The objective of this application is to develop innovative tumor- targeted therapies for lung cancer and bronchial premalignancy. The general hypothesis is that therapeutic strategies that combine anatomical and molecular targeting should constitute improved therapeutic modalities for these conditions. Three major therapeutic strategies will be pursued: 1) inhaled therapeutics for bronchial premalignancy, 2) inhibition of pathways that play a major role in lung cancer dysregulated growth, and 3) anatomical targeting. Three prototype projects within these three major strategies are proposed: 1) preclinical and initial clinical evaluation of an aerosolized liposome/p53 formulation in patients with lung cancer and bronchial premalignancy carrying p53 mutations, 2) clinical studies of synergism between chemotherapy and the anti-EGFR monoclonal antibody C225 in stage IIIA NSCLC, and 3) integration of intrapleural therapy in the treatment of patients with stage IIB NSCLC with malignant pleural effusion. All three projects include the performance of clinical trials that incorporate the measurement of pharmacological or molecular parameters potentially correlated with the observed antitumor effect. The work proposed is a logical continuation of the applicant's translational research efforts in the areas of drug delivery and lung cancer therapy research during the last decade. The specific projects will be conducted by young clinical investigators mentored by the applicant. Candidates for mentorship under this proposal will include fellows enrolled in the Medical Oncology fellowship at NYU and junior staff members of the Divisions of Hematology, Pulmonary Medicine, and Surgery. Four such candidates have already been identified. It is anticipated that a total of ten young clinical investigators will be mentored during a five-year period.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
7K24CA084119-02
Application #
6485212
Study Section
Subcommittee G - Education (NCI)
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$125,620
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Ling, Yi-He; Aracil, Miguel; Zou, Yiyu et al. (2011) PM02734 (elisidepsin) induces caspase-independent cell death associated with features of autophagy, inhibition of the Akt/mTOR signaling pathway, and activation of death-associated protein kinase. Clin Cancer Res 17:5353-66
Ling, Yi-He; Aracil, Miguel; Jimeno, José et al. (2009) Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models. Eur J Cancer 45:1855-64
Ling, Yi-He; Lin, Ruoping; Perez-Soler, Roman (2008) Erlotinib induces mitochondrial-mediated apoptosis in human H3255 non-small-cell lung cancer cells with epidermal growth factor receptorL858R mutation through mitochondrial oxidative phosphorylation-dependent activation of BAX and BAK. Mol Pharmacol 74:793-806
Li, Tianhong; Ling, Yi-He; Goldman, I David et al. (2007) Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res 13:3413-22
Dai, Qun; Ling, Yi-He; Lia, Marie et al. (2005) Enhanced sensitivity to the HER1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib hydrochloride in chemotherapy-resistant tumor cell lines. Clin Cancer Res 11:1572-8
Zhong, Yun; Lopez-Barcons, Lluis; Haigentz Jr, Missak et al. (2004) Exogenous expression of H-cadherin in CHO cells regulates contact inhibition of cell growth by inducing p21 expression. Int J Oncol 24:1573-9
Ling, Yi-He; Liebes, Leonard; Zou, Yiyu et al. (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278:33714-23