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Oncogenic Kras drives stromal adipogenesis to promote colorectal cancer (CRC) progression

Award Number: K00CA274661
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Oncogenic Kras drives stromal adipogenesis to promote colorectal cancer (CRC) progression - Genomic instability is a characteristic hallmark of cancer, leading to an increased propensity for mutations in tumor suppressor genes, activation of oncogenes, and chromosomal alterations. These genomic changes not only contribute to tumor initiation but also play a critical role in tumor progression and the response to anti-cancer treatments. Targeted therapy aims to trigger cancer cell death by disrupting cell cycle pathways, while also exploiting the high levels of genomic instability present in cancer cells. In small cell lung cancer (SCLC), the use of the WEE1 kinase inhibitor AZD1775 exhibits potent anti-cancer activity by disrupting the G2/M checkpoint, allowing damaged cells to undergo mitosis, eventually leading to mitotic catastrophe. However, despite its promising anti-tumor effects in clinical settings, AZD1775 resistance emerges rapidly, indicating the development of genomic instability, acquired gene alterations, or compensatory mechanisms to bypass cell death. A genetically engineered mouse model of breast cancer with WEE1 conditional deletion shows that WEE1 deficiency increases the activity of APC/C, allowing cancer cells to progress through mitosis, impairing genomic integrity and resulting in carcinogenesis. Moreover, gene expression analysis in SCLC patients revealed PKN1 as a highly expressed cell cycle-related gene that is involved in G2/M delay in a WEE1-low expression group. These observations lead us to hypothesize that WEE1 inhibitory-mediated genomic instability is a driving factor in tumor resistance, promoting the acquisition of neo-oncogenic events and compensatory mechanisms in the G2/M checkpoint, enabling SCLC cells to evade cell death when treated with WEE1 inhibitors. Given the significance of genomic instability in cancer resilience, this K00 project aims to investigate whether WEE1 inhibition promotes acquired genomic instability and gene mutations that drive resistance while exploring the potential role of PKN1 in WEE1 inhibitor-resistant SCLC.


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 = $92,845 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	5	1/26/2026	NON-COMPETING CONTINUATION	$92,845
														Subtotal = $92,845

Issue Date FY: 2025 ( Subtotal = $98,998 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	4	11/19/2024	NON-COMPETING CONTINUATION	$98,998
														Subtotal = $98,998

Issue Date FY: 2024 ( Subtotal = $95,067 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	003	3	9/25/2024	EXTENSION WITH OR WITHOUT FUNDS	-$95,067
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	3	8/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$6,939
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	3	2/19/2024	EXTENSION WITH OR WITHOUT FUNDS	$88,128
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	004	3	9/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$95,067
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	002	3	8/28/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $95,067

Grand Total All Awards = $286,910

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Oncogenic Kras drives stromal adipogenesis to promote colorectal cancer (CRC) progression

Award Number: K00CA274661

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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