Wednesday, May 8, 2024 5/8/2024

Nanotechnology for targeted therapy and fundamental understanding oftherapeutic resistance in triple negative breast cancer

Award Number: R01CA243023
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Breast cancer is the second leading cause of cancer-related deaths of American women. In particular, no targeted therapy is clinically available for nearly all triple negative breast cancer (TNBC). Cancer arises as a result of accumulating genetic alterations. Therefore, developing novel strategies to precisely target the genetic alterations of TNBC may be valuable for combating the malignant disease. TP53 is a pivotal tumor suppressor gene inactivated by mutation or deletion in most human cancers. Tremendous effort has been made to restore the activity of the p53 protein encoded by TP53 for cancer treatment. Unfortunately, no p53-based therapy has been successfully translated into the clinic, due to the complexity of p53 signaling. Therefore, identifying vulnerabilities conferred by TP53 deletion instead of restoring the p53 activity is a novel strategy for combating cancer. In our recent work published in Nature and Nature Nanotechnology, we revealed genomic deletion of TP53 is often accompanied by hemizygous (i.e., partial) loss of a neighboring gene POLR2A essential for cell survival, and virtually all 53% TNBCs with TP53 deletion harbor hemizygous POLR2A loss (TP53/POLR2Aloss). Our preliminary data show that suppressing POLR2A expression by RNA interference with small interfering RNA (siRNA) delivered using a low pH-activated nanobomb selectively inhibits the proliferation, survival, and tumorigenic potential of TP53/POLR2Aloss TNBC cells. The nanobomb protects the siRNA in blood and enables endo/lysosomal escape of the siRNA into the cytosol where the siRNA performs its POLR2A inhibition function after cell uptake. Moreover, the nanobomb-mediated delivery of POLR2A-targeting siRNA selectively inhibits the growth of orthotopic TP53/POLR2Aloss TNBC tumors, with no evident systemic toxicity demonstrated by the data on animal body weight and blood proteins (for liver function) and cytokines (for immune responses). However, a small fraction of breast cancer cells overexpressed with the variant CD44 (note: not the non- variant or normal CD44 on normal stem cells) have been shown to be particularly resistant to clinically used chemotherapy drugs of TNBC such as paclitaxel (PTX). Since POLR2A is indispensable for cancer cells to survive, we hypothesize that targeted co-delivery of the POLR2A-targeting siRNA and PTX to the variant CD44+ cancer cells can overcome the TNBC drug resistance. We will further develop the aforementioned low pH-activated nanobomb that has no active targeting, to be capable of actively targeting both the variant CD44+ cells and tumor vasculature. Since cancer metastasis is the major cause of cancer-related death, we will test the hypothesis using not only the aforementioned orthotopic/primary TNBC tumors but also metastatic TNBC model. Furthermore, we will investigate the mechanisms of resistance to the POLR2A-targeted therapy using not only 2D and xenograft but also 3D TNBC models generated using microfluidic approach developed by us. Collectively, this project may result in a novel therapy for drug-resistant TNBC with mechanistic understanding, which is invaluable for combating TNBC and possibly many other types of cancers harboring TP53 deletion.


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 = $428,759 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	5	2/27/2024	NON-COMPETING CONTINUATION	$406,193
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$22,566
														Subtotal = $428,759

Issue Date FY: 2023 ( Subtotal = $441,858 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	4	3/24/2023	NON-COMPETING CONTINUATION	$441,858
														Subtotal = $441,858

Issue Date FY: 2022 ( Subtotal = $441,579 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	001	3	5/19/2022	NON-COMPETING CONTINUATION	$36,050
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	3	3/17/2022	NON-COMPETING CONTINUATION	$405,529
														Subtotal = $441,579

Issue Date FY: 2021 ( Subtotal = $455,670 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	2	3/23/2021	NON-COMPETING CONTINUATION	$455,670
														Subtotal = $455,670

Issue Date FY: 2020 ( Subtotal = $472,539 )
2020	2020	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	1	2/10/2020	NEW	$472,539
														Subtotal = $472,539

Grand Total All Awards = $2,240,405

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Nanotechnology for targeted therapy and fundamental understanding oftherapeutic resistance in triple negative breast cancer

Award Number: R01CA243023

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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