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Harnessing the power of exosomes for non-coding RNA delivery

Award Number: R35CA209904
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Harnessing the power of exosomes for non-coding RNA delivery - Project Abstract: Despite the promise of RNA interference (RNAi) approach for targeting undruggable targets, major challenges remain including specific delivery of siRNA into cell types of interest in vivo, poor stability and off-target effects. We have been at the forefront of addressing these issues and my laboratory has pioneered many studies using RNAi approaches for cancer treatment and has made key discoveries related to RNAi biology. We were among the first to demonstrate that RNAi processing machinery is deregulated in a high proportion of ovarian and other cancers (Merritt et al., New Engl J Med 2008). To achieve systemic delivery of RNAi therapeutics, we systematically identified safe and effective methods for siRNA delivery. After extensive testing, our first successful platform utilized the neutral DOPC nanoliposomal delivery system (Landen et al., Cancer Res 2005; Ahmed et al., Cancer Cell 2010), which has subsequently been tested in multiple tumor model systems (Liu et al., Nature 2015; Kim et al., Cell 2013). With a robust portfolio of preclinical studies and all of the requisite safety studies based on FDA guidance, a first-in-human phase I clinical trial with EPHARNA (EphA2 targeted siRNA in DOPC) is nearing completion for patients with solid tumors. We have made great strides in applying this technology for cancer therapy. However, despite the promise of synthetic delivery systems that we and others have developed, novel and biocompatible delivery strategies that are independent of reliance on vascular leakiness are highly desirable. In this project, we propose to develop a biomimetic exosomal system that will enable active delivery of cancer therapeutics to the tumor microenvironment. These naturally occurring particles represent a promising, and safe alternative approach for delivering RNAi therapeutics. We will package RNAi cargos into these particles and engineer their surface membrane to actively target distinct cell types. Finally, we will develop this approach for enhancing anti-tumor immune response in ovarian and other cancers. If successful, this biomimetic exosomal system can be rapidly applied more broadly to other “undruggable” targets. Support through the R35 mechanism will greatly facilitate this undertaking, which would not otherwise be possible.


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 = $0 )
2024	2023	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	7	9/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $436,053 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	7	8/1/2023	NON-COMPETING CONTINUATION	$436,053
														Subtotal = $436,053

Issue Date FY: 2022 ( Subtotal = $895,013 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	6	7/22/2022	NON-COMPETING CONTINUATION	$895,013
2022	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	2/10/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $895,013

Issue Date FY: 2021 ( Subtotal = $680,538 )
2021	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	8/2/2021	NON-COMPETING CONTINUATION	$680,538
														Subtotal = $680,538

Issue Date FY: 2020 ( Subtotal = $775,509 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	7/10/2020	NON-COMPETING CONTINUATION	$775,509
														Subtotal = $775,509

Issue Date FY: 2019 ( Subtotal = $633,104 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	7/16/2019	NON-COMPETING CONTINUATION	$633,104
														Subtotal = $633,104

Issue Date FY: 2018 ( Subtotal = $905,873 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	8/1/2018	NON-COMPETING CONTINUATION	$905,873
														Subtotal = $905,873

Issue Date FY: 2017 ( Subtotal = $704,789 )
2017	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	8/2/2017	NEW	$704,789
														Subtotal = $704,789

Grand Total All Awards = $5,030,879

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Harnessing the power of exosomes for non-coding RNA delivery

Award Number: R35CA209904

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/02/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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