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Biology and genetics of metastatic disease

Award Number: R35CA274446
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Biology and genetics of metastatic disease - Biology and Genetics of Metastatic Disease My laboratory studies the molecular alterations that contribute to metastasis formation, a poorly understood process and primary cause of solid cancer deaths. It has long been thought that metastasis is caused by somatic metastasis driver mutations—postulated alterations that have yet to be identified. By showing that levels of specific microRNAs become altered in metastatic tumors and identifying their target genes, my lab identified and characterized critical pathways and processes underlying metastasis formation. By studying germline variants of one such target metastasis gene, we discovered that metastatic potential can also pre- date tumor formation and be genetically inherited—revealing an unanticipated genetic underpinning for metastasis and opening up a new direction for the field. Specifically, we determined that two common human germline variants of the secreted glycoprotein ApoE promote or suppress metastasis in melanoma, with recent data suggesting this principle may apply to additional cancers. ApoE signaling was found to govern vascular and immune interactions as well as cellular invasiveness that collectively contribute to metastasis formation. These insights have significant translational potential and formed the basis of clinical trials that are providing proof-of-concept for ‘metastasis targeting therapy’, where multiple metastasis regression responses were observed in advanced stage patients for whom standard of care and immunotherapy treatments had failed. Going forward, we will use allelic variants of ApoE as powerful genetic entry points to understand the molecular events underlying metastasis formation, where we will define how ApoE signals are received by cells and how ApoE mediates intracellular events. We will also extend the concept of hereditary metastasis genetics to additional cancers and genes, applying our reverse genetic and mouse modeling approaches to breast and colorectal cancer metastasis. To achieve this understanding, we will employ innovative optical, physiological, genetic modeling and screening methods to interrogate mouse and human metastatic transitions. This award will enable our group to establish the first genetically guided framework for understanding the molecular mechanisms governing metastasis formation—enabling new avenues for its therapeutic treatment and prevention.


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 = $1,017,000 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	4	9/2/2025	NON-COMPETING CONTINUATION	$1,017,000
														Subtotal = $1,017,000

Issue Date FY: 2024 ( Subtotal = $966,151 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	3	7/31/2024	NON-COMPETING CONTINUATION	$966,151
														Subtotal = $966,151

Issue Date FY: 2023 ( Subtotal = $996,660 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	2	8/9/2023	NON-COMPETING CONTINUATION	$996,660
														Subtotal = $996,660

Issue Date FY: 2022 ( Subtotal = $709,351 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	9/7/2022	NEW	$709,351
														Subtotal = $709,351

Grand Total All Awards = $3,689,162

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Biology and genetics of metastatic disease

Award Number: R35CA274446

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/07/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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