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Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer

Award Number: R01CA240603
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/03/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive disease that is projected to become the second leading cause of cancer deaths in the Western world by 2030. Recently, studies utilizing transcriptional profiling from resected PDA specimens have identified two molecularly distinct subtypes termed Classical and Basal. These subtypes correlate with overall patient survival, with the Basal subtype predictive of higher rates of metastasis, poor response to therapy and the worst outcomes. While this classification represents an important breakthrough for identifying patients with the most aggressive variant of PDA, the underlying circuits that drive key features of this variant are unknown. Without a clear understanding of this biology, our ability to effectively treat patients with the deadliest form of PDA is compromised. Thus, a major goal in the field is to identify drivers of the Classical and Basal subtypes of PDA in order to 1) effectively target Basal PDA or 2) promote conversion to a less aggressive variant (Classical) that may respond more effectively to therapy. Towards this goal, we have discovered that the Hedgehog pathway transcription factor, GLI2, functions in a non-canonical ligand independent manner as a critical regulator of the most aggressive Basal subtype of PDA (Adams et al eLife, 2019; PMC6538376). The key findings in support of this model are, (1) GLI2 expression is elevated in Basal PDA cell lines and patient tumors and predicts shorter survival in patients, (2) GLI2 suppression leads to loss of Basal identity and inhibits tumor growth while ectopic GLI2 expression in Classical PDA cells causes a switch to the Basal state (3). Our findings underscore a previously unrecognized level of plasticity in PDA cells and highlight an entirely new role for GLI2 in driving Basal identity in this disease. Building on this work, we hypothesize that suppression of GLI2 represents a unique vulnerability in Basal PDA to combat KRAS* resistance and tumor progression. Thus, we propose 2 specific aims that will 1) define the non-canonical transcriptional circuits regulated by GLI2 in a cell-autonomous manner to mediate resistance to KRAS* pathway suppression and 2) determine how GLI2-dependent secreted factors condition surrounding cells to promote primary and metastatic tumor growth. These studies will determine the cellular circuits that control Basal identity, define their role in the context of KRAS* resistance, tumor relapse and metastasis and lay the groundwork for increasing the effectiveness of KRAS-targeted therapies that have entered the clinic.


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: 2024 ( Subtotal = $350,960 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	5	5/6/2024	NON-COMPETING CONTINUATION	$350,960
														Subtotal = $350,960

Issue Date FY: 2023 ( Subtotal = $362,043 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	4	5/12/2023	NON-COMPETING CONTINUATION	$362,043
														Subtotal = $362,043

Issue Date FY: 2022 ( Subtotal = $362,043 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	3	5/24/2022	NON-COMPETING CONTINUATION	$362,043
														Subtotal = $362,043

Issue Date FY: 2021 ( Subtotal = $369,431 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	2	5/11/2021	NON-COMPETING CONTINUATION	$369,431
														Subtotal = $369,431

Issue Date FY: 2020 ( Subtotal = $369,431 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	1	9/3/2020	NEW	$369,431
														Subtotal = $369,431

Grand Total All Awards = $1,813,908

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Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer

Award Number: R01CA240603

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/03/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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