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Understanding the regulatory role and therapeutic potential of long non-coding RNAs in metastatic colorectal cancer

Award Number: K22CA241329
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Understanding the regulatory role and therapeutic potential of long non-coding RNAs in metastatic colorectal cancer - Project Summary/Abstract The overall research goal of this proposal is to elucidate the mechanisms driving mCRC to better assess the critical need for discovery of biomarkers and targeted therapies. Although early stage colorectal cancer (CRC) is curable with surgery and adjuvant therapy, metastatic CRC (mCRC) is usually lethal. Despite advances in our understanding of primary CRC oncogenesis, the mechanisms by which CRC becomes metastatic and leads to patient death is poorly characterized. In addition, the lack of reliable biomarkers to predict development of mCRC and select patients for further treatment is a critical barrier. To address this critical knowledge gap, our proposal seeks to understand how long non-coding RNAs (lncRNAs) enable primary tumors to invade and metastasize to develop improved diagnostics and therapeutics. Therefore, we performed transcriptome analysis of 37 patient matched normal, primary, and distant metastatic colorectal cancer tissues to discover 148 differentially expressed (DE) RNA Associated with Metastasis (RAMS). Notably, the top up-regulated novel candidate, RAMS11, (i) is associated with poor survival, (ii) induces invasion in vitro and in vivo, (ii) increases resistance to topoisomerase inhibitors, (iii) interacts with chromobox homology 4 (CBX4), and (iv) and can be targeted with locked nucleic acids in vitro. This serves as the rationale for our hypothesis that RAMS11 may serve as a prognostic biomarker associated with poor outcome by interacting with CBX4 to epigenetically regulate genes and can be therapeutically targeted in mCRC. To demonstrate this, Aim 1 will evaluate RAMS11 as a prognostic biomarker associated with poor long-term outcome. Aim 2 will characterize RAMS11-dependant CBX4 regulation. Lastly, Aim 3 will evaluate RAMS11 therapeutic potential. This proposal will establish the importance of RAMS11 as a master epigenetic regulator to promote colon cancer metastasis. Furthermore, this research is of translational impact by evaluating the prognostic and therapeutic potential of targeting RAMS11 directly with locked nucleic acid antisense oligonucleotides.


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 = -$956 )
2025	2022	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	3	11/5/2024	NON-COMPETING CONTINUATION	-$956
														Subtotal = -$956

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	3	10/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $189,462 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	3	9/8/2022	NON-COMPETING CONTINUATION	$189,462
														Subtotal = $189,462

Issue Date FY: 2021 ( Subtotal = $189,462 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	2	6/24/2021	NON-COMPETING CONTINUATION	$189,462
														Subtotal = $189,462

Issue Date FY: 2020 ( Subtotal = $188,496 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Research Manpower	000	1	6/8/2020	NEW	$188,496
														Subtotal = $188,496

Grand Total All Awards = $566,464

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Understanding the regulatory role and therapeutic potential of long non-coding RNAs in metastatic colorectal cancer

Award Number: K22CA241329

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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