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Modeling tumor heterogeneity and treatment resistance in small cell lung cancer

Award Number: R50CA243698
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/04/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Modeling tumor heterogeneity and treatment resistance in small cell lung cancer - PROJECT SUMMARY Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid onset of chemoresistance and poor clinical outcomes. Recent advances in immunotherapy have changed the standard of care for SCLC for the first time in over 30 years. Dr. Allison Stewart (Resarch Specialist) and Dr. Lauren Byers (Unit Director) in the Department of Thoracic Head and Neck Medical Oncology at University of Texas M.D. Anderson Cancer Center aim to address major, unmet needs in SCLC, including development of novel therapeutic targets, investigation of approaches to enhance response to immunotherapy, and the study of heterogeneity and its contribution to drug resistance. Mechanisms underlying treatment-resistance remain obscure due to scarcity of tissue samples from relapsed patients. To address this deficiency, Dr. Stewart has led efforts to establish novel SCLC models and analyze serial blood and tumor biopsies from patients using innovative genomic, transcriptomic, and proteomic assays to study mechanisms driving treatment resistance to chemotherapy, immunotherapy, or targeted therapies in SCLC. Patient liquid biopsies are non-invasive, facilitate both serial and post-relapse tissue sampling and contain sufficient circulating tumor cells (CTCs) for generation of CTC-derived xenograft (CDX) models of SCLC, as well as for direct single-cell transcriptional profiling. CDXs mirror patient disease by expression of SCLC markers, sites of metastatic disease and platinum response. Intratumoral heterogeneity (ITH) of SCLC and its contribution to clinical outcomes has not been fully characterized. To investigate ITH, single-cell analyses (including single-cell RNAseq) were performed on novel platinum-sensitive and -resistant SCLC CDX models, as well as longitudinal analyses of CDX models and patient CTCs over the course of therapy. Dr. Stewart has demonstrated that refractory SCLC is characterized by increased heterogeneity and the development of multiple, disparate resistant cell populations within the same patient. In order to address the scarcity of SCLC tissue samples, especially paired and post-relapse samples, Dr. Byers has spearheaded an effort to integrate serial tissue acquisition into the design of all SCLC- focused clinical trials at MDACC. Dr. Stewart's goal is to coordinate a SCLC platform by working with multi-disciplinary teams, including a clinical team (identify and consent patients), a laboratory processing team (process/bank specimens, as well as generate animal models), an experimental analysis team (perform experiments with CTCs, tumor specimens and animal models) and a bioinformatics team (scientific analysis) to establish a repository of SCLC specimens for understanding treatment resistance and developing methods to recognize patient response.


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 = $0 )
2026	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	11/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $96,499 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	8/12/2024	NON-COMPETING CONTINUATION	$96,499
														Subtotal = $96,499

Issue Date FY: 2023 ( Subtotal = $96,644 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	9/12/2023	NON-COMPETING CONTINUATION	$96,644
														Subtotal = $96,644

Issue Date FY: 2022 ( Subtotal = $116,847 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	8/11/2022	NON-COMPETING CONTINUATION	$116,847
														Subtotal = $116,847

Issue Date FY: 2021 ( Subtotal = $116,847 )
2021	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	8/5/2021	NON-COMPETING CONTINUATION	$116,847
														Subtotal = $116,847

Issue Date FY: 2020 ( Subtotal = $116,847 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	9/4/2020	NEW	$116,847
														Subtotal = $116,847

Grand Total All Awards = $543,684

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Modeling tumor heterogeneity and treatment resistance in small cell lung cancer

Award Number: R50CA243698

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/04/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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