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Multiscale Modeling of Bone Environment Responses to Metastatic Prostate Cancer

Award Number: U01CA202958
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Multiscale Modeling of Bone Environment Responses to Metastatic Prostate Cancer - DESCRIPTION (provided by applicant): Bone metastatic prostate cancer is fatal and causes extensive pathological bone growth and destruction by manipulating osteoblasts and osteoclasts respectively. Understanding the factors driving the disease can help identify new therapeutic targets. Experimental approaches have dissected many of the molecular mechanisms involved but how factors at different scales collectively impact complex multi-cellular interactions over time is a significant challenge. Integrating molecular, cellular and clinical information into computational models offers a novel and powerful way to overcome this road-block: cell processes and mechanisms from different scales can be broken down into discrete and continuous components and used to parameterize a multi-scale model. This model can then be used to examine the temporal dynamics emerging from the multi scale cellular interactions. Rationale: Using our own and published data, we generated a novel computational model of normal bone remodeling controlled by TGFβ and RANKL. Seeding the model with a metastatic prostate cancer cell generated in silico lesions that qualitatively and quantitatively mimic the pathophysiology of the human disease. As expected, our preliminary model confirmed the role of TGFβ but predicted novel roles for cyclical osteoclast infiltration and mesenchymal stem cells in prostate cancer growth. Based on these emerging data, we believe that the enhancement of the computational model with cellular and molecular factors that control prostate cancer-bone interaction (PTHrP, Wnts, interleukins, chemokines and polarizing macrophages) will allow us to predict the key circuits driving the behavior of bone metastatic prostate cancer and to define new therapeutic strategies to treat this disease. We will test this hypothesis using the following integrated approaches: Approaches: In Aim 1, an enhanced molecular and cellular multiscale computational model will be developed and the key circuits driving bone metastatic cancer growth will be predicted. In Aim 2, we will predict the role of cyclical osteoclast infiltration and macrophage polarization (M1/M2) in promoting prostate cancer growth. Aim 3 will dissect the role of MSC recruitment in prostate cancer induced osteogenesis in silico. Importantly, the predictions generated in each aim will be tested with relevant in vivo rodent models of bone metastatic prostate cancer and validated in human clinical specimens. Quantitative biological values will be used to recalibrate the computational model in the event that outputs are discordant. Innovation/Impact: Our innovative studies will; 1) generate a robust and dynamic multi-scale computational model of the prostate cancer-bone microenvironment, 2) will define novel roles for monocyte derived cells (osteoclasts/M1/M2 macrophages) in driving prostate cancer growth, 3) will define new roles for MSCs in promoting prostate cancer induced osteogenesis, 4) will predict the key circuits driving bone metastatic prostate cancers and 5) will predict and test curative strategies for eradicating bone metastatic prostate cancer.


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: 2023 ( Subtotal = -$22,044 )
2023	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	11/16/2022	NON-COMPETING CONTINUATION	-$22,044
														Subtotal = -$22,044

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	4/13/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $637,735 )
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	5/20/2020	NON-COMPETING CONTINUATION	$637,742
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	001	5	5/21/2020	NON-COMPETING CONTINUATION	-$7
														Subtotal = $637,735

Issue Date FY: 2019 ( Subtotal = $581,609 )
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	4	5/31/2019	NON-COMPETING CONTINUATION	$581,609
														Subtotal = $581,609

Issue Date FY: 2018 ( Subtotal = $668,427 )
2018	2018	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	3	5/25/2018	NON-COMPETING CONTINUATION	$668,427
														Subtotal = $668,427

Issue Date FY: 2017 ( Subtotal = $690,824 )
2017	2017	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	2	5/31/2017	NON-COMPETING CONTINUATION	$690,824
														Subtotal = $690,824

Issue Date FY: 2016 ( Subtotal = $686,385 )
2016	2016	H LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE	12902 MAGNOLIA DRIVE	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	6/8/2016	NEW	$686,385
														Subtotal = $686,385

Grand Total All Awards = $3,242,936

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Multiscale Modeling of Bone Environment Responses to Metastatic Prostate Cancer

Award Number: U01CA202958

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 06/08/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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