Introduction

In 2005, an estimated 172,570 Americans will be diagnosed with lung cancer, and there will be an estimated 163,510 deaths, representing 13 percent of all incident cancers annually and 29 percent of all cancer deaths. Lung cancer remains the leading cause of cancer mortality for both men and women in the United States, killing more patients than the next five most common cancers combined. These sobering statistics are compounded by the inescapable fact that there have been only the most modest of improvements in five year survival rates. The Lung PRG report noted that progress will continue to be limited in the future by the absence of a well-defined mechanism and infrastructure to enroll patients in trials and systematically collect and archive tissue. Progress has also been limited in applying new therapeutic approaches for patients with stage I and II lung cancer, in verifying the clinical utility of molecular predictors of prognosis or response to treatment, and in being able to rapidly and efficiently perform phase I and II studies of new targeted therapies with defined biologic endpoints. It is thus clear that we must take drastic and bold actions if we are to positively impact these statistics.

Accordingly, the 2015 Vision of the I2 Lung Cancer Team is to

• Significantly and measurably reduce the morbidity and mortality attributable to lung cancer by 2015.

In order to accomplish this Vision, the integrated plan targets 3 critical strategies:

• Reducing the risk for lung cancer by achieving more effective tobacco control
• Improving the likelihood of cure by accomplishing earlier detection and treatment of early lung cancer and pre-cancer
• Introduction of novel targeted therapies through tight coupling with ongoing or planned biology initiatives.

In order to implement these critical strategies, we are also proposing that lung cancer be a major focus of activity for:

• Genomic and proteomic research
• In vivo imaging
• Biospecimen acquisition and analysis

Our implementation plan has been crafted as a comprehensive approach that does not duplicate existing or planned initiatives. Rather, we will build upon those initiatives with a lung-specific focus, and for those initiatives without such a focus, we request redirection of efforts to include a lung cancer focus. We are not suggesting that all existing activities related to lung cancer pre-clinical and clinical research be included in the scope of the I2 Lung Team. Instead, we strongly suggest that the Team focus on high opportunity and potentially high return strategies. We believe that the efforts of the Team should not be diverted by the incorporation of incremental strategies but should instead focus on transformational strategies.

Finally, we recognize the unique opportunity for the Lung Cancer Integration and Implementation Team to develop strategic alliances with the two parallel Integration and Implementation teams focused, respectively, on Imaging and Bioinformatics.

Management and Organizational Structure

There is no single operational focus within NCI dedicated for lung cancer initiatives in prevention, diagnosis and therapy. We therefore propose to establish a "Virtual Distributed Corporate" model (I2 Lung Cancer) to manage the business plan. In order to operationalize this business model, we also propose to create the position of Program Director for I2 Lung Cancer, a nationally recognized lung cancer clinical or basic researcher, with extensive administrative experience. Alternatively a small tightly integrated team, appointed by the NCI Director, could be constituted to serve in this capacity. The activities necessary to accomplish the proposed outcome(s) will be implemented and accomplished through NCI Divisions, Programs, and Branches chosen as "best of breed" with proven and documented areas of expertise, and accomplished using a variety of funding mechanisms.

We also propose the immediate creation of a Lung Cancer Scientific Advisory Committee (LCSAC) to serve as an advisory body to provide scientifically grounded advice to the NCI Director (through the Program Director of I2 Lung Cancer) on the status of cross-cutting lung cancer research activities across research entities. The goal is to adopt a comprehensive approach to the lung cancer problem by evaluating the success of existing efforts in lung cancer biology, screening, prevention and therapy; and to catalog and review novel concepts and data regarding new agents, diagnostics, and emerging technologies emanating from the Lung SPOREs (Specialized Programs of Research Excellence), NCI program project (P01) applications and other research initiatives. This committee would also identify critical questions and unmet needs across the spectrum of lung cancer research.

The LCSAC will be led by the Program Director of the I2 Lung Cancer. The committee would include a broad and appropriate representation of about 12 to 15 intramural and extramural scientists representing the various NCI Divisions, research entities (SPOREs, cancer centers, cooperative groups, community oncologists, regulatory agencies, industry, and patient advocacy groups) and disciplines (clinicians, biologists, epidemiologists, behavioral scientists imagers, tobacco addiction and tobacco control, experts in pharmacokinetics/pharmacogenomics and specialists in molecular diagnostics). The committee will be appointed by the Director of the NCI, and will meet in person at least twice a year initially and by monthly teleconferencing.

In order to achieve synergy with the Clinical Trials Working Group (CTWG) recommendations, we propose to create a Lung Cancer Scientific Steering Subcommittee constituted as a subcommittee of the proposed LCSAC to provide advice to the NCI Director on the conduct, oversight, and implementation of lung cancer clinical trials across the Institute, to involve the broad oncology community, facilitate open communication and increase the involvement of patients and community oncologists in clinical trials.

We also recommend an augmentation of the current Cancer Intervention and Surveillance Modeling Network (CISNET) to derive applicable metrics by which the I2 Lung Team will measure its impact on both patient and societal levels.

Risk reduction through tobacco control efforts

Proposed Initiatives

Fewer than 40% of providers currently recommend specific treatment for tobacco use. Furthermore, even with combined behavioral and pharmacologic interventions, quit rates are no more than 15-25%. Therefore, the NCI integrated plan proposes a multi-pronged transdisciplinary approach to improve the success rates of smoking cessation and prevention in order to have a significant impact on the 2015 lung cancer goals. Specifically, initiatives that address both the etiology and treatment of tobacco use are proposed:

• Genetics of Nicotine Dependency: Advance the discovery of how tobacco dependency occurs and the linkages between biology and behavior by exploring the role of gene variants in the nicotine dependent phenotype. The goal is to more effectively prevent tobacco use and increase the chances of successful cessation through identification of drug targets.
• Targeted Pharmacotherapy: Fund research on the development of molecularly targeted therapies to improve the success rate of the treatment of tobacco use and dependence.
• Imaging research: Support functional neuro-imaging studies to characterize the neural substrates of addiction.
• Promote testing of nicotine vaccines that have a potential role in treatment of addiction and also may provide a future opportunity to prevent addiction.
• Liaison with Nanotechnology Initiative for targeted delivery of novel nanoparticle-based therapies.
• Dissemination/Implementation of Effective Cessation Interventions: Support efforts to optimize the delivery of effective treatments to clinical and community environments - along with feedback mechanisms so that the delivery process serves as an additional component of discovery.
• Policy: Support analyses on the role of policy change (e.g. clean indoor air laws, coverage of medications by health plans, tobacco tax increases) on tobacco use uptake, dependence and cessation for more strategic decisions on what interventions can have the greatest impact.

Early Detection

Nearly 60% of patients diagnosed with lung cancer die within one year of their diagnosis and nearly 75% die within two years. Therefore this plan highlights the need for effective and validated early detection techniques, and builds upon the lung specific projects of I2 Imaging recommendations to leverage several of its lung cancer-specific objectives at substantial cost savings.

Proposed Initiatives

• Allocate resources for the maintenance and oversight of the American College of Radiology Imaging Network (ACRIN)/National Lung Screening Trial (NLST) Specimen Biorepository both during and after the period of the trial to oversee the quality and integrity of samples, development of seamless integration of biospecimens with all associated metadata, and ensure the optimal uses of these depletable archives for the most promising molecular research. Also, fund advertising of the repository to the scientific community.
• Fund collection of remnant tissue specimens from participants with proven lung cancers diagnosed within the ACRIN-NLST initiative, and incorporate biospecimen and imaging data within the Image Archive being established.
• Fund collection of pathology tissue from lung cancer cases diagnosed in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) Trial.
• Promote standardized procedures and employ technologies that have demonstrated utility and feasibility through peer-reviewed publications. Such an initiative could potentially be part of the proposed NCI-wide Molecular Biomarkers Initiative, once approved.
• Bootstrap on existing initiatives that promote the development and validation of in vivo imaging in early lung cancer detection.

New Drug Development and Imaging of Response to Therapy

Targeted drug development is impeded because only a fraction of the molecular targets involved in lung tumorigenesis has been identified in small numbers of subjects. With large-scale sequencing now a viable tool for discovery, a unique opportunity exists to create a well-defined strategy to systematically identify all the genomic and epigenomic lesions associated with lung cancer. These genetic insights and advances in biology will drive new drug development and help in monitoring of therapy response. Success requires coordinated efforts to improve target identification, and the development of functional imaging agents, and novel clinical trial methodologies.

Proposed Initiatives

• Identify all the genomic and epigenomic lesions associated with lung cancer in coordination with the Human Cancer Genome Project Initiative proposed by Drs. Eric Lander and Lee Hartwell. Launch parallel lung-specific projects as proof of principle studies to systematically characterize lung cancer and transform treatment, by improving selection of therapeutic targets with higher efficacy and decreased side effects; identification of patients most likely to respond, rational development of combination therapies; resolution of cancer into homogeneous groups; improved understanding of the molecular events triggered by carcinogenic exposures, and refined estimates of susceptibility.
• Define the contribution of inflammation, infection, and injury to lung carcinogenesis, with the aim of identifying appropriate targets for cancer treatment and prevention. It is recognized that the microenvironment may also be an important factor in developing therapeutic approaches.
• Speed the translation of above findings to clinical care and propose an alternative drug delivery system initiative for lung cancer treatment or prevention, synergizing with the NCI Nanotechnology initiative. The goal is to promote delivery of multiple payloads for combination therapy, and use of reporting systems to target receptors and avoid systemic toxicities, potentially allowing use of agents at concentrations previously unattainable.
• Advance the science of imaging response assessment with molecular imaging technologies that directly reflect response to targeted therapies and by providing uniform, high quality imaging acquisition, quality control, and analysis and creation of a lung cancer meta-directory within the conduct of clinical trials.

Budget:

Proposed Distribution of Lung Cancer Dollars:
Approximately 8 million dollars each year over the next five years plus an additional 40 million dollars for leveraged activities.

Management and Organizational Structure Chart

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