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Last Updated: 08/31/20

Yale SPORE in Lung Cancer

Yale University

Principal Investigator: Roy Herbst, MD, PhD

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

OVERVIEW

The Biology and Personalized Treatment of Primary and Metastatic Lung Cancer: The YSILC unites translational scientists spanning diverse areas of cancer research to converge on addressing the challenge of lung cancer. The goal of the YSILC is to reduce mortality from lung cancer through development of novel therapeutics and treatment approaches that are based on an understanding of targetable biochemical and immunological pathways involved in progression of lung cancer, acquisition of resistance, and development of metastasis The YSILC translational research team will accomplish this objective through three projects: Project 1: Test the hypotheses that Siglec-15 (S15) is a major immune suppressor in PD-L1/B7-H1-null lung cancer and that blockade of S15 can be efficacious for a subset of lung cancer patients; Project 2: Evaluate mechanism-based approaches to counter tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer; Project 3: Targeting lung cancer metastasis and drug resistance in the central nervous system. There are three Cores (Administrative; Biostatistics and Bioinformatics; and Biospecimen, Pathology, and Genomics) to support the projects and their clinical aims, mechanistic studies, and evaluation of biomarkers for clinical application. Strong Developmental Research and Career Enhancement Programs (DRP, CEP) with a history of choosing diverse and productive projects with good outcomes are also proposed. 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. Each of these projects has a clinical trial (either investigator-initiated or NCI-based) designed to test the sensitivity and resistance of the new therapy with molecular correlates. The expected translational outcomes of the program include: (1) a highly coordinated and focused development of a novel immune agent discovered during our current SPORE research; (2) an improved understanding of genetic and epigenetic mechanisms of resistance to EGFR therapies and how to combat it; (3) an understanding of the mechanism underlying brain metastasis; (4) expanding the breadth of lung cancer research by developing the next generation of investigators and encouraging established investigators in other fields to pursue studies on lung cancer through our CEP and DRP programs.

Project 1: Siglec15 as a new target for lung cancer immunotherapy

Co-Leaders:
Lieping Chen (Basic Co-leader)
Roy Herbst (Clinical Co-leader)
David Rimm (Translational Co-leader)

The inability of tumor infiltrating lymphocytes (TILs) to target and kill tumor cells is a major hurdle in treating many malignancies. New treatment strategies that block immune inhibitory mechanisms, such as antibodies that block the interaction of programmed death-1 (PD-1) with its ligand, B7 homolog 1 (B7-H1, also known as PD-L1), have shown promising efficacy in the clinic. Termed checkpoint inhibitor therapy, these drugs have been approved for many indications, including melanoma, Hodgkin lymphoma and lung cancer, and are increasingly being used in combination or in conjunction with other cancer therapies, such as chemotherapy and radiation. Although checkpoint inhibitor treatments have resulted in durable clinical responses in a large proportion of cases, many patients present with tumor types that do not respond to treatment. For instance, ~26% of NSCLC cases, which are negative for B7-H1/PD-L1 and positive for TILs, have been shown to be resistant to anti-PD-1/B7-H1(PD-L1) (anti-PD) therapy. This type of NSCLC, denoted as Type III, is suspected to harbor a mechanism of immune inhibition distinct from other NSCLC types, which has been found to be driven, at least in part, by sialic acid binding immunoglobulin-like lectin 15 (siglec-15).

Siglec-15 expression is mutually exclusive from B7-H1/PD-L1 expression in NSCLC cohorts and has been shown to inhibit T cell proliferation and effector function. Blocking of siglec-15 using anti-siglec-15 (S15) monoclonal antibody (mAb) is therapeutic in mouse models and human cell culture systems and results in amplified T cell responses. Based on these findings, a phase I/II, dose escalation, safety and tolerability clinical trial for S15 mAb treatment in patients with advanced or metastatic solid tumors is on-going.

Although preliminary studies have generated promising results with regard to the potential efficacy of S15 mAb in the clinic, the mechanism of S15-mediated immune suppression remains unknown. Furthermore, to enhance and improve treatment response rates, more work must be done to identify pertinent biomarkers for S15 mAb therapy and modes that modulate S15 expression. Finally, developing combination strategies that alter the tumor microenvironment (TME), such that conversion of the tumor Type is achieved, is imperative for successful targeting and killing of tumor by immune cells and in attaining increased patient response rates to available checkpoint inhibitor therapies. A newly generated immune PDX (iPDX) mouse model, which uses patient-derived tumor tissue to recapitulate and manipulate immune cell responses in the TME, will be utilized to investigate these topics specifically in the NSCLC setting. A proposed investigator-initiated phase II clinical trial in patients with S15+ advanced NSCLC who have progressed on PD-1 axis inhibitor therapy will evaluate S15 mAb efficacy and support biomarker validation studies. Strategies to combine S15 mAb with other agents, such as anti-FGL1 and anti-4-1BB/CD137, to improve therapeutic effect will also be explored. Taken together, the studies proposed here will improve our understanding of the NSCLC TME and enhance therapeutic approaches.

Project 2: Mechanism-based approaches to counter TKI resistance in EGFR mutant lung cancer

Co-Leaders:
Katerina Politi (Translational Co-leader)
Mark Lemmon (Basic Co-leader)
Sarah Goldberg (Clinical Co-leader)

Targeted therapies have completely transformed the landscape for diagnosis and treatment of metastatic lung cancer. Despite this success, targeted therapies are not curative and acquired resistance is a major impediment to cures or durable responses for patients treated with these therapies. A paradigm for the success of targeted therapies in lung cancer, comes from Epidermal Growth Factor Receptor (EGFR) mutant lung cancer. Mutations in exons encoding the tyrosine kinase domain of EGFR are found in approximately 10-15% of lung adenocarcinomas in the US. These mutations confer sensitivity to tyrosine kinase inhibitors (TKIs) and four TKIs (erlotinib, gefitinib, afatinib and, most recently, osimertinib) are currently approved for the first-line treatment of EGFR mutant lung cancer. Acquired drug resistance, however, is a major challenge with all of these TKIs including osimertinib, but we have very limited knowledge of the mechanisms of resistance to osimertinib given its recent adoption in the clinic. Without knowledge about resistance mechanisms, optimal post-osimertinib treatment strategies remain to be defined. Data from our labs and others indicate that osimertinib resistance can arise through both EGFR-dependent mechanisms involving several different types of EGFR mutation and EGFR-independent mechanisms — frequently epigenetic in origin — that are poorly understood. Very little is known about the molecular context(s) in which these resistance mechanisms emerge, their frequency, biochemistry and how to target them pharmacologically. Given the speed of adoption of osimertinib as 1st line therapy, there is an urgent need to identify these mechanisms and resulting vulnerabilities. We propose to leverage our collective expertise in lung cancer biology, mouse models, resistance to targeted therapies and EGFR structural biology to address these issues. Using unique in vitro and in vivo models and patient resources of acquired resistance to osimertinib, innovative genomic and biochemical tools we will: 1) Identify molecular features and new therapeutic vulnerabilities of osimertinib-resistance EGFR variants. 2) Establish mutant EGFR heterodimerization patterns and determine whether these can be leveraged therapeutically to overcome osimertinib resistance; 3) Identify epigenetic processes that confer TKI resistance. Our studies will yield a comprehensive understanding of osimertinib resistance and insight with which to develop new mechanism-based approaches to target osimertinib-resistant tumors — an urgent unmet clinical need.

Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer

Co-Leaders:
Don Nguyen (Basic Co-leader)
Abhijit Patel (Translational Co-leader)
Veronica Chiang (Clinical Co-leader)

Lung cancers are the major source of metastasis in the central nervous system (CNS). There is an important gap in our understanding of how brain metastases respond to therapies and what mechanisms sustain metastatic tumors in the CNS. Historically, the blood brain barrier has been viewed as an impediment to systemic drugs, and novel brain penetrant agents such as the mutant EGFR inhibitor osimertinib have been developed. However, despite improved clinical responses with these agents, brain metastases still progress, and it is unknown how perturbations in the brain tumor microenvironment (TME) can be leveraged for more effective treatments in patients with CNS disease. We have developed novel methods to molecularly characterize human cerebral spinal fluid (CSF) as well as distinguish tumor from stromal gene alterations of brain metastasis in vivo. Our approaches uncover genetic mutations as well as brain TME induced alterations that converge onto cooperating pathways, such as those regulated by VEGF, NOTCH, β-catenin and PI3K. We hypothesize that these molecular alterations: 1) cooperatively drive NSCLC brain metastasis and drug resistance in the brain, 2) are clinically actionable, and 3) are more accurately detected in human CSF or brain biopsies, due to divergent genetic evolution and TME induced adaptation of brain metastasis.

Our hypothesis will be studied in 3 independent yet complimentary aims. In Aim1, we propose to collect human CSF from craniotomies as well as lumbar punctures of lung cancer patients with brain metastases who will be undergoing a bronchoscopic biopsy. By comparing the mutational landscape of matched CSF, plasma and tumor tissue, we will molecularly characterize humans with asymptomatic brain metastasis. Moreover, we will use novel orthotopic patient derived xenograft models (PDXs) to determine if brain metastasis progression and drug response correlates with co-occurring mutations identified in human CSF. In Aim 2, we will test the novel hypothesis that an activated brain microvasculature enhances the survival of drug resistant tumor cells via stromal induced NOTCH signaling in vivo. We will assess if novel bi-specific agents which simultaneously inhibit VEGF and NOTCH can delay brain metastasis progression and/or improve osimertinib response in pre-clinical models. Using human biospecimens, we will correlate the expression of VEGF and NOTCH pathway components with brain metastatic relapse. In Aim 3, we will conduct a clinical trial combining a mutation specific TKI (osimertinib) with a brain vascular targeting agent (bevacizumab) in treatment naïve lung cancer patients with EGFR mutant tumors and CNS disease. Finally, molecular markers (including those studied in Aims 1 and 2) of response or resistance to this combination will be identified by analyzing CSF, plasma and tumor biopsies.

This proposal will help uncover the biological basis of brain metastasis relapse. Importantly, our study will generate insight as to how current and prospective therapies can be harnessed to target both tumor specific mutations and the TME, in a manner that improves clinical outcomes for lung cancer patients with CNS disease.

Core A: Administrative

Co-Director:
Roy Herbst (Director)
Ed Kaftan (Co-Director)

The Administrative Core (Core A) is 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 YISLC Co-PI (Dr. Chen) 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 is 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 monitors finances, maintains communications among project and core leaders and coordinates 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 the annual YSILC SEP and DRP Symposium. In addition to these functions, the Core is the primary interface with the NCI, other lung cancer SPOREs, Yale Cancer Center and Yale University, and coordinates outreach efforts, including publications (internal and external), website development, seminars, patient/research advocacy activities, and fundraising programs. Through these administrative activities, Core A is 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:
Shuangge Ma (Director)
Hongyu Zhao (Co-Director)

The main objective of the Biostatistics and Bioinformatics Core is to collaborate with all YSILC (Yale SPORE in Lung Cancer) investigators to address analytical needs arising from individual projects. In the present award period, the Core has been a critical and effective component of the YSILC. In the next award period, we will further strengthen our effort. We will keep our open door policy and interact with all YSILC investigators on a regular basis. The Core will keep playing a critical role in accomplishing the projects’ goals by ensuring that all studies are rigorously designed, executed, analyzed, and reported. We will also take an important role in data management and ensure that all data are properly managed and protected. All NIH guidelines on data publication and sharing will be properly followed. The Core will also contribute to the YSILC and broader lung cancer community by developing more effective analytics and by being involved in training and education.

The specific aims are as follows. Aim 1: Provide strong biostatistical and bioinformatics support to all YSILC projects and investigators. The Core will maintain regular and dynamic interactions with all investigators. We will be available to all investigators of the projects, other Cores, and projects funded through the Developmental Research Program (DRP) and Career Enhancement Program (CEP). The Core has been and will remain actively involved in the whole spectrum of study design. In execution, we will ensure that the plans are rigorously followed. We will closely monitor study progress, conduct regular monitoring and analysis, and revisit/revise study designs if needed. After data collection is completed, we will conduct comprehensive analysis using existing as well as new methods and assist in preparing manuscripts, abstracts, posters, and grant applications. Aim 2: Provide effective data management for all projects. Our Core, along with the Administrative and Biospecimen Cores, will offer cost-effective and efficient data management services using a centralized data management system, which will reduce data management burden for individual investigators and projects and also guarantee the uniformity of collected data. We will ensure that downstream analyses are fully taken into consideration in the process and that all NIH data-sharing regulations are properly followed, which includes depositing properly curated data to public repositories. Aim 3: Develop innovative biostatistical and bioinformatics methods. The Core has been and will keep developing and implementing state-of-the-art new analysis methods tailored to lung cancer data. This effort will facilitate more effective utilization of the YSILC data, foster lung cancer analytic research, and benefit the broad research community.

The Core will be co-led by Drs. Hongyu Zhao (bioinformatics) and Shuangge Ma (biostatistics). A stellar team has been assembled, with extensive experiences and all the necessary expertise.

Core C: Biospecimen, Pathology, and Genomics Core

Co-Directors:
David Rimm (Director)
Kurt Schalper (Co-Director)

The Biospecimen, Pathology and Genomics (BPG) Core for the Yale Lung Cancer SPORE will serve as the facility for all human biospecimen acquisition, processing and analysis for all SPORE-sponsored research. We will continue to manage, bank and distribute lung cancers obtained from 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. Furthermore, 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 facilitate safe and rapid acquisition of all fresh lung cancer resection specimens. The Biospecimen, Pathology and Genomics Core presents the following specific aims to achieve the goals and mission of the Core in service to the Yale SPORE in Lung Cancer:

Specific Aim 1. To collect, store and distribute human biospecimens with complete clinical, pathological, and demographic annotation for use in Projects 1-3, Developmental Projects and Career Enhancement Awards.

Specific Aim 2. To conduct or assist in molecular pathology analyses of biospecimens including nine modalities for analysis of tyrosine kinase signaling pathways, immune microenvironment, immune profiling and immune monitoring.