Edward Gabrielson - US grants

tissue resource /registry; cancer registry /resource; pathology; biomedical facility; colon neoplasms; neoplastic cell; in situ hybridization; immunocytochemistry; human tissue;

method development; breast neoplasms; carcinoma; genetic markers; breast neoplasm /cancer diagnosis; neoplastic process; loss of heterozygosity; biomarker; diagnosis design /evaluation; chromosome aberrations; clinical research; human tissue; histology; women's health;

cell bank /registry; cancer registry /resource; biomedical facility; immunocytochemistry; human tissue;

DESCRIPTION (provided by applicant) This project will target the enzyme, fatty acid synthase (FAS), for the chemoprevention of lung cancer. Our preliminary studies have found that the vast majority of non-small cell lung cancers express much higher levels of this enzyme than normal tissues, and that this increased expression of FAS occurs relatively early in lung cancer development. Furthermore, inhibition of this enzyme in neoplastic cells leads to a metabolic imbalance and cellular apoptosis. In preliminary experiments, we found a promising anti-tumoral response when treating human lung cancer orthotopic nude rat xenografts with an FAS inhibitory compound. Importantly, these treatments did not result in any recognizable damage to normal tissue but did lead to doselimiting anorexia. The studies proposed in this application will develop the use of FAS inhibitory therapy for lung cancer chemoprevention. In the first aim of our preclinical studies, we will compare several novel FAS inhibitory agents that show less anorectic effects than C-75 to identify a lead compound with high level of anti-neoplastic activity and minimal toxicity. These experiments will examine activity of candidate compounds against human lung cancer cell lines and lung cancer explants in vitro, and against lung cancer xenografts in vivo to assure that the selected compound has activity against a broad range of human lung cancer phenotypes. In the second phase of these preclinical studies, we test this lead compound for ability to prevent tumorigenesis in A/J mice that have been exposed to the tobacco specific carcinogen, 4-(methylnitrosamino)-l-(3-pyridyl)-1-butanone (NNK). To optimize the chemoprevention protocols in this mouse model of lung carcinogenesis, we will use positron emission tomography (PET) imaging to monitor tumor development and response of tumors to the metabolic inhibitor. This optimization of treatment protocols could be useful for designing treatment protocols to be applied in the clinical setting, potentially coupled with PET imaging for monitoring efficacy. The third aim of this project is to examine the effects of the FAS inhibitory compound when used in combination with other agents, such as those currently being considered for chemoprevention of lung cancer. Because the FAS target represents a pathway distinct from those targeted by other compounds, there is a significant potential that such combinations could have synergistic antineoplastic activity. Furthermore, a combination of agents is likely to have activity against the development of a broader range of lung cancer phenotypes than individual agents. Successful completion of these preclinical studies will provide a framework for further evaluation of an FAS inhibitory compound for the chemoprevention of lung cancer in the clinical setting.

[unreadable] DESCRIPTION (provided by applicant): This is revised application for the second renewal of a training program designed to train pathology- oriented medical scientists grounded in molecular, pathobiologic, and clinical aspects of cancer. This Program has three major aims: 1) to train MD or MD/PhD scientists (particularly pathologists) for careers in cancer research at academic institutions or in industry; 2) to train PhD scientists - at the post-doctoral and pre-doctoral levels - to understand morphological and clinical, as well as mechanistic, aspects of cancer while preparing them for investigative careers; and 3) to recruit and train highly qualified minority trainees for productive careers in a field in which they are currently underrepresented. The Training Program has made significant achievements in each of these areas. For example, twenty of twenty nine post-doctoral trainees supported during the first two funding periods (10 years) now have faculty positions at the rank of Instructor or higher, three have positions .as Research Associate or equivalent, four have undertaken further training, and only two have positions not directly reflecting their training in this Program. Additional progress in the training of PhD scientists has been made with initiation of a Neoplasia Tract in the Pathobiology Graduate Program, beginning with the most recent funding period. With support from this training grant, highly qualified graduate students, committed to careers in cancer research, have been recruited to the Training Program. Finally, the Program has been successful in achieving goals of third major aim, to train highly qualified minority trainees for careers in cancer research and related fields. During the past funding period, 3 African American and 2 Hispanic trainees have been sponsored (including 2 trainees who entered the program in the most recent year of funding). Thus, this Training Program has assumed a critical role in the overall educational duties of Johns Hopkins and of the cancer research field. [unreadable] [unreadable] The cancer research field continues to have needs for qualified MD (or MD/PhD) pathologists, for PhD scientists trained to understand the pathological basis of disease, and for well-trained scientists from minority groups. For these reasons, this Program seeks a renewal of funding for pre-doctoral and post- doctoral trainees in the Pathobiology of Cancer. With a committed faculty and an outstanding cancer research environment, this Program is positioned for continued success in this important training mission. [unreadable] [unreadable] [unreadable]

The Pathology and Tissue Core of the Johns Hopkins Lung SPORE program was initiated approximately 14 years ago. The Core activities have evolved over this time period. While the initial emphasis of the Core was to collect frozen tissue samples, services added in response to evolving need of the SPORE include tissue microdissection, collection of specialized samples (lymph nodes, bronchiolaveolar lavage, sputum), expanded data collection and management services, establishing tissue microarrays (TMAs), and pathology consultation for use of human specimens as well as animal models. In addition, the Core has supported the continuous development and refinement of a relational database that provides comprehensive clinical data for all lung cancer patients at the institution in addition to annotation for the pathology specimens in the Core. All of the resources of this Core are leveraged beyond our own SPORE program, as we continue to have active collaborative efforts with investigators at other institutions, including investigators in other SPORE programs. In the past two years, investigators in our program have recognized a need for laboratory models that resemble human lung cancer more closely that do the standard cultured lung cancer cell lines. This prompted the development of a new resource in the Core for establishing transplantable xenografts from clinical samples of human lung cancers. We expect that this resource will contribute significantly to work of investigators throughout the lung cancer research community in coming years, as well as to the projects of our SPORE. Thus, the basic functions of this Core can be summarized as follows: [unreadable] Collect, store, and distribute tissues and other biological samples relevant to the study of lung cancer. [unreadable] Collect, maintain, and provide access to clinical and pathological data related to all lung cancer patients treated at Johns Hopkins, including those related to these specimens. [unreadable] Develop newtransplantable xenograft models of lung cancer from clinical samples [unreadable] Provide expert pathologist consultation for molecular studies of human lung cancer and for studies involving rodent models of lung cancer. Relevance to Public Health: This Core provides valuable resources to link laboratory studies to clinical applications.

This project will continue studies on the use of pharmacological inhibitors of fatty acid synthase (FAS) for lung cancer treatment in both the setting of clinical trials (with correlative markers) and in the laboratory setting for refinement of this treatment strategy. Under current funding from the SPORE mechanism, we have 1) confirmed that FAS is a promising target for lung cancer treatment, 2) identified a class of pharmacological compounds that can selectively inhibit FAS activity without significantly affecting fatty acid oxidation (with associated anorexia), and 3) demonstrated that these compounds effectively inhibit growth of human lung cancer xenograftsand mouse lung tumors, without causing significant toxicity. Furthermore, our work has evaluated pharmacokinetics of a FAS inhibitor and demonstrated the ability to administer these compounds orally, which support our expectations of moving this project to clinical trials for lung cancer treatment. Finally, experiments conducted during the initial funding period have demonstrated the ability of positron emission tomography (PET) imaging to monitor response to FAS inhibitors, and also found additive or synergistic effects when FAS inhibitors are used in combination with other chemotherapeutic agents. In the first specific aim of this proposed project, we will evaluate a pharmacological inhibitor of fatty acid synthase in early stage clinical trials. We expect to initiate a phase 1 trial in the current funding period, and phase 2 clinical trails in the proposed funding period. Both phase 1 and phase 2 clinical trials will include monitoring patients with the candidate markers of response developed in Specific Aim #2 (including FDG/PET imaging), in addition to standard measures of patient response. Specific aim #2 will determine the effect of fatty acid synthase inhibitors on signal transduction pathways and cellular metabolism in pre-clinical models of lung cancer, to identify potential markers for predicting and monitoring response to these agents. As noted above, these markers will be applied to the clinical trial setting. Finally, in specific aim #3, we will evaluate the potential role for fatty acid synthase inhibitors in combination cancer therapy. We will evaluate potential additive or synergistic effects of combining FAS-inhibiting compounds with conventional chemotherapeutic agents for lung cancer, as well as with novel agents that target specific signal transduction pathways. Understanding how a FAS inhibitor can be effectivelycombined with other agents will provide a framework for effective use of this compound in the clinical setting. Relevance to Public Health: This project will develop a new therapeutic strategy for lung cancer treatment.