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Therapeutic Strategies to Prevent Small Cell Lung Cancer Histological Transformation

Award Number: K99CA304214
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/14/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Therapeutic Strategies to Prevent Small Cell Lung Cancer Histological Transformation - Project Summary Histological transformation is a common mechanism of resistance to EGFR inhibitors as 5-25% EGFR-mutant lung adenocarcinomas (LUAD) transform into either small cell lung cancer (SCLC) or a squamous cell carcinoma (SCC) in response to EGFR tyrosine kinase inhibitors. LUAD patients with RB1 and TP53 inactivation are at a much greater risk (50X) for SCLC transformation suggesting therapeutic strategies to block SCLC transformation may be particularly beneficial for EGFR-Mutant LUADs with RB1 and TP53 inactivation. Due to a paucity of clinical samples and model systems, the mechanistic basis that drives LUAD to SCLC transformation is not well understood nor are there effective therapeutic strategies. EED is an indispensable subunit of the Polycomb Repressive Complex 2 (PRC2) whose activity increased during LUAD to SCLC transformation in human lung cancers. My preliminary data shows that inactivation of EED promotes SCLC to LUAD transformation in an autochthonous CRISPR-based SCLC genetically engineered mouse model (GEMM) demonstrating that EED is necessary for SCLC neuroendocrine phenotype. Therefore, my central hypothesis is that EED is necessary for LUAD to SCLC transformation and EED inactivation will block SCLC transformation induced by EGFR inhibitors. Specific Aims: 1. Determine Mechanisms by which Eed Inactivation Promotes SCLC to LUAD Histological Transformation; 2: Determine how Rb1 Inactivation Mediates EGFR-mutant Lung Adenocarcinoma to SCLC Transformation; 3: Determine if EED Inhibition is a Druggable Therapeutic Strategy to Block EGFR-mutant LUAD to SCLC Transformation. In Aim 1, transcriptomic and epigenomic profiling will be used on EED-isogenic SCLC tumors to determine direct mechanisms by which loss of EED promotes histological transformation from SCLC to LUAD. For Aims 2 and 3, I generated a novel CRISPR-based EGFR-mutant LUAD to SCLC transformation GEMM with Rb1/Trp53 inactivation which I will use to uncover how Rb1 loss mediates SCLC transformation (Aim 2) and to determine whether Eed inhibition blocks SCLC transformation (Aim 3). This proposal will lay the preclinical foundation for EED inhibition as a therapeutic strategy to combat LUAD to SCLC transformation. My long-term goal is to establish myself as an independent researcher with the focus on lung cancer drug resistance. My research bridges multiple disciplines to study lung cancer drug resistance and requires a unique skill set and in-depth knowledge of lung cancer, drug resistance, epigenetics, bioinformatics, and mouse modeling. The K99/R00 award will help in achieving my goal, as I will be guided towards becoming an independent investigator under the guidance of extremely well-established scientists such as Drs. Matthew Oser and Pasi Janne (thoracic oncology), Dr. Carla Kim (mouse modeling), Drs. Matthew Freedman (epigenetics), and Himisha Beltran (lineage plasticity and translational science). This proposal will identify a potential therapeutic strategy to overcome lung cancer drug resistance and will seed a research program that leverages a deep understanding of epigenetics and mouse modeling to help to develop novel cancer therapies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $137,281 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	2	6/11/2026	NON-COMPETING CONTINUATION	$137,281
														Subtotal = $137,281

Issue Date FY: 2025 ( Subtotal = $136,266 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	1	7/14/2025	NEW	$136,266
														Subtotal = $136,266

Grand Total All Awards = $273,547

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Therapeutic Strategies to Prevent Small Cell Lung Cancer Histological Transformation

Award Number: K99CA304214

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/14/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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