receptor and FGF-1 receptor; and ZD4190, a VEGF RTK inhibitor produced by AstraZeneca (82). Furthermore, several matrix metalloproteinase (MMP) inhibitors are being studied for efficacy in the treatment of both SCLC and NSCLC. Marimastat (BB2516), a synthetic MMP inhibitor produced by British Biotech, is currently in Phase III trials for the treatment of SCLC and Stage III NSCLC. BMS-275291 is a synthetic MMP inhibitor produced by Bristol-Myers Squibb. It is in Phase II/III trials for advanced NSCLC. Neovastat, a naturally occuring MMP inhibitor extracted from shark cartilage, is undergoing Phase II/III clinical trials for the treatment of advanced NSCLC.

Proliferation of SCLCs is often driven by autocrine loops involving neuropeptides and their cognate G protein coupled receptor (GPCR). Binding of neuropeptide to its receptor results in activation of the associated G protein and production of second messengers which go on to activate several downstream signaling pathways. The production of two such second messengers, inositol triphosphate and diacylglycerol (DAG) result in the activation of protein kinase C (PKC). PKC then activates several other signal cascades involved in the regulation of cellular proliferation. PKC is also thought to function downstream of RTKs, and thus may also be involved in autocrine loops stimulating the growth of NSCLC. Furthermore, the cancer promoting agent, phorbol ester, is present as an air pollutant and may be important in the induction of lung cancer, especially that of the squamous cell type. Phorbol ester is a DAG analogue, and induces tumor formation through activation of PKC (8). Thus PKC may be an important therapeutic target in the treatment of lung cancer. ISIS 3521, an antisense inhibitor of PKC-Alpha has shown promising results in Phase I/II trials for the treatment of NSCLC (16); a Phase III clinical trial is ongoing.

Inactivating mutations of the p53 tumor suppressor gene are very common in both SCLC (80%) and NSCLC (50%). The p53 protein normally functions to induce cell cycle arrest or apoptosis in response to DNA damage, oncogene expression and other cellular stresses. Loss of p53 function also correlates with increased resistance to radiation and chemotherapy. Adenoviral p53 gene therapy was shown to be well tolerated and to have significant clinical activity for the treatment of advanced NSCLC when injected into a single tumor (77, 102) and is also being tested when delivered by bronchoalveolar lavage. Furthermore, Phase II trials are underway to assess the efficacy of immunotherapy with mutant p53 peptide-pulsated autologous dendritic cells in treating NSCLC patients with appropriate p53 mutations. Additional trials on tumor specific p53 peptide vaccines are also underway in patients with advanced cancers.

Activating mutations of the K-ras oncogene occur in approximately 30% of pulmonary adenocarcinomas. Point mutations at codons 12, 13 and 61 of the ras genes result in proteins with decreased intrinsic GTPase activity leading increased signaling of downstream effector proteins regulating cell proliferation, survival and differentiation. Phase I studies are being conducted to test ras peptide cancer vaccines in which NSCLC patients receive mutant peptide vaccines specific to the mutation in their tumors. The ras proteins must be localized to the cell membrane in order to function in the cell. Such localization occurs through post translation prenylation of the protein, including farnesylation and geranylgeranylation (45). Farnesyl protein transferase (FT) is the enzyme that catalyzes the transfer of a farnesyl moiety to the ras protein, and thus presents an attractive target for inhibiting ras function. The FT inhibitor R115777 is currently in clinical trials for the treatment of advanced NSCLC.

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