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Jon Zugazagoitia MD-PhD

2020 LCFA/IASLC/BMS Young Investigator

Dr. Zugazagoitia is an Attending Physician-Scientist in Medical Oncology at 12 de Octubre Hospital, Madrid

Dr. Zugazagoitia’s Personal Statement

I am a physician scientist in thoracic oncology. In the past 5 years I have acquired a strong expertise in clinical and translational research in thoracic tumors. Clinically I treat mostly lung cancer patients. I gained solid clinical abilities and extensive training in the methodology of clinical research in lung cancer under the supervision of Luis Paz-Ares (Rio Hortega contract for young clinical investigators, CM15/0096). Currently I actively participate in the initiation and development of clinical trials, as well as in the early phases of clinical development of novel immunotherapy drugs for lung cancer. From a scientific perspective, I have solid background in molecular taxonomy of lung cancer, biomarker science, and immunobiology. I have made relevant contributions related to molecular subsets of non-small-cell lung cancer (NSCLC), particularly for EGFR-mutant and ALK-rearranged NSCLCs. In the past two years I have been focused on biomarker research in the prestigious laboratory of Dr. Rimm at Yale. Here I gained solid knowledge in immunotherapy biomarker science and immunobiology, including being among the first scientist in the world becoming an expert operator in the Digital Spatial Profiling system (NanoString) (see letter of reference). I have authored several research articles related to genotype-based precision oncology and biomarkers for immunotherapy in high impact per-reviewed journals, including Annals of Oncology, Journal of Thoracic Oncology, Clinical Cancer Research, European Respiratory Journal, and Lung Cancer, and Clinical Lung Cancer.

I have been recently appointed full-time attending physician-scientist back in the 12 de Octubre Hospital (Madrid, Spain) through the award of a peer-reviewed contract from the prestigious Carlos III Research Institute (Juan Rodes contract, JR19/00028). I am an independent investigator since October 2019. My research interest is mainly focused on discovery of novel biomarkers and targets for immune therapies. I currently have 60 % protected time for research and my own laboratory at the 12 de Octubre research facilities (see institutional letter of support attached in the annex). I have the necessary resources to accomplish the objectives of this proposal, including the Digital Spatial Profiling system (NanoString) recently acquired by our group which is located in my lab. I believe that my demonstrated scientific record, commitment, team work, and hard work has prepared me to lead this exciting research project.

The proposed project is a new and exciting area of research in my laboratory. We have generated substantial preliminary data at Yale to support the hypothesis and aims proposed for this project. In addition, we have already started collaborations with Joao Barata Lab (University of Lisbon, Portugal) a renowned expert in IL-7R/IL-7. We believe that this collaboration substantially increases the chances for a successful development of this proposal. I am committed to developing precision immunotherapy strategies to improve outcomes of patients with NSCLC. The receipt of this prestigious award will likely contribute to this major goal.

Dr. Zugazagoitia’s LCFA Funded Project

RESISTANCE TO PD-1 CHECKPOINT BLOCKADE IN NSCLC INDUCED BY TUMOR CELL CD127 (IL-7R) EXPRESSION: VALIDATION, FUNCTIONAL ASSESSMENT, AND TARGETED THERAPEUTIC STRATEGIES

Relevance of the project in the study of lung cancer

Immunotherapies that block the PD-1/PD-L1 checkpoint have transformed lung cancer treatment and outcome. However, most patients do not derive significant benefits particularly when these drugs are given as single agents. Therefore, there is a medical need to identify therapeutically amenable mechanisms by which tumors induce resistance to PD-1 axis inhibition, in order to expand the treatment opportunities in these immunotherapy-refractory patients. Our preliminary findings derived from immunotherapy-treated non-small-cell lung cancer (NSCLC) patients revealed that those with high levels of surface IL-7R protein expression in tumor cells experienced poor outcomes under monotherapy with PD-1 axis inhibitors. On the basis of this novel finding, we have designed a research plan with the overall aim of demonstrating that tumor cell IL-7R overexpression is a mechanism of resistance to PD-1 blockade in NSCLC, and that it can be therapeutically targeted with drugs that block IL-7R. First, we will begin with validating our preliminary findings in aa large and independent set of immunotherapy-treated patients from 12 de Octubre Hospital (Madrid). For this aim, we will use innovative tumor profiling technologies to quantitative assess IL-7R expression. Then, we will work backwards to uncover the mechanistic basis of these findings using mouse models adequately suited for this aim. Finally, we will test the therapeutic efficacy of blocking tumor cell IL-7R overexpression using mouse models that closely recapitulate human disease. Overall, this project has the potential to facilitate two major clinical goals in the future; 1) To help clinicians identify which patients are not likely to benefit from single-agent PD-1 checkpoint blockade using IL-7R expression as a clinical biomarker; 2) To develop novel treatment strategies to these bad prognosis patients unlikely to derive benefit from PD-1 axis inhibition.