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Functional Proteomic Analysis and Biomarker Identification in a Novel Mouse Model of Metastatic Hepatocellular Carcinoma (HCC)

Award Number: K08CA222676
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/09/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Functional Proteomic Analysis and Biomarker Identification in a Novel Mouse Model of Metastatic Hepatocellular Carcinoma (HCC) - Research Proposal Summary Hepatocellular carcinoma (HCC) is a highly lethal malignancy, and is a worldwide public health problem. The main cancer-related cause of death in patients with HCC is metastatic tumor progression. But the precise molecular mechanisms of HCC metastasis are not well understood. Also, there are no accurate prognostic plasma biomarkers which can help in early detection of aggressive HCC and thereby predict clinical outcome or guide treatment selection. We have developed an autochthonous mouse model of metastatic HCC where conditional overexpression of MYC and Twist1 genes in the mouse liver leads to step-wise progression of liver cancer simulating human HCC. This study proposes to use this novel mouse model of metastatic HCC to explore the mechanisms of tumor progression and identify proteomic biomarkers for HCC. Our central HYPOTHESIS is that Twist1 modulates innate immune system specific proteomic and glycoproteomic changes which promote metastatic progression. In Aim 1 we will perform proteomic and glycoproteomic analyses of MYC HCC and MYC/Twist1 HCC using mass spectrometry. We will then undertake a systems biology approach to large scale proteomics data and perform gene knockout experiments to gain mechanistic insights into how Twist1 promotes metastasis. In Aim 2 we will identify and validate plasma proteomic and glycoproteomic biomarkers of metastatic progression in the MYC/Twist1 mice that are relevant to human HCC. Successful completion of this study has significant translational potential by identifying prognostic biomarkers which will improve treatment allocation. Candidate Career Development Plan The objective of this K08 Mentored Award application is to enable Dr. Renumathy Dhanasekaran to undertake supervised research and career development training to become an independent physician scientist. She is a board certified Hepatologist who joined the Department of Medicine at Stanford in 2015 and is pursuing advanced translational research training under the mentorship of Dr. Dean Felsher. Her long term career goal is to build an independent translational research program to identify biomarkers for HCC. This K08 will provide her with the protected time and support needed to undertake the following training: (1) receive hands-on training in advanced techniques in cancer biology (2) acquire skills in computational biology to perform integrated analyses of genomic data; (3) acquire critical talents required for success in academic medicine like grantsmanship, and communication skills and (4) gather preliminary data required to apply for a NIH R01 grant during year 4-5 of the K08 award. The candidate has an excellent mentor with vast expertise in cancer biology and is working in a well- funded lab. The Chief of the Division of Gastroenterology, will also serve as her co-mentor and he is personally committed to her academic success. She has assembled a team of seasoned mentors with expertise in cancer biology, advanced proteomics, biomedical informatics and clinical hepatology, who will serve on her mentorship advisory committee. Stanford is a world-class institution with particular strength in cancer biology, computational bioinformatics and translational medicine, and hence is the ideal environment to advance her academic career.


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: 2024 ( Subtotal = -$4 )
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	5	1/12/2024	NON-COMPETING CONTINUATION	-$4
														Subtotal = -$4

Issue Date FY: 2022 ( Subtotal = $202,144 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	5	6/22/2022	NON-COMPETING CONTINUATION	$202,144
														Subtotal = $202,144

Issue Date FY: 2021 ( Subtotal = $202,144 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	4	6/11/2021	NON-COMPETING CONTINUATION	$202,144
														Subtotal = $202,144

Issue Date FY: 2020 ( Subtotal = $202,144 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	3	6/16/2020	NON-COMPETING CONTINUATION	$202,144
														Subtotal = $202,144

Issue Date FY: 2019 ( Subtotal = $202,144 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	2	5/29/2019	NON-COMPETING CONTINUATION	$202,144
														Subtotal = $202,144

Issue Date FY: 2018 ( Subtotal = $202,144 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	7/9/2018	NEW	$202,144
														Subtotal = $202,144

Grand Total All Awards = $1,010,716

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Functional Proteomic Analysis and Biomarker Identification in a Novel Mouse Model of Metastatic Hepatocellular Carcinoma (HCC)

Award Number: K08CA222676

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/09/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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