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Regulation of prostate cancer progression by ALCAM proteolysis

Award Number: F31CA189764
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2014
PERIOD OF PERFORMANCE END DATE: 08/31/2017

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Regulation of prostate cancer progression by ALCAM proteolysis - DESCRIPTION (provided by applicant): Long-Term Goals: This proposal investigates mechanisms of tumor cell migration controlled by the cell surface adhesion molecule ALCAM (Activated Leukocyte Cell Adhesion Molecule). We found that ALCAM is required for metastasis of prostate cancer (PCa) to the bone and that increased proteolysis of its ectodomain corresponds to poor outcome for cancer patients. Our objective is to determine how the proteolysis of ALCAM contributes to PCa progression. The long-term goal is to use the molecular understanding of this process to improve the detection of disease progression and to identify suitable targets for therapeutic intervention. Specific Aims: ALCAM is cleaved by both ADAM17 and ¿-secretase, creating extracellular and intracellular fragments with potential biological activity relevant to tumor progression. The function of these fragments has yet to be explored. The aims of this proposal include: 1. Determining the functional contribution of ALCAM proteolysis to PCa progression 2. Identifying gene expression changes associated with ALCAM proteolysis. Impact: Despite significant advances in the screening and treatment of PCa, the disease continues to be the second highest cause of cancer-related death in men. Better mechanistic understanding of tumor cell dissemination will improve detection of patients with molecularly advanced disease and identify new therapeutic targets that may be suitable for patients with metastatic disease. Research Training Program: The proposal outlines the training, collaborations, and resources that will help Kate reach her research goals and prepare her for a career as an independent scientist. Kate is receiving her didactic training in the department of Cancer Biology at Vanderbilt University (VU) through courses, seminars, and retreats. Her technical training will take place in the laboratories of Andries Zijlstra, Ph.D. and Simon Hayward, Ph.D. with aid from collaborating laboratories, giving her access to experts in models of PCa, bone biology and genomics. Clinical collaborators will direct clinic experience and training in PCa histopathology.VU cores offer access to state-of-the-art resources including animal imaging and next generation sequencing. Methods for Achieving Stated Goals: The contribution of ALCAM to PCa progression will be dissected using six structural variants of ALCAM. Tumor cells expressing these variants of ALCAM will be analyzed using in vitro and in vivo models of migration, invasion, metastasis, and survival. The clinical relevance of ALCAM proteolysis will be determined by analyzing previously collected tissue and fluid samples from PCa patients. Additionally, gene expression changes in response to ALCAM proteolysis will be analyzed by performing RNAseq on tumor cells expressing the ALCAM structural variants. ALCAM-mediated gene expression changes will be evaluated for correlation to outcome and identification of novel PCa therapeutic targets. Execution of the research proposal will provide Kate with the knowledge, clinical perspective and technical, communication, and critical thinking skills needed to be an excellent scientist and a leader in the field of cancer research.


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: 2021 ( Subtotal = -$1,962 )
2021	2016	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cancer Research Manpower	000	3	1/12/2021	NON-COMPETING CONTINUATION	-$1,962
														Subtotal = -$1,962

Issue Date FY: 2016 ( Subtotal = $21,750 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	3	7/13/2016	NON-COMPETING CONTINUATION	$21,750
														Subtotal = $21,750

Issue Date FY: 2015 ( Subtotal = $27,480 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	2	8/3/2015	NON-COMPETING CONTINUATION	$27,480
														Subtotal = $27,480

Issue Date FY: 2014 ( Subtotal = $27,036 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	001	1	9/1/2014	NEW	$27,036
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	1	9/1/2014	NEW	$0
														Subtotal = $27,036

Grand Total All Awards = $74,305

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Regulation of prostate cancer progression by ALCAM proteolysis

Award Number: F31CA189764

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2014

PERIOD OF PERFORMANCE END DATE: 08/31/2017

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