INNOVATIVE TUMOR TARGETED THERAPIES FOR LUNG CANCER

本申请的目的是为肺癌和支气管恶性前病变开发创新的肿瘤靶向治疗方法。一般的假设是，结合解剖和分子靶向的治疗策略应该构成改善这些疾病的治疗方式。将采用三种主要的治疗策略：1)支气管恶性前肿瘤的吸入疗法，2)抑制在肺癌生长失调中起主要作用的途径，以及3)解剖靶向。在这三个主要策略中提出了三个原型项目：1)雾化脂质体/p53制剂在肺癌和携带p53突变的支气管恶性前肿瘤患者中的临床前和初步临床评估，2)化疗与抗egfr单克隆抗体C225在IIIA期非小细胞肺癌中的协同作用的临床研究，以及3)胸膜内整合治疗IIB期非小细胞肺癌合并恶性胸腔积液患者。这三个项目都包括临床试验的表现，包括测量与观察到的抗肿瘤效果可能相关的药理学或分子参数。申请的工作是申请人在过去十年中在药物输送和肺癌治疗研究领域的转化研究工作的合理延续。具体项目将由申请人指导的年轻临床研究者进行。本提案下的指导候选人将包括纽约大学肿瘤医学奖学金的研究员以及血液学、肺部医学和外科部门的初级工作人员。目前已经确定了四个这样的候选人。预计在五年内，将有10名年轻的临床研究人员接受指导。

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.