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Mechanistic and therapeutic investigation of secondary metastatic seeding from breast cancer bone lesion

Award Number: R01CA251950
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Mechanistic and therapeutic investigation of secondary metastatic seeding from breast cancer bone lesion - Metastasis to distant organs is the major cause of breast cancer-related death. Bone is the most frequent destination of metastasis. Over 45% first-site metastases occur to bone, as compared to 19% to lung, 5% to liver and 2% to brain. Patients with skeleton as the first site of metastasis usually have better prognosis than those with visceral organs as first site. However, in more than two third of cases, bone metastases will not be confined to the skeleton, but rather subsequently occur to other organs and eventually kill patients. This raises the possibility of secondary metastatic dissemination from the initial bone lesions to other sites. In fact, some metastases first found in non-bone organs may be seeded from subclinical bone micrometastases as well, as suggested by the finding that cancer cells arrived in the bone can acquire more aggressive phenotypes even before establishing overt metastases. Recent genomic analyses indeed concluded that the majority of metastases result from seeding from other metastases, rather than primary tumors. Thus, it is of imperative importance to investigate further metastatic seeding from bone lesions, as it might lead to prevention of the terminal stage, multi-organ metastases that ultimately cause the vast majority of deaths. Despite the potential relevance, we know very little about metastasis-to-metastasis seeding. Current pre-clinical models focus on seeding from primary tumors, but cannot distinguish further dissemination. Taking advantage of a recently developed approach that selectively deliver cancer cells to hind limb bones, we have uncovered frequent metastatic seeding from established bone lesions to multiple other organs. This seeding is hypothetically enabled by the bone microenvironment-induced effects that confer more stem-like properties through a combination of clonal selection and epigenomic adaptation. In this application, we will elucidate the underlying mechanisms and temporal course of this process in order to provide the first ever insights into time window and strategies of potential therapeutic interventions. We hypothesize that clonal selection and epigenetic adaptation driven by the bone microenvironment engender the ability of disseminated breast cancer cells to further metastasize and blockade of the microenvironment-induced alterations may confine bone metastases and prevent further dissemination to other fetal organs. Our specific aims are 1) to characterize the kinetics of metastatic seeding from bone lesions and determine potential therapeutic windows accordingly, and 2) to identify key druggable targets and design therapeutic strategies against secondary metastatic seeding from bone lesions. This project is innovative and impactful because it is the first in the field that focuses on secondary metastasis and the profound reprogramming effects of bone microenvironment on metastatic seeding. The outcome will likely generate significant impact on our understanding of metastatic evolution and provide insights into novel therapies confining metastases for ultimate cure.


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 = -$71,651 )
2026	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	12/3/2025	NON-COMPETING CONTINUATION	-$71,651
														Subtotal = -$71,651

Issue Date FY: 2024 ( Subtotal = $599,434 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	5	9/12/2024	SUPPLEMENT FOR EXPANSION	$71,650
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	5	9/13/2024	SUPPLEMENT FOR EXPANSION	$66,138
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	7/3/2024	NON-COMPETING CONTINUATION	$461,646
														Subtotal = $599,434

Issue Date FY: 2023 ( Subtotal = $551,645 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	6/8/2023	NON-COMPETING CONTINUATION	$476,224
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	7/26/2023	SUPPLEMENT FOR EXPANSION	$75,421
														Subtotal = $551,645

Issue Date FY: 2022 ( Subtotal = $476,224 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	6/21/2022	NON-COMPETING CONTINUATION	$476,224
														Subtotal = $476,224

Issue Date FY: 2021 ( Subtotal = $485,943 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	6/7/2021	NON-COMPETING CONTINUATION	$485,943
														Subtotal = $485,943

Issue Date FY: 2020 ( Subtotal = $500,945 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	6/29/2020	NEW	$500,945
														Subtotal = $500,945

Grand Total All Awards = $2,542,540

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Mechanistic and therapeutic investigation of secondary metastatic seeding from breast cancer bone lesion

Award Number: R01CA251950

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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