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Ligand-mediated, vehicle-free delivery of small RNAs

Award Number: R01CA226259
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Ligand-mediated, vehicle-free delivery of small RNAs - PROJECT SUMMARY Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of two mRNA vaccines to prevent against SARS-CoV-2 and the first three FDA approved RNAi drugs targeted to the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this space is attributed to inability to deliver RNAi safely and effectively. We previously developed a method that can safely deliver therapeutic microRNAs (miRNAs) to tumors that overexpress the folate receptor. However, the anti-tumor response was short-lived due to instability of the miRNA and poor pharmacokinetics, necessitating frequent dosing. To overcome these insufficiencies requires a stabilized miRNA that retains targeting activity. Recently we screened a panel of fully modified versions of miR-34a (FM-miR-34a) and identified one with >400- fold increased stability and outstanding in vivo efficacy when conjugated to folate. Treatment of mice implanted with breast cancer xenografts with folate-FM-miR-34a resulted in complete cures in two out of six mice and significant tumor regression in the remaining four. Based on this exciting data, here we propose to advance FM- miR-34 forward in two ways. In Aim 1 we will evaluate the activity, efficacy, and safety profile of FM-miR-34a in in vivo models of lung and prostate cancer. FM-miR-34a will be conjugated to: i) folate for delivery to lung cancer, and ii) PSMA-617, a ligand that targets prostate specific membrane antigen (PSMA) for delivery to prostate cancer. In Aim 2 we propose to capitalize on the stability afforded by FM-miR-34 to increase the circulation ½ time of folate-FM-miR-34 and PSMA-617-FM-miR-34a though incorporating an albumin binding moiety (ABM) into the ligands. Using these ligands we will evaluate serum albumin binding and stability of the new ligands. We will also verify that conjugation to ABM does not alter the activity of miR-34a nor cell binding and internalization kinetics. Finally, we will assess in vivo distribution of ligand-ABM-miR-34a conjugates. At the completion of this work we expect to have an all-encompassing miRNA delivery vehicle that can target a stabilized tumor suppressive RNAs specifically to NSCLC and prostate cancer. We will also have new ligands with increased circulation ½ life. The data obtained will ultimately have a significant impact in cancer treatment by providing new opportunities to advance the next phase of miRNA-based therapeutics. While proposed for NSCLC and prostate cancer, based on the utility of miR-34a for treating other cancers and overexpression of the folate receptor alone on many epithelial cancers, including ovary, kidney, and colon cancers, successful completion of this study could have far-reaching positive consequences.


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 = $366,844 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	002	7	8/30/2024	NON-COMPETING CONTINUATION	$366,844
2024	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	6	8/26/2024	COMPETING CONTINUATION	$63,656
2024	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	5	8/26/2024	NON-COMPETING CONTINUATION	-$63,656
														Subtotal = $366,844

Issue Date FY: 2023 ( Subtotal = $386,276 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	6	9/8/2023	COMPETING CONTINUATION	$386,276
2023	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	5	9/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $386,276

Issue Date FY: 2022 ( Subtotal = $362,589 )
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	003	5	8/31/2022	NON-COMPETING CONTINUATION	$20,600
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	002	5	4/25/2022	NON-COMPETING CONTINUATION	$15,658
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	5	3/16/2022	NON-COMPETING CONTINUATION	$326,331
2022	2021	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	4	4/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $362,589

Issue Date FY: 2021 ( Subtotal = $406,459 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	4	3/26/2021	NON-COMPETING CONTINUATION	$406,459
														Subtotal = $406,459

Issue Date FY: 2020 ( Subtotal = $406,567 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	3	3/10/2020	NON-COMPETING CONTINUATION	$406,567
														Subtotal = $406,567

Issue Date FY: 2019 ( Subtotal = $382,571 )
2019	2019	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	001	2	9/10/2019	SUPPLEMENT FOR EXPANSION	$43,760
2019	2019	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	2	3/18/2019	NON-COMPETING CONTINUATION	$338,811
														Subtotal = $382,571

Issue Date FY: 2018 ( Subtotal = $348,866 )
2018	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	1	3/27/2018	NEW	$348,866
														Subtotal = $348,866

Grand Total All Awards = $2,660,172

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Ligand-mediated, vehicle-free delivery of small RNAs

Award Number: R01CA226259

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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