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Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates

Award Number: R01CA251730
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates - Project Summary/Abstract Mutant forms of KRAS are a key driver in human tumors but remains refractory to therapeutic intervention despite over three decades of research. Clinical attempts to directly or indirectly inhibit KRAS function have both yielded unsatisfactory results. The difficulty for developing small molecule KRAS inhibitors has heightened the importance of alternative methods targeting the oncogene. One such strategy involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed pacDNA, that substantially enhances the antitumor activity of nucleic acid drugs by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and tumor accumulation, allowing a much lower dosage to be used compared to conventional methods. The pacDNA also suppresses nearly all side effects associated with traditional nucleic acid drugs by reducing unwanted nucleic acid-protein interactions. In this proposal, we aim to build upon our promising preliminary results, and gain deeper insights into the cell biology of the pacDNA with respect to cell uptake mechanism, intracellular trafficking, KRAS depletion and subsequent cell signaling, and demonstrate efficacy in KRAS-dependent non-small cell lung cancer cell lines and 3D models. In addition, we will study the primary pharmacology and antitumor activity of pacDNA in advanced preclinical lung cancer models including an orthotopic tumor model, a patient derived tumor model, and a syngeneic genetically engineered mouse model (GEMM), and perform initial in vivo safety and tolerability studies. The outcome of this project will be a safe and potent anti-KRAS agent that can be readily translated into clinical studies for non-small cell lung cancer and potentially additional cancer classes.


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 = $355,927 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	5	6/6/2024	NON-COMPETING CONTINUATION	$355,927
														Subtotal = $355,927

Issue Date FY: 2023 ( Subtotal = $367,167 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	4	6/30/2023	NON-COMPETING CONTINUATION	$367,167
														Subtotal = $367,167

Issue Date FY: 2022 ( Subtotal = $367,167 )
2022	2022	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	3	6/24/2022	NON-COMPETING CONTINUATION	$367,167
														Subtotal = $367,167

Issue Date FY: 2021 ( Subtotal = $374,660 )
2021	2021	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	2	6/15/2021	NON-COMPETING CONTINUATION	$374,660
														Subtotal = $374,660

Issue Date FY: 2020 ( Subtotal = $388,910 )
2020	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	1	7/6/2020	NEW	$388,910
														Subtotal = $388,910

Grand Total All Awards = $1,853,831

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Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates

Award Number: R01CA251730

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/06/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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