Thursday, December 26, 2024 12/26/2024

Defining the Role of the Cancer Circadian Clock in Tumor Immunity and Tumorigenesis

Award Number: R01CA051497
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Circadian rhythms are biological processes a period of 24 hours driven by the circadian CLOCK-BMAL1 transcription factor that regulates diurnal variations of cellular metabolism and inflammation signaling. Disruption of the circadian clock has been linked to cancer, but mechanisms of how the clock affects cancer progression are not well understood. We previously shown that oncogenic MYC could disrupt the circadian clock in cancer cells and in vivo in Drosophila and note that analysis of TCGA data indicates widespread mutations in the circadian clock circuitry genes. To address the role of the clock heterogeneity in tumor biology, we chose to study melanomas, which respond to immunotherapy and targeted therapy with varying degrees of therapeutic resistance. In preliminary studies of a panel of 14 patient-derived melanoma cell lines, we found heterogeneity in clock function and increased interferon response genes when the clock is molecularly disrupted in engineered cells. Further we found in a mouse model of melanoma that clock disruption was associated with accelerated tumorigenesis in immunocompetent but not immunocompromised mice. Increased or decreased BMAL1, the central clock component, induced dedifferentiation, rendering mouse melanoma cells immune privileged with altered chemokine expression and resistance to immunotherapy in vivo. Based on our preliminary studies, we hypothesize that functional clock heterogeneity alters cancer cell immunity and contribute variable therapeutic responses. We propose to alter clock function through loss and gain of BMAL1 function in engineered human and mouse melanoma cell lines and determine the molecular mechanisms underlying resistance of melanoma to anti-PD1 treatment. We will use a humanize mouse (Hu-mice) system to study the clock-engineered human melanoma cells in vivo. These findings are expected to contribute novel concepts of therapeutic resistance, biomarkers based on clock biology, and eventual better therapeutic strategies.


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: 2025 ( Subtotal = $298,434 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	000	33	11/20/2024	NON-COMPETING CONTINUATION	$298,434
														Subtotal = $298,434

Issue Date FY: 2024 ( Subtotal = $315,014 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	003	32	4/17/2024	NON-COMPETING CONTINUATION	$16,580
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	002	32	11/29/2023	NON-COMPETING CONTINUATION	$298,434
2024	2023	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	001	31	11/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$213,236
2024	2022	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	30	11/14/2023	NON-COMPETING CONTINUATION	-$213,236
														Subtotal = $315,014

Issue Date FY: 2023 ( Subtotal = $331,594 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	002	31	3/23/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,632
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	001	31	2/16/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$324,962
2023	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	30	2/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $331,594

Issue Date FY: 2022 ( Subtotal = $363,222 )
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	30	11/30/2021	NON-COMPETING CONTINUATION	$333,572
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	30	5/19/2022	NON-COMPETING CONTINUATION	$29,650
														Subtotal = $363,222

Issue Date FY: 2021 ( Subtotal = $370,636 )
2021	2021	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	29	12/10/2020	COMPETING CONTINUATION	$370,636
2021	2018	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	28	11/12/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,636

Issue Date FY: 2018 ( Subtotal = $382,892 )
2018	2018	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	003	28	4/24/2018	NON-COMPETING CONTINUATION	$382,892
2018	2017	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	27	11/14/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,449
2018	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	26	11/14/2017	NON-COMPETING CONTINUATION	-$27,000
2018	2016	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	25	11/14/2017	NON-COMPETING CONTINUATION	-$8,449
														Subtotal = $382,892

Issue Date FY: 2017 ( Subtotal = $377,375 )
2017	2017	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	27	8/25/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$350,375
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	26	8/24/2017	NON-COMPETING CONTINUATION	-$297,000
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	26	5/23/2017	NON-COMPETING CONTINUATION	$324,000
														Subtotal = $377,375

Issue Date FY: 2016 ( Subtotal = $733,273 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	25	4/29/2016	NON-COMPETING CONTINUATION	$324,000
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	25	9/6/2016	NON-COMPETING CONTINUATION	$409,273
														Subtotal = $733,273

Issue Date FY: 2015 ( Subtotal = $394,000 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	24	6/4/2015	NON-COMPETING CONTINUATION	$394,000
														Subtotal = $394,000

Issue Date FY: 2014 ( Subtotal = $456,800 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	23	5/14/2014	COMPETING CONTINUATION	$289,837
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	23	9/8/2014	COMPETING CONTINUATION	$132,800
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Cause and Prevention Research	001	23	6/19/2014	COMPETING CONTINUATION	$34,163
														Subtotal = $456,800

Issue Date FY: 2012 ( Subtotal = -$6,716 )
2012	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	22	4/19/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$268,659
2012	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	000	21	4/19/2012	NON-COMPETING CONTINUATION	-$275,375
														Subtotal = -$6,716

Issue Date FY: 2011 ( Subtotal = $297,082 )
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	000	21	7/20/2011	NON-COMPETING CONTINUATION	$297,082
														Subtotal = $297,082

Issue Date FY: 2010 ( Subtotal = $306,270 )
2010	2010	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	000	20	7/6/2010	NON-COMPETING CONTINUATION	$306,270
														Subtotal = $306,270

Issue Date FY: 2009 ( Subtotal = $306,270 )
2009	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	001	19	7/20/2009	NON-COMPETING CONTINUATION	$306,270
2009	2008	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	000	18	11/10/2008	COMPETING CONTINUATION	$0
														Subtotal = $306,270

Issue Date FY: 2008 ( Subtotal = $306,270 )
2008	2008	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	000	18	9/15/2008	COMPETING CONTINUATION	$306,270
														Subtotal = $306,270

Issue Date FY: 1998 ( Subtotal = $225,856 )
1998	1998	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Biology Research	000	9	1/22/1998	NON-COMPETING CONTINUATION	$225,856
														Subtotal = $225,856

Grand Total All Awards = $5,458,272

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Defining the Role of the Cancer Circadian Clock in Tumor Immunity and Tumorigenesis

Award Number: R01CA051497

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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