Rajiv Dhand Ph.D.

Lay Description

Lung cancer is a world-wide menace causing enormous suffering, misery, and death. Bronchioalveolar carcinoma (BAC) is one type of lung cancer that typically presents as a single or multiple nodules in the outer areas of the lung, where it is hard to diagnose and difficult to treat effectively. The ultimate goal of our proposed study is to employ newly emerging technologies to diagnose and treat BAC effectively. The new technologies are real time, electromagnetic, navigational bronchoscopy and the intracorporeal nebulizing catheter (INC) system for aerosol delivery of chemotherapy to the lung. The electromagnetic bronchoscopy guides the bronchoscopist to a lesion in the peripheral part of the lung and the INC is then used through the bronchoscope channel to deliver targeted chemotherapy using single or combined anti-cancer drugs. This new combined method of lung cancer therapy offers many potential advantages over existing treatments. Higher levels of the active anti-cancer drugs can be safely and quickly achieved in the lung directly where the tumor is growing than is possible by conventional delivery methods. This non-invasive technique also allows concurrent treatment of lung tumors at multiple sites and avoids exposure of normal lung tissue to potentially toxic drugs. Moreover, development of the systemic side-effects of chemotherapy, such as, nausea, hair loss, or bone marrow suppression could be reduced or eliminated by such localized chemotherapy.

In our earlier studies, we have successfully targeted cisplatin chemotherapy with the INC inserted through the bronchoscope channel into the lungs of models. These studies showed that after intrabronchial delivery with INC, almost 26-fold higher levels of the drug were achieved in the lung tissue, whereas, the levels in the blood were 19-fold lower than those achieved with a similar dose given by the conventional intravenous route. Moreover, there was almost no systemic toxicity after administration of serially increasing doses of cisplatin administered through the airway with the INC. In the current proposal, we plan to establish tolerance and safety in at least two experimental models. Such studies are needed before this technique of administering localized chemotherapy can be approved for use in humans. We propose to first identify the most important active drug combinations by testing against human BAC cells in tissue culture. Next, we will use the most effective chemotherapy agents in combination by targeted, aerosol delivery of chemotherapy into the lungs of healthy experimental models. If this route of delivery is well tolerated, these novel studies would help in identifying a dosing regimen (drug combination and dose) that could be employed for clinical trials in patients with BAC. The team of investigators for the project combines the expertise of experienced basic science and clinical investigators, so that the results of the proposed studies can be readily translated to the bedside.

Scientific Abstract

Lung cancer is currently the most prevalent cause of cancer-related mortality, however, development of new effective therapies has lagged the treatment advances achieved with other cancers. Up to 6% of lung cancers are classified as bronchioalveolar carcinoma (BAC). This type of tumor commonly presents as a nodule, or multiple nodules, in the peripheral part of the lung where it is difficult to diagnose by conventional, fiber optic bronchoscopy. New developments, like real-time electromagnetic navigational bronchoscopy with CT, provide a reliable method to accurately extend standard bronchoscopy by positioning at sites of peripheral lung lesions for diagnostic biopsy. Navigational bronchoscopy also offers new alternatives for localized chemotherapy of peripheral lung tumors when combined with the AeroProbe Intracorporeal Nebulizing Catheter (INC). By this method, cytotoxic drugs [e.g., cis-platinum (CDDP) and combinations] in targeted chemotherapy could be safely and efficiently delivered to peripheral BAC lesions with increased effectiveness and reduced potential for pulmonary and systemic toxicities. This approach remains to be tested in humans with BAC. Our earlier studies in models demonstrate that after intrabronchial delivery with the INC, at least 26-fold higher local tissue levels of CDDP can be achieved in a lung lobe than with IV dosing and that the localized chemotherapy is well tolerated. The hypothesis of our current proposal is that combinations of chemotherapeutic agents that are effective against BAC cell lines in vitro could be efficiently and safely delivered by localized aerosol chemotherapy in experimental models. We propose to determine efficacy of CDDP and combinations against BAC cells in vitro and subsequently assess tolerance of CDDP and CDDP/combinations administered directly into the airway by INC in healthy models. The expected result is that highly effective doses of chemotherapeutic agents could be delivered to the lungs of these animals without producing significant pulmonary or systemic toxicity. Our objective is to obtain tolerance and toxicity data from two species in order to begin the process to obtain IRB and FDA IND approval for clinical trials of targeted intracorporeal chemotherapy in humans with BAC. Coupling real-time electromagnetic navigational bronchoscopy and localized, aerosol chemotherapy within the lung could provide a much needed breakthrough in the treatment of BAC.