This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancers of the lung and bronchus, primarily small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), are predicted to have the second greatest number of new cases in 2003 and will have the highest mortality rate: 31% of cancer deaths in men, and 25% of cancer deaths in women, will be caused by lung/bronchus cancers. Platinum-based combination chemotherapies are the most widely used first-line treatments for NSCLC; however, response rates in most studies are 33% or less, median survival is 8 to 9 months and only about one-third of treated patients survive for one year. Docetaxel as a second line chemotherapy has demonstrated benefits in terms of survival and quality of life in two controlled trials. The benefits, though real, are quite modest: median duration of response was 7.4 to 9.0 months for Docetaxel compared to 5.9 months for best supportive care. Iressa was recently approved for treatment of locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies. Tumor response rate as a third-line therapy was 10.6% with a median duration of response of 7 months. SCLC patients have an equally poor prognosis. Standard treatment for SCLC patients who present with extensive disease also is chemotherapy (CTX), typically etoposide and cisplatinum, which produces response rates of approximately 60-70%, and a median survival of approximately 9 months. Irinotecan plus cisplatin yielded improved median survival in one study: 12.8 months compared to 9.4 months in patients treated with etoposide plus cisplatin, with a two-year sirvival rate of 19.5%. Following treatment with front-line regimen, therapy with topotecan has demonstrated some benefit and other agents such as taxanes and vinorelbine have also yielded measurable responses. Overall, however, the results of therapy in Stage IV NSCLC or extensive SCLC remain poor. There is a compelling need for additional therapeutic options. Novel approaches are needed for this disease. Radioimmunotherapy using monoclonal antibodies to target radiotherapy (RT) to specific tissues has been used successfully in treating some cancers, but currently, no radioimmunotherapies are approved to treat solid tumors. Moreover, compared to monoclonal antibodies, peptides offer a better prospect for solid tumor internally administered radiotherapy (IAR). Smaller than antibodies, peptides may be able to reach actively growing cells within solid tumors. They have a short plasma half-life and thus deliver a lower radiation dose to many normal tissues, such as the bone marrow. Small synthetic peptides (less than 30 amino acids) that have high affinity for molecular receptors in tumors and exhibit rapid clearance from the blood are a particularly attractive class of small molecules for IAR. P2045, an 11 amino acid peptide, is an analog of the peptide in technetium Tc 99m depreotide (NeoTect), which is approved for detection of somatostatin receptor (SSTR)-expressing pulmonary masses. Radiolabeled with Rhenium Re 188, P2045 retains the SSTR affinity of depreotide but with lower kidney and whole body retention. In studies with nude mice, Rhenium Re 188 P2045 caused almost complete inhibition of SSTR-bearing pancreatic tumors with no acute damage on histopathologic examination to any other organ or tissue. Two Phase 1 studies of radiolabeled P2045 have been conducted. No adverse events were noted, and all intrathoracic lung tumors showed uptake of P2045. A subsequent phase 1 study evaluated safety, pharmacokinetics, biodistribution and radiation absorbed dose in patients administered a 20-25 mCi dose of Technetium Tc 99m P2045, followed by a 20-30 mCi dose of Rhenium Re 188 P2045 five to ten days later. There were no drug-related serious adverse events and all intrathoracic tumors showed uptake of the study drug. The purpose of the current sutdy is to further investigate the safety of Technetium Tc 99m P2045 and escalating doses of Rheunium Re 188 P2045 and to establish the maximum tolerable dose of the latter. Efficacy of Rhenium Re 188 P2045 in the treatment of lung cancer also will be explored.
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