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Deciphering the Code for Senescence Escape During Cancer Progression in Humans

Award Number: R01CA136533
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/09/2010
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Deciphering the Code for Senescence Escape During Cancer Progression in Humans - Most cancers arise by an evolutionary process as genetic and epigenetic changes accumulate in somatic cells allowing them to escape the proliferative restrains that control cell growth. In recent years it has become evident that one critical barrier to cancer progression is a proliferative arrest termed cellular senescence. Our studies have demonstrated that the reasons for the inactive nature of certain human cancer precursor lesions, such as melanocytic nevi, ductal hyperplasias of the breast, and colonic adenomas is because cells within these lesions had undergone telomere dysfunction-induced senescence (TDIS). Yet, given that cells within these lesions occasionally continue to proliferate and thereby allow these neoplasms to progress to more advanced cancer stages, it is likely that cells can escape TDIS following a long period of inactivity. Indeed, our preliminary data demonstrate that, depending on the signaling pathways activated in senescent cells, TDIS is not always stable and cells can escape this proliferative arrest following a prolonged period in senescence. Surprisingly, senescent cells acquire a gene expression signature that in part resembles that of stem cells, suggesting that senescent cells undergo epigenetic changes that provide cells with stem cell-like characteristics. In order to better understand the molecular changes that promote escape from senescence and to predict which lesions remain inactive virtually indefinitely and which have the potential to progress to more advanced cancer stages, we propose to identify the stages during breast, colon, and (melanocytic) skin cancer development in which the telomere-initiated senescence responses are inactivated. We will use this knowledge to improve diagnostic and prognostic tools that evaluate cancer stage and potential for cancer progression, develop novel biomarkers for cancer stage, and facilitate decision making for patient treatment. Additionally, we will compare transcriptomes, epigenomes, and exomes from normal, senescent, and senescence-escaped cells, both from cell cultures and isolated from human tissue, in order to characterize the earliest changes that result in inactivation of the tumor suppressing functions of TDIS. A thorough understanding of the changes that promote senescence escape will allow us to facilitate development of novel anti cancer strategies and/or improving existing ones. Finally, we will use cell culture and mouse model systems to characterize escape from telomere-initiated cellular senescence in greater detail and in a physiologically relevant setting. These model systems will allow us to not only differentiate changes that are causative from those that are a consequence of senescence escape, but they will also provide a platform for testing drugs and therapies that target malignant cancer growth at its earliest stages.


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 = $0 )
2024	2021	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	000	11	5/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	000	11	2/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $376,527 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	000	11	1/15/2021	NON-COMPETING CONTINUATION	$376,527
														Subtotal = $376,527

Issue Date FY: 2020 ( Subtotal = $399,385 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	000	10	1/9/2020	NON-COMPETING CONTINUATION	$399,385
														Subtotal = $399,385

Issue Date FY: 2019 ( Subtotal = $463,817 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	000	9	12/20/2018	NON-COMPETING CONTINUATION	$463,817
														Subtotal = $463,817

Issue Date FY: 2018 ( Subtotal = $440,674 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	000	8	1/8/2018	NON-COMPETING CONTINUATION	$396,608
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	001	8	5/22/2018	NON-COMPETING CONTINUATION	$44,066
														Subtotal = $440,674

Issue Date FY: 2017 ( Subtotal = $472,455 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	001	7	1/27/2017	COMPETING CONTINUATION	$472,455
2017	2014	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cancer Detection and Diagnosis Research	000	6	11/4/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $472,455

Issue Date FY: 2014 ( Subtotal = $310,426 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	002	6	5/7/2014	NON-COMPETING CONTINUATION	$310,426
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	001	5	1/10/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$41,707
2014	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	000	4	1/10/2014	NON-COMPETING CONTINUATION	$41,707
														Subtotal = $310,426

Issue Date FY: 2013 ( Subtotal = $300,826 )
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	000	4	6/7/2013	NON-COMPETING CONTINUATION	$295,150
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cancer Detection and Diagnosis Research	001	5	8/13/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$300,826
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	002	4	8/13/2013	NON-COMPETING CONTINUATION	-$295,150
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Cancer Detection and Diagnosis Research	004	5	1/10/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$41,707
2013	2013	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	003	4	1/10/2014	NON-COMPETING CONTINUATION	$41,707
														Subtotal = $300,826

Issue Date FY: 2012 ( Subtotal = $313,989 )
2012	2012	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	000	3	5/17/2012	NON-COMPETING CONTINUATION	$313,989
														Subtotal = $313,989

Issue Date FY: 2011 ( Subtotal = $313,989 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	000	2	5/24/2011	NON-COMPETING CONTINUATION	$313,989
														Subtotal = $313,989

Issue Date FY: 2010 ( Subtotal = $323,700 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	POST OFFICE BOX 2100	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Detection and Diagnosis Research	000	1	8/9/2010	NEW	$323,700
														Subtotal = $323,700

Grand Total All Awards = $3,715,788

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Deciphering the Code for Senescence Escape During Cancer Progression in Humans

Award Number: R01CA136533

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/09/2010

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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