Wednesday, December 17, 2025 12/17/2025

Context dependent tumor suppression

Award Number: R01CA279698
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Context dependent tumor suppression - Project Summary We have identified a novel mode of autonomous programmed cell death that is controlled by p53 in small cell lung cancer (SCLC) — the most deadly form of lung cancer. We capitalized on a genetically engineered mouse model that we created to regulate endogenous p53 inactivation and its temporally controlled reactivation in established mouse models of SCLC. We found that p53 controls a canonical senescence program in approximately half of the tumors and a non-apoptotic cell death program in the rest. The mechanism of cell death is distinct from known forms of programmed cell death but is dependent on multiple members of the cyclophilin protein family of peptydyl-prolyl isomerases. We demonstrate that p53 regulates a distinct transcriptional program in dying SCLC tumors not active in senescing SCLC. Moreover, the activation of this transcriptional program is abolished by small molecule inhibitors of cyclophilins. In aim 1 of our project, we will interrogate the molecular underpinnings of this p53-cyclophilin interaction. At the cell physiological level, p53-mediated SCLC cell death is associated with features of paraptosis; a poorly defined mode of cell death not previously associated with p53 but characterized by excessive accumulation of cytoplasmic vacuoles, cell swelling, and plasma membrane dysfunction. Additionally, we observed massive induction of an endoplasmic reticulum-directed autophagy program (ER-phagy) during p53-mediated SCLC death. In aim 2 of our project we will interrogate the molecular features and dissect the molecular determinants of paraptosis and ER-phagy in this context. Finally, we present comparative genomics that implicates that the `classical' molecular subtype of SCLC is represented by SCLC tumors that die after p53 restoration and that the `variant' molecular subtype of SCLC is represented by SCLC tumors that senesce after p53 restoration. In aim 3 of our project, we will determine if the effects of p53 restoration are distinct based on either the cell of origin, or the collection of driver mutations as each of these impacts the molecular subtype that develops in SCLC. Together, our project will elucidate an important molecular mechanism for controlling SCLC, shed light on targetable vulnerabilities, and identify specific subsets of SCLC patients that may be susceptible to such approaches.


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 = $409,430 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	3	12/12/2025	NON-COMPETING CONTINUATION	$409,430
														Subtotal = $409,430

Issue Date FY: 2025 ( Subtotal = $454,922 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	12/18/2024	NON-COMPETING CONTINUATION	$409,430
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	2	5/29/2025	NON-COMPETING CONTINUATION	$45,492
														Subtotal = $454,922

Issue Date FY: 2024 ( Subtotal = $454,922 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	12/29/2023	NEW	$454,922
														Subtotal = $454,922

Grand Total All Awards = $1,319,274

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Context dependent tumor suppression

Award Number: R01CA279698

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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