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Targeting Pancreatic Cancer Senescence with ImmunoPET

Award Number: K99CA276804
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Targeting Pancreatic Cancer Senescence with ImmunoPET - Project Summary Pancreatic cancer is the fourth-most lethal cancer across both sexes, with five-year overall survival of all stages at 12%. In patients diagnosed with pancreatic cancer, first-line chemotherapy with gemcitabine and nab- paclitaxel with or without FOLFIRINOX often requires second-line chemotherapy combinations, with median survival ranging from 6 to 26 months. New therapeutic combinations are needed. One promising approach for overcoming this impasse centers on senescence. Cells can undergo senescence in response to replication, oncogene induction, or targeted drug therapy, including most chemotherapeutic regimens used for pancreatic cancer. However, while senescent cells have been implicated in tumorigenesis via pro-inflammatory factors seen in circulation as part of the senescence-associated secretory phenotype (SASP), their direct tumoral activity over time and distribution elsewhere is unknown. Moreover, current senescence imaging agents are small molecules measuring lysosome activity. An antibody-based approach, in contrast, offers greater targeting specificity and biological links to surface antigens. Noninvasive PET tools for senescence antigens will improve our ability to identify senescence with the option to change the isotope for targeted alpha therapy in the tumor. The members of the Scott Lowe Lab have pioneered senescence induction in pancreatic cancer with the combination of trametinib (T) and palbociclib (P), leading to the release of cytokines as SASP remodels the tumor microenvironment and beyond. Using immunoPET to study combination TP therapy in their models, we have found that shed antigens such as VEGF and IL-6 are decreased in the tumor environment while membrane- bound antigens like uPAR are elevated. We hypothesize that senescence induced by chemotherapy is temporal and immunoPET can be used noninvasively to quantify these dynamics during therapy. In collaboration with the Scott Lowe and Christine Iacobuzio-Donahue Labs at Memorial Sloan Kettering Cancer Center, we will use noninvasive immunoPET imaging to (1) quantify previously identified senescence markers during senescence- inducing therapy in human and murine pancreatic cancer models, (2) independently discover more senescence- specific markers, and (3) use targeted immunoPET agents for endoradiotherapy and improved senolytic delivery. In collaboration with Patricia Ribeiro Pereira at Washington University at St. Louis, we will also identify pharmacologic methods to prevent antigen shed, while advanced PET reconstruction with Joaquin Lopez- Herraiz at Complutense University Madrid will enable dual radiotracer immunoPET imaging of immune populations during therapy. Our efforts to quantify senescence in vivo with the proposed markers and enhance targeted alpha therapy with senescence will be guided by Dr. Lisa Bodei for clinical relevance and Andrea Schietinger for immunological insight. This work will unlock multiple directions in the precision theranostics of senescence, with great potential for career development and R01 research encompassing numerous cancers.


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	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	12/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $148,282 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	001	2	8/1/2025	NON-COMPETING CONTINUATION	$0
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	2/28/2025	NON-COMPETING CONTINUATION	$148,282
														Subtotal = $148,282

Issue Date FY: 2024 ( Subtotal = $148,282 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	4/12/2024	NEW	$148,282
														Subtotal = $148,282

Grand Total All Awards = $296,564

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Targeting Pancreatic Cancer Senescence with ImmunoPET

Award Number: K99CA276804

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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