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RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies

Award Number: R01CA226898
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/07/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies - Project Summary Ovarian carcinoma is the fifth deadliest cancer among women in the United States. In spite of advances in surgical resection and platinum-taxane combination therapy over the past several decades, cure rates remain relatively low (~30%) and a majority of women diagnosed with advanced ovarian cancer will die with drug-resistant disease within 5 years. The long-term goal of this project, “RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Anti-Cancer Therapies”, is to identify specific RNA-binding proteins that, together with their upstream protein kinase regulators, control the resistance and sensitivity of high-grade serous ovarian cancers to these clinically used first line anti-cancer therapies. The project involves: (1) a detailed computational analysis that queries pre-existing publically available RNA expression data using RNA-BP recognition motifs to identify specific RNA binding proteins whose mRNA targets are up- or down- regulated in ovarian cancer patients with chemo-sensitive versus chemo-resistant tumors; and (2) an independent CRISPR-interference and CRISPR-activation genome-wide screen for RNA-BPs whose manipulation alters the resistance and sensitivity of ovarian cancer cells to platinum and taxane agents in vitro, and in vivo using cell line xenografts and human PDX ovarian cancer mouse models. The RNA-BPs identify by these two complimentary approaches, together with a collection of RNA-BPs that we have already identified in previous experiments and preliminary data, are then directly validated for their effects on drug resistance in these model systems, and the identity of their bound RNAs and their effects on gene expression determined using CLIP technologies and RNA-Seq. In selected cases the importance of specific phosphorylation sites on RNA-BP function is examined to further elucidate the molecular basis for anti-cancer drug resistance through pathway-specific regulation of RNA-BP action. The project builds on a broad foundation of expertise and related work from all of the co-Investigators laboratories. Expected outcomes from the studies include the identification of specific RNA-BPs and upstream regulatory kinase pathways whose targeting can prevent or reverse the resistance of ovarian cancers to current clinically used front-lime therapeutics; the elucidation of new molecular circuits that control gene expression in cancers after chemotherapy treatment; and the creation of a suite of web-based tools available to the entire scientific community that can be used to query any set of differentially expressed genes for RNA-BP-based regulation, particularly in a form that is optimized for analysis of new and existing cancer patient RNA expression datasets.


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 = $0 )
2025	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	5	4/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $525,766 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	001	5	3/15/2023	NON-COMPETING CONTINUATION	$42,919
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	5	11/28/2022	NON-COMPETING CONTINUATION	$482,847
														Subtotal = $525,766

Issue Date FY: 2022 ( Subtotal = $536,497 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	4	11/10/2021	NON-COMPETING CONTINUATION	$536,497
														Subtotal = $536,497

Issue Date FY: 2021 ( Subtotal = $536,497 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	001	3	2/1/2021	NON-COMPETING CONTINUATION	$26,823
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	3	11/19/2020	NON-COMPETING CONTINUATION	$509,674
														Subtotal = $536,497

Issue Date FY: 2020 ( Subtotal = $536,497 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	001	2	1/14/2020	NON-COMPETING CONTINUATION	$53,651
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	2	11/11/2019	NON-COMPETING CONTINUATION	$482,846
														Subtotal = $536,497

Issue Date FY: 2019 ( Subtotal = $536,497 )
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	1	12/7/2018	NEW	$536,497
														Subtotal = $536,497

Grand Total All Awards = $2,671,754

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RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies

Award Number: R01CA226898

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/07/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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