New treatment options for New treatment options for lung cancerlung cancer

• Lung cancer is a Lung cancer is a leading cause of leading cause of death world widedeath world wide

• 90% of lung cancer 90% of lung cancer is caused by is caused by smokingsmoking

• 20% of patients are 20% of patients are suitable for surgerysuitable for surgery

• 5% of all cases 5% of all cases have 5 year have 5 year survivalsurvival

• Most of the patients are in Most of the patients are in advanced stages and have advanced stages and have very poor prognosisvery poor prognosis

• Only 20% of patients are Only 20% of patients are operable and only 5% of all operable and only 5% of all cases survive 5 yearscases survive 5 years

• In general, patients with In general, patients with untreated lung cancer untreated lung cancer survive 8 monthssurvive 8 months

• Lung cancer is classified Lung cancer is classified based on TNM system based on TNM system Tumor, Node, Tumor, Node, Metastasis)Metastasis)

• The most common The most common among lung cancers is among lung cancers is non-small cell lung non-small cell lung carcinoma (NSCLC)carcinoma (NSCLC)

• Diagnosis by history and Diagnosis by history and x-rayx-ray

• Spiral CT screeningSpiral CT screening

• Surgery is a treatment Surgery is a treatment of choice. of choice. (Chemotherapy, (Chemotherapy, radiation)radiation)

• Cure is rareCure is rare

New treatment New treatment optionsoptions

• To survive and replicate cancer cells have very complex molecular pathwaysTo survive and replicate cancer cells have very complex molecular pathways. . Many Many epithelial tumors have abnormally activated epidermal growth factor (EGF). Several epithelial tumors have abnormally activated epidermal growth factor (EGF). Several mechanisms lead to the activation of epidermal growth factor receptor (EGFR). This mechanisms lead to the activation of epidermal growth factor receptor (EGFR). This activation promotes series of reactions.activation promotes series of reactions.

• Two classes of EGFR anti-cancer agents:Two classes of EGFR anti-cancer agents:

1.1. Erlotinib Erlotinib 2.2. Cetuximab Cetuximab

Erlotinib Erlotinib (Tarceva)(Tarceva)

Erlotinib (Tarceva)Erlotinib (Tarceva)

• Erlotinib is an anti – EGFR tyrosine kinase inhibitor. This Erlotinib is an anti – EGFR tyrosine kinase inhibitor. This drug has been approved for treatment of the patients with drug has been approved for treatment of the patients with locally advanced or metastatic non – small cell lung cancer locally advanced or metastatic non – small cell lung cancer after failure at least one prior chemotherapy regimen. It after failure at least one prior chemotherapy regimen. It was approved in U.S. in November 2004.was approved in U.S. in November 2004.

• Erlotinib is the only EGFR TKI therapy that have shown to Erlotinib is the only EGFR TKI therapy that have shown to improve the survival for NSCLC patients (6.7 months vs. 4.7 improve the survival for NSCLC patients (6.7 months vs. 4.7 months for erlotinib and placebo respectively)months for erlotinib and placebo respectively)

• Erlotinib has proved to be safe for patients. Only 5% of Erlotinib has proved to be safe for patients. Only 5% of patients had to discontinue treatment because of toxicity.patients had to discontinue treatment because of toxicity.

Erlotinib (Tarceva)Erlotinib (Tarceva)• Some groups of patients Some groups of patients

may benefit more from this may benefit more from this drug. They are: female drug. They are: female patients, nonsmokers, patients, nonsmokers, patients of Asian decent, patients of Asian decent, and patients with and patients with adenocarcinoma.adenocarcinoma.

• The most recent research The most recent research of 2006 made a discovery of 2006 made a discovery of EGFR mutations in of EGFR mutations in tumor cells. This mutant tumor cells. This mutant EGFR is required for tumor EGFR is required for tumor maintenance. Surprisingly, maintenance. Surprisingly, Erlotinib was found to be Erlotinib was found to be more efficacious in mutant more efficacious in mutant EGFR (Mendelsohn, 2006)EGFR (Mendelsohn, 2006)

Iressa (Gefitinib)Iressa (Gefitinib)

• Iressa (Gefitinib) is very similar to Erlotinib. It was the Iressa (Gefitinib) is very similar to Erlotinib. It was the first selective EGFR inhibitori. Iressa reseived accelerated first selective EGFR inhibitori. Iressa reseived accelerated approval based on the data from phase II study. approval based on the data from phase II study. However, Iressa failed to improve a survival advantage in However, Iressa failed to improve a survival advantage in confirmatory trials requested by FDA.confirmatory trials requested by FDA.

• Some scientists have speculated that Iressa and Tarceva Some scientists have speculated that Iressa and Tarceva had different interactions depending on the type of had different interactions depending on the type of mutations in EGF receptors in human lung cancer. There mutations in EGF receptors in human lung cancer. There are at least twenty different mutations in EGFR and are at least twenty different mutations in EGFR and scientists do not know if the same drug has the same scientists do not know if the same drug has the same effect for every mutation.effect for every mutation.

• Another issue that has been discussed by research Another issue that has been discussed by research community was the use of different doses, suggesting community was the use of different doses, suggesting that higher dose of Iressa was still probably effective that higher dose of Iressa was still probably effective (Twombly, 2006). (Twombly, 2006).

CetuximabCetuximab

• The second class of The second class of EGFR agents is EGFR agents is represented by represented by Cetuximab.Cetuximab.

• It is a MONOCLONAL It is a MONOCLONAL ANTIBODY that binds ANTIBODY that binds to EGFR and inhibits to EGFR and inhibits intracellular intracellular phosphorylation of phosphorylation of EGFR and its signaling EGFR and its signaling pathways.pathways.

• Cetuximab is less Cetuximab is less potent than potent than Erlotinib/Gefinib, it Erlotinib/Gefinib, it has its definite has its definite advantages. advantages. Cetuximab Cetuximab demonstrated to demonstrated to be effective on be effective on Gefitinib resistant Gefitinib resistant mutant EGFRmutant EGFR

BevasizumabBevasizumab

BevasizumabBevasizumabAngiogenesis is one of the Angiogenesis is one of the

hallmarks of tumor hallmarks of tumor formation. Majority of formation. Majority of NSCLC tumors express NSCLC tumors express vascular endothelial growth vascular endothelial growth factor (VEGF). Studies factor (VEGF). Studies proved that the higher proved that the higher expression of VEGF expression of VEGF correlate with poor correlate with poor prognosis for lung cancer prognosis for lung cancer patients (Herbst, 2006).patients (Herbst, 2006).

Bevasizumab is a recombinant Bevasizumab is a recombinant humanized monoclonal humanized monoclonal antibody against VEGFantibody against VEGF

Molecular pathways Molecular pathways involved in stimulation and involved in stimulation and proliferation of cancer cells proliferation of cancer cells are involved in multiple are involved in multiple levels. If one molecular levels. If one molecular target is blocked by anti-target is blocked by anti-cancer agent, the others cancer agent, the others can be an escape routes for can be an escape routes for cancer cell stimulators.cancer cell stimulators.

This concept brought the This concept brought the next step in exploring next step in exploring possibilities of anti-cancer possibilities of anti-cancer research. Combining drugs research. Combining drugs that affect different that affect different pathways can have pathways can have additional clinical benefits additional clinical benefits (Sandler, 2006)(Sandler, 2006)

Combined therapyCombined therapy Based on this concept, some investigators Based on this concept, some investigators

have speculated that the use of EGFR TKI have speculated that the use of EGFR TKI with new agiogenesis inhibitors can be with new agiogenesis inhibitors can be more efficacious. Preliminary data has more efficacious. Preliminary data has shown no pharmacokinetic interaction shown no pharmacokinetic interaction between Erlotinib and Bevasizumab. The between Erlotinib and Bevasizumab. The median overall survival for the treated median overall survival for the treated patients was 12.6 months vs. 4 months for patients was 12.6 months vs. 4 months for control group, with progression free control group, with progression free survival of 6.2 months vs. 2.5 months for survival of 6.2 months vs. 2.5 months for untreated controls. untreated controls.

StatinsStatins Lovastatin is inhibitor of 3-NMG Lovastatin is inhibitor of 3-NMG

CoA reductase. It leads to the CoA reductase. It leads to the inhibition of EGF-induced EGFR inhibition of EGF-induced EGFR autophosphorylation and its autophosphorylation and its signaling cascade within 24 signaling cascade within 24 hours.hours.

Studies of combining Lovastatin Studies of combining Lovastatin and Erlotinib showed inhanced and Erlotinib showed inhanced inhibition and cytotoxisity in a inhibition and cytotoxisity in a variety of cell lines. However, variety of cell lines. However, combinig Lovastatin and Erlotinib combinig Lovastatin and Erlotinib is contraindicated because of is contraindicated because of high risk of toxicity (both drugs high risk of toxicity (both drugs are metabolized by CYP3A4).are metabolized by CYP3A4).

Rosuvastatin + ErlotinibRosuvastatin + Erlotinib

New possible alternative is New possible alternative is mevolanate pathway inhibitor mevolanate pathway inhibitor Rosuvastatin. The studies of Rosuvastatin. The studies of combining Erlotinib and combining Erlotinib and Rosuvastatin are proposed Rosuvastatin are proposed for a phase I/II in advanced for a phase I/II in advanced non-small cell lung cancer.non-small cell lung cancer.

COX-2 inhibitorsCOX-2 inhibitors• Lung tumors induce very immunosuppressive Lung tumors induce very immunosuppressive

microenvironment. This may explain a very microenvironment. This may explain a very high unresponsiveness to immunological-high unresponsiveness to immunological-based therapies. To enhance immunotherapy based therapies. To enhance immunotherapy the use of COX-2 inhibitors was suggested. the use of COX-2 inhibitors was suggested. Although this mechanism is poorly Although this mechanism is poorly understood, it has shown some effect on understood, it has shown some effect on improvement in immunotherapy. Blocking improvement in immunotherapy. Blocking arginase I through careful use of COX-2 arginase I through careful use of COX-2 inhibitors promoted better outcomes of inhibitors promoted better outcomes of immunotherapy of lung cancer (Rodriguez, immunotherapy of lung cancer (Rodriguez, 2006).2006).

Lung cancer blood test Lung cancer blood test

• A team of University of A team of University of Kentucky Chandler Medical Kentucky Chandler Medical Center researchers has been Center researchers has been working on developing the working on developing the blood test to detect lung blood test to detect lung cancer in early stages.cancer in early stages.

• The blood test identifies The blood test identifies body’s own immune response body’s own immune response to tumors.to tumors.

• This test is 90 % accurate and This test is 90 % accurate and diagnostic for lung cancer at diagnostic for lung cancer at early stages in the patients early stages in the patients with high risk factors such as with high risk factors such as smoking, family history and smoking, family history and age. This test can correctly age. This test can correctly predict NSCLC years before predict NSCLC years before CT scan can detect it. CT scan can detect it.

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