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Novel bioengineered microRNA therapeutics for lung cancer

Award Number: R01CA225958
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Novel bioengineered microRNA therapeutics for lung cancer - Lung cancer remains a leading cause of cancer death in both women and men in the United States. There is a clear need for developing new and more effective therapeutics for the treatment of lung cancer, especially the most common subtype non-small cell lung cancer (NSCLC). As master regulators of transcriptome and proteome dynamics, microRNAs (miRNAs or miRs) govern many critical cancer cellular processes including proliferation, invasion and stemness. Therefore, restoration of tumor suppressive miRNAs (e.g., miR-34a and miR-124) lost in NSCLC cells represents a new therapeutic strategy. However, current miRNA mimics for research and development are made by chemical synthesis and decorated with various and extensive artificial modifications. This is in sharp contrast to miRNA molecules produced in living cells that do not carry any modifications or just a few necessary posttranscriptional modifications. Indeed it has been well documented that chemically-engineered/synthesized oligoribonucleotides (e.g., miRNA mimics) are readily recognized as foreign RNA molecules and thus cause immunogenicity. To break this barrier, we have made large efforts to develop novel approach for large-scale production of biologic miRNA agents (BERAs) in living cells. Our identification of hybrid tRNA/pre-miRNA molecules stably expressed in E. coli opens up a new avenue for RNA bioengineering. Furthermore, we have demonstrated that target miRNAs (e.g., miR-34a) are selectively released from BERA “prodrugs” in human cells, and consequently regulate target gene expression, inhibit NSCLC cell proliferation, and suppress xenograft tumor growth while they do not induce severe immune responses. In addition, our studies have found that liposome-polyethylenimine (LPP) nanocomplex increases BERA stability in serum and improves delivery efficiency to lung tissues. Given these exciting preliminary findings, we hypothesize that BERAs can be engineered at higher levels and on large scale; and fully-humanized BERA/miR-34a and BERA/miR-124 may be delivered by LPP as novel therapeutics for the treatment of NSCLC. To test the hypothesis, we proposed to establish more stable ncRNA carriers and produce a set of full-humanized ready-to-use BERAs (Aim 1), delineate the molecular pharmacological actions of BERAs in the control of human NSCLC cellular processes critical for therapeutic outcomes (Aim 2), and define the effectiveness and safety profiles of LPP-loaded BERA/miR-34a and miR-124 in metastatic NSCLC xenograft and patient-derived xenograft (PDX) mouse models (Aim 3). The proposed research will establish a novel technology for the production of fully-humanized biologic miRNA agents and open up new directions for the development of biologic RNA therapeutics.


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	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	000	5	3/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $394,349 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	001	6	7/26/2024	COMPETING CONTINUATION	$394,349
2024	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	000	5	7/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $394,349

Issue Date FY: 2023 ( Subtotal = $339,085 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	001	5	3/22/2023	NON-COMPETING CONTINUATION	$27,680
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	000	5	11/15/2022	NON-COMPETING CONTINUATION	$311,405
														Subtotal = $339,085

Issue Date FY: 2022 ( Subtotal = $342,824 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	000	4	11/19/2021	NON-COMPETING CONTINUATION	$314,838
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	001	4	4/28/2022	NON-COMPETING CONTINUATION	$27,986
														Subtotal = $342,824

Issue Date FY: 2021 ( Subtotal = $358,723 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	000	3	11/18/2020	NON-COMPETING CONTINUATION	$340,788
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	001	3	1/22/2021	NON-COMPETING CONTINUATION	$17,935
														Subtotal = $358,723

Issue Date FY: 2020 ( Subtotal = $360,586 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	001	2	1/13/2020	NON-COMPETING CONTINUATION	$36,059
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	000	2	11/7/2019	NON-COMPETING CONTINUATION	$324,527
														Subtotal = $360,586

Issue Date FY: 2019 ( Subtotal = $363,948 )
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Treatment Research	000	1	11/29/2018	NEW	$363,948
														Subtotal = $363,948

Grand Total All Awards = $2,159,515

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Novel bioengineered microRNA therapeutics for lung cancer

Award Number: R01CA225958

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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