2024 Peg’s Fight for Life Early Career Research Award Recipient

Principal Investigator: Lindsay LaFave, PhD, Albert Einstein College of Medicine

Project title:Exploring Differences in Immunotherapy Response in EGFR and KRAS-mutated Lung Cancer

We are honored to announce the winner of A Breath of Hope’s 2024 Peg’s Fight for Life Early Career Award: Dr. Lindsay LaFave, of the Albert Einstein College of Medicine and Montefiore Einstein Comprehensive Cancer Center for her project entitled, Exploring Differences in Immunotherapy Response in EGFR and KRAS-mutated Lung Cancer.

Dr. LaFave has a long-standing interest in studying chromatin biology in normal and malignant contexts using epigenomic technologies and murine modeling approaches. Her laboratory at Albert Einstein College of Medicine uses this toolkit to investigate the regulation of gene expression in the development of heterogeneity and plasticity in lung cancer. Her research group has the overarching goal of better understanding the non-genetic mechanisms that contribute to cellular diversification in tumors and response to lung cancer treatment. Her aim is to use relevant in vitro and in vivo models to study mechanisms of gene regulation in normal lung cells and lung cancer cells, interrogate the role of transcriptional and epigenetic regulators in lung cancer development, and investigate the therapeutic implications of these findings. One specific aim of the ABOH-funded project is to compare immune responses in KRAS and EGFR mutant murine models and lung adenocarcinoma lung adenocarcinoma human samples.

Dr. LaFave completed her graduate training at the Gerstner Sloan Kettering Graduate School at Memorial Sloan Kettering in Dr. Ross Levine’s lab. Her graduate work primarily focused on studying the mechanism(s) by which loss of the tumor suppressors ASXL1 and BAP1, genes that are commonly mutated in a spectrum of hematopoietic malignancies, contribute to disease progression. In her graduate work, she identified that ASXL1 loss contributed to dysregulation of the Polycomb Repressive Complex 2 (PRC2) complex which was published as a co-first author paper in Cancer Cell. Her graduate work also demonstrated that loss of BAP1 leads to increased activity and that EZH2 is a therapeutic target in BAP1-mutant disease which was published in Nature Medicine. This training in hematopoiesis and stem cell biology continues to inform her scientific approach after she shifted her focus to the study of solid tumors, specifically lung cancer. In her postdoctoral training, she joined Dr. Tyler Jacks’ lab at MIT and Dr. Jason Buenrostro’s lab at Harvard to continue to explore epigenetic mechanisms of disease progression in lung cancer models. In this work, she performed single-cell ATAC-Sequencing to generate epigenomic profiles of individual tumor cells in heterogeneous tumors in the “KP” lung adenocarcinoma model. She made several striking findings which were published in Cancer Cell, including that KP tumors (i) exhibit substantial epigenetic intratumoral heterogeneity, (ii) lose cell identity across tumor progression, and (iii) develop distinct transcriptional dependencies in late-stage tumors. Her independent research group pairs this expertise in epigenomic technology with mechanistic lung biology to identify new therapeutic rationales in individuals with lung cancer. She has an interest in understanding how chromatin biology impacts gene regulation in epithelial cells and how this ultimately influences cancer evolution and response to treatment. The goal is to improve treatment for individuals with lung cancer.

With the A Breath of Hope research award, Dr. LaFave aims to use her expertise in murine and organoid modeling to understand why EGFR mutations have reduced responses to immunotherapy. In this grant, she will examine differences in the immune environment in KRAS and EGFR mutant models and if these distinct immune environments could be modulated to improve responses to immunotherapy.

Progress Report April 2026

During this reporting period, we made significant progress in understanding key biological differences between EGFR- and KRAS-mutant lung cancers, with a particular focus on transcription factors (proteins which impact gene expression) which have differential activity. We found a transcription factor that is more active in EGFR-mutant tumors and appears to contribute to tumor immune evasion, helping cancer cells avoid detection by the immune system.

Using laboratory models, we showed that removing this transcription factor makes cancer cells more sensitive to targeted therapy and reduces immunosuppressive signaling, shifting the tumor environment toward a more active immune response. These findings suggest that rewiring chromatin regulation may be a promising therapeutic target for improving immunotherapy treatment outcomes.

We also expanded our use of advanced research models, including organoids and mouse systems, to study how genetic factors such as CEBPA influence tumor-immune interactions. Early results indicate that EGFR- and KRAS-driven tumors respond differently, highlighting important biological distinctions that may impact treatment strategies.

In parallel, we expanded our lung cancer biobank to include over 70 patient samples and continued improving laboratory models, particularly for EGFR-driven tumors. We have established patient derived organoids from patient samples, and we will continue to study these models through co-culture systems.