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Last Updated: 10/10/18

Yale SPORE in Lung Cancer

Principal Investigator: Roy Herbst
Co-Principal Investigator: Lieping Chen

Principal Investigator Contact Information

Roy S. Herbst, MD, PhD
Ensign Professor of Medicine
Professor of Pharmacology
Chief of Medical Oncology
Director, Thoracic Oncology Research Program
Associate Director for Translational Research
Yale Comprehensive Cancer Center
Yale School of Medicine
333 Cedar Street, WWW221
New Haven, CT  06520-8028
Phone: 203-785-6879
Fax: 203-737-5698
Email: roy.herbst@yale.edu

OVERVIEW

The Biology and Personalized Treatment of Lung Cancer: The Yale SPORE in Lung Cancer (YSILC) coalesces translational scientists spanning all aspects of cancer research to converge on the lung cancer problem. The YSILC leverages existing Yale Cancer Center (YCC) strengths including immunobiology, microRNA research, experience with anti-EGFR treatments with acquired resistance, and the behavioral interventions/biological underpinnings of smoking cessation. The goal of the YSILC program is to improve the overall survival rate of lung cancer patients by developing novel therapeutics and personalized prevention strategies based on an understanding of the targetable biochemical and immunological pathways involved in the progression of lung cancer and the acquisition of resistance to therapy. The YSILC translational research team will accomplish this objective through five specific aims: Specific Aim 1: Develop and test novel therapeutics by discovering the mechanisms underlying the response and resistance to anti-PD-1 and anti-B7-H1 (PD-L1) therapies; Specific Aim 2: Evaluate the potential of non-coding microRNAs as targeted therapies; Specific Aim 3: Understand and target the EGFR pathway in mutant/resistant lung cancer; Specific Aim 4: To develop and test the efficacy of a new personalized approach to gain-framed messaging to improve smoking cessation in Americans with asymptomatic lung nodules who continue to smoke; and Specific Aim 5: To develop new research directions and nurture the next generation of translational investigators in lung cancer through a Developmental Research Program and a Career Development Program. Three cores (Administrative; Biostatistics and Bioinformatics; and Biospecimen, Pathology, and Genomics) are proposed to support the projects and their clinical aims, mechanistic studies, and evaluation of biomarkers for clinical application. The highly coordinated YSILC projects, cores, and programs are focused on developing novel lung cancer therapies, with analysis of patient samples, cell-based assays, production of human cell lines and animal models of disease as a guide to design prospective trials that translate these innovative targeted approaches to clinical therapies. The expected translational outcomes of the program include: (1) A highly coordinated and focused development of novel lung cancer therapies; (2) an improved understanding of resistance pathways to PD-1/B7-H1 blockade and EGFR therapies, including prospective studies to overcome/prevent these effects; (3) an understanding of the therapeutic potential of miRNAs in patients; (4) development of effective smoking cessation methods while exploring correlative mechanistic markers; and (5) the development of the next generation of investigators.

PROJECT 1: Immunotherapy of Advanced Non-small Cell Lung Cancer

Lieping Chen (Basic Co-leader)
Scott Gettinger (Clinical Co-leader)
David Rimm (Translational Co-leader)

Recent evidence suggests that tumors may exploit immune inhibitory mechanisms to create a barrier against antitumor immune responses — including endogenous inflammatory immune responses and those induced by immunotherapies. One key mechanism appears to be mediated by the programmed death-1 (PD-1)/B7 homolog 1 (B7-H1) pathway, which restrains antitumor T cell function in the tumor microenvironment (TME). PD-1 is induced on the surface of activated T cells and, after engaging its ligand, down-modulates T cell functions. Our early studies include cloning and identification of B7-H1 (PD-L1, CD274) as an inhibitory ligand for T cell response and characterization of B7-H1 as a major ligand for PD-1 in suppressing tumor immunity in TME. We demonstrated that B7-H1 was upregulated on the cell surface by inflammation (mainly via IFN-gamma), and that high levels of B7-H1 expression were found in many human cancers including non-small cell lung cancer (NSCLC). Blocking the interaction of B7-H1 on tumor cells with PD-1 on tumor-specific T cells can eliminate this barrier in the TME and protect ongoing antitumor immunity, leading to tumor regression in mouse tumor models. Recent clinical trials have demonstrated that anti-PD-1 or anti-B7-H1 monoclonal antibodies (mAb) induced objective clinical responses in a significant fraction of patients with advanced chemo-refractory metastatic NSCLC. Responses were highly durable with manageable toxicity. While these clinical findings are promising, it is now critical to better understand the effects of PD-1/B7-H1 blockade on antitumor immunity and to develop new strategies to overcome resistance. In this project, we will test the hypothesis that NSCLC is immunologically heterogeneous and only a subgroup of NSCLC with membranous B7-H1 (PD-L1) expression on cancer cells and the presence of functional tumor-infiltrating lymphocytes (TILs) will respond to anti-PD-1/B7-H1 therapy, whereas resistance to anti-PD-1/B7-H1 therapy is largely mediated via PD-1/B7-H1-independent suppressive pathways. We will identify subgroups of NSCLC patients who respond to and resist anti-PD-1/B7-H1 therapy by analysis of B7-H1 expression and immune responses in the TME. In addition, we will delineate cellular and molecular mechanisms underlying resistance to anti-PD-1/B7-H1 therapy in each NSCLC subgroup. Finally, we will maximize the therapeutic effect of PD-1/B7-H1 blockade by additionally targeting resistance mechanisms using mouse models with induced lung cancer. The current project integrates basic and clinical sciences, and will use animal models and human specimens in the context of ongoing clinical trials of anti-PD-1 and B7-H1 antibodies to achieve the goals. Taken together, results from our studies will enhance future anti-PD-1/B7-H1 therapy and potentially lead to novel immune-based therapies for lung cancer.

Project 2: MicroRNA Therapeutics in Non-small Cell Lung Cancer

Frank Slack (Basic Co-leader)
Roy Herbst (Clinical Co-leader)
Patricia LoRusso (Translational Co-leader)

Patients with metastatic non-small cell lung cancer (NSCLC) remain incurable with few options. New therapies are critically needed. In this project we propose to translate a fundamental understanding of microRNAs (miRNAs) in NSCLC. The EGFR/RAS and p53 pathways are the most frequently dysregulated pathways in NSCLC and are regulated in part by two miRNAs, miR-34and let-7, tumor suppressors that regulate key lung cancer oncogenes such as KRAS andare lost or poorly expressed in many lung tumors. miR-34 is directly up-regulated by p53 and is one of the most important outputs of p53 signaling. We will test the hypothesis that a novel miRNA-based therapeutic strategy focused on miR-34 reverses NSCLC tumor phenotypes. Preliminary data generated from our lab shows that MRX34, a nanoparticle encapsulated mir34 molecule, provides a benefit in Kras and in Kras;p53 mutant NSCLC mouse models. Our goal is to evaluate MRX34 in patients with metastatic NSCLC while incorporating novel imaging methods to determine drug delivery and effect.

In Specific Aim 1 we will investigate miR-34 therapeutics in NSCLC mouse models. We have preliminarily shown that miR-34 administered to KRAS or KRAS;p53 mutant tumor cells blocks proliferation and induces apoptosis, including when delivered systemically as MRX34 to Kras or Kras;p53 mutant mouse models. We propose to investigate efficacy and optimal dosingand scheduling of MRX34 using mouse models; test the effects of MRX34 in combination with drugs known to be active against NSCLC in vitro in KRAS; p53 NSCLC cell lines and in vivo and test if MRX34 treatment shows therapeutic potential in EGFRL858R;p53, and erlotinib-resistant EGFRT790M;p53 mutant mice (in collaboration with Dr. Katie Politi [Project 3]). In Specific Aim 2 we will investigate if MRX34 is delivered to the appropriate tissues and engages its targets. We propose to discover serum and tumor biomarkers in the Kras and Kras;p53 mutant mice treated with MRX34 that will be useful for PK, PD, and efficacy analyses in the clinical trial proposed in Aim 3; to apply 18F-ICMT-11 PET imaging of caspase-3 to measure MRX34-induced apoptosis in lung tumors in Kras;p53 mice. We will radiolabel MRX34 particles with F-18 and if successful, incorporate this as an imaging endpoint to validate magnitude and kinetics of particle delivery to in these models. In Specific Aim 3 we will conduct a clinical trial with MRX34 in patients with NSCLC preselected based on genotype, evaluating response/efficacy and PD endpoints to assess drug delivery and drug:target effects using both novel imaging tools developed in Aim 2 (18F-labelled MRX34 nanoparticle) as well as direct tumor signal transduction effects using 18F-ICMT-11 (caspase) as an exploratory biomarker for drug-induced apoptosis. Patient biopsies will be genotyped for the KRAS, EGFR and p53 status, and tumor and serum miR-34 (and let-7) levels determined. These data will be correlated with outcome and could inform patient selection in these and future trials.

Project 3: Targeting the EGFR Pathway in Lung Adenocarcinoma

Katerina Politi (Translational Co-leader)
Sarah Goldberg (Clinical Co-leader)
Joseph Schlessinger (Basic Co-leader)

Lung adenocarcinomas (LUADs) frequently harbor mutations in genes encoding components of the Epidermal Growth Factor Receptor (EGFR) signaling pathway. Mutations are found in EGFR itself, related receptor tyrosine kinases (RTKs) and in downstream signaling molecules. Emerging evidence from sequencing studies of LUADs by our group and others has also revealed mutations in genes encoding negative regulators of RTKs including the CBL proto-oncogene, an E3 ubiquitin ligase that targets EGFR for degradation. Despite the convergence of these genetic alterations on related and overlapping signaling pathways, each specific mutation determines the sensitivity of the disease to different therapies and defines unique clinical subsets of lung cancer each with its own set of characteristics. For example, mutations in EGFR are the only genetic alteration associated with sensitivity to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Tumors with these mutations represent a paradigm for the use of targeted therapies in lung cancer. However, responses to EGFR TKIs are not sustained and tumors become resistant on average within a year after drug-treatment is initiated. Acquired resistance to therapies targeting the EGFR is a major impediment to cures or durable responses for these patients. For other subsets of tumors, such as those harboring mutations in CBL, very little is known to date on the biology and drug sensitivity of these tumors. In this project, centered on the EGFR pathway in LUADs, we seek 1) to clarify the mechanisms of acquired resistance to EGFR-directed therapies in EGFR mutant LUADs, 2) to develop rational approaches to overcome resistance to EGFR-directed therapies and, 3) to understand the vulnerabilities of LUADs with mutations in other genes that control EGFR signaling.

Project 4: Personalized Prevention: Smoking Cessation in Lung Nodule Patients

Benjamin Toll (Clinical Co-leader)
Brenda Cartmel (Population Science Co-leader)

The use of computed tomography (CT) for medical evaluation for lung cancer screening has resulted in a growing number of patients identified with pulmonary opacities, or lung "nodules". Patients with lung nodules are at heightened risk of lung cancer; for those who currently smoke, cessation is the most important strategy available to reduce lung cancer risk. To date, there has been no research on tobacco cessation in lung nodule patients, who may have unique attributes (e.g., anxiety about having a nodule coupled with tobacco dependence) that warrant research for the development of maximally effective tobacco cessation interventions. We thus have designed and propose to evaluate 2 novel behavioral interventions as adjuncts to pharmacotherapy. Intervention 1 is based on a large body of research on gain-framed messages for promotion of smoking cessation, which in this case will be designed and personalized specifically for patients with lung nodules, to increase rates of quitting. Intervention 2 is based on our findings that tobacco cessation leads to improvements in health biomarkers (skin carotenoids, plasma bilirubin), and this information can be fed back to participants to prevent relapse and promote longer-term cessation. Specifically, we will enroll and randomize patients with lung nodules to Intervention 1, consisting of a personalized video and print intervention, emphasizing the benefits (gain-framed) of quitting smoking, to evaluate the hypothesis that this will improve tobacco quit rates above and beyond standard of care smoking cessation treatment over 8 weeks. Then we will perform a second randomization to Intervention 2, an individual-level, biofeedback intervention to examine the hypothesis that this intervention will reduce smoking at 6 months. In addition, we propose to evaluate the impact of smoking cessation on microRNA profiles in human serum, with particular interest in levels of the let-7 family of microRNAs, to better understand the biological mechanisms by which smoking cessation reduces lung tumor promotion and to explore another potential biomarker of cessation. Blood/DNA will also be banked to support future biomarker-based studies. Overall, this project aims to develop transferable interventions to improve short- and longer-term smoking cessation rates in this understudied high-risk patient population, while also evaluating mechanisms involving tobacco carcinogenesis, with clear translational potential.

Core A: Administrative

Leaders:
Roy Herbst
Ed Kaftan

The Administrative Core (Core A) will be directed by Roy Herbst, Principal -Investigator of the Yale SPORE in Lung Cancer (YSILC), and co-directed by Ed Kaftan, with support from the program financial management team. Careful oversight by the Administrative Core will be critical to ensure the success of the Yale SPORE in Lung Cancer. Core A is an extension of existing infrastructure provided by YCC Research Administration to support and facilitate transdisciplinary research efforts. The Administrative Core serves as the central coordination point for all YSILC investigators, with responsibility for monitoring the progress of all projects and cores toward a translational/clinical endpoint. The Core Director and Co-Director along with the YSILC Co-PI (Dr. Chen) will have responsibility for leading the YSILC program, setting translational research priorities, identifying new translational research opportunities from emerging data, monitoring the progress of all projects, cores and developmental projects and determining changes in direction of projects, cores and translational research as needed. Interactions among YSILC investigators will be facilitated by Core A to accelerate the translation of laboratory findings into the proposed and future clinical studies. If required, the Core A Director will manage conflicts among YSILC investigators. As a team, the Core personnel will monitor finances, maintain communications among project and core leaders and coordinate meetings, including the weekly lung cancer translational group seminar series, monthly meetings of the Executive Committee, annual meetings of the Internal/External Advisory boards and an annual YSILC retreat. In addition to these functions, the Core will be the primary interface with the NCI, the Beth Israel Deaconess Medical Cancer Center, other lung cancer SPOREs, Yale Cancer Center and Yale University, and will coordinate outreach efforts, including publications (internal and external), website development, seminars, patient/research advocacy activities, and fundraising programs. Through these administrative activities, Core A will be essential to the organization of the YSILC program, to developing a widespread culture of lung cancer basic/clinical/translational research at Yale and to the efficient achievement of the stated program objectives, with the ultimate goal of a significant clinical impact for patients with lung cancer

Core B: Biostatistics and Bioinformatics

Directors:
Daniel Zelterman
Hongyu Zhao

The goal of the Biostatistics and Bioinformatics Core (Core B) is to address the statistical design and analysis needs of the Yale SPORE in Lung Cancer (YSILC) Projects, the other Cores, the Developmental Research Program (DRP), and the Career Development Program (CDP). To accomplish this goal we have assembled a highly interactive team of cancer biostatisticians and bioinformaticians who will work collaboratively with basic, clinical, translational, and population science researchers to advance the frontiers of cancer medicine. The specific aims of the Biostatistics and Bioinformatics Core are: Aim 1: Provide collaboration and consulting in the design and analysis of basic, translational, population and clinical studies for YSILC; Aim 2: Oversee data management and ensure that data collected on all YSILC studies are of high quality and evaluated with statistical rigor; and Aim 3: Design and monitor the statistical conduct of clinical trials, ensuring data are collected and evaluated with statistical rigor and innovation. For Aim1 the Core will address the analytic and informatics questions arising from the SPORE projects. Services provided by the Core will range from planning activities to consulting on specific analytic questions. More specifically, the Core will schedule regular meetings with the YSILC investigators, and maintain an open door policy for any biostatistical and bioinformatics questions. For Aim 2 the Core will work closely with the investigators to analyze clinical trial data, next generation sequencing data, and bioinformatics data mining. For Aim 3 the Core will design and monitor the statistical aspects of clinical trials for safety, efficacy and futility. Since the observed data can have characteristics different from what was hypothesized, the Core will conduct regular interim analyses, dynamically update the power calculations, develop new statistical and bioinformatics methodology as needed, provide timely suggestions to YSILC investigators, and thus play an important role in the projects in the YSILC. Biostatistics and Bioinformatics is also a key partner in the YSILC with representation on their Senior Leadership Team and participation in all core meetings.

Core C: Biospecimen, Pathology, and Genomics Core

Directors:
David Rimm
Bonnie Gould Rothberg

The Biospecimen, Pathology and Genomics Core for the Yale Lung Cancer SPORE will serve as the nexus for all human biospecimen acquisition, processing and analysis for all SPORE-sponsored research as well as provide support for all non-human model system specimen molecular analytics not currently offered through Yale shared facilities. Tissue biopsy procurement will be coordinated with all interventionalists and surgeons as this occurs at the bedside or in the operating room with research tissues derived from extra passes of the biopsy needle after the diagnostic specimen has been collected or collection at the surgical pathology bench. The Biospecimen, Pathology and Genomics Core will work closely with Yale Pathology Tissue Services, the research tissue procurement service supported within the Department of Pathology (also directed by David Rimm) to obtain fresh resection specimens. Specifically the Biospecimen, Pathology and Genomics Core will: 1) coordinate the acquisition, processing, aliquoting, storage and distribution for all whole blood samples and their derivatives (e.g., plasma, serum, buffy coat) required for the described research in Projects 1-4 as well as the Developmental and Career Development Award Programs’ approved projects; 2) coordinate the acquisition, handling, storage and distribution for all lung cancer tissue sample collection required for Projects 1-4, Developmental and Career Development Awards; 3) generate conditionally reprogrammed primary lung cancer cell lines from fresh tissue samples for use in Projects 1-3; and 4) conduct molecular pathology experiments including partial support of whole exome sequencing, RNA-Seq and Copy Number Variation analysis (Projects 2 and 3); quantitative microRNA in situ hybridization (Projects 1 and 2) and other molecular pathology support as needed during the term of the SPORE.