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Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines using Targeted Photo-Activable Multi-Inhibitor Liposome

Award Number: R01CA260340
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines using Targeted Photo-Activable Multi-Inhibitor Liposome - ABSTRACT The prognosis for patients with advanced stage ovarian or pancreatic cancer has remained dismal for decades. The poor response rates result, in part, from resistance to salvage chemotherapies, including topoisomerase I (Top1) inhibitors such as irinotecan and topotecan. The full potential of Top1 inhibitors is hindered mainly by two mechanisms: (1) ATP-binding cassettes (ABC) transporters (i.e., P-glycoprotein and ABCG2) that actively pump drugs out of cancer cells, and (2) Upregulation of the DNA repair enzyme, tyrosyl- DNA phosphodiesterase 1, which resolves the topoisomerase I-DNA cleavable complexes to allow DNA religation and cell proliferation. It is becoming increasingly clear that no single treatment is likely to overcome this complex problem, and combination treatments of newly emerging modalities may offer the most promise. Here, we introduce a complementary, two-pronged approach to address chemoresistance: (i) Employing photodynamic priming (PDP) to damage ABC transporters, improve the delivery of Top1 inhibitors, and reduce the normal tissue toxicity, and (ii) Repurposing tetracycline antibiotics to inhibit the DNA damage repair enzyme tyrosyl-DNA phosphodiesterase 1. PDP is a clinically relevant, photochemistry-based modality that involves light activation of photosensitizers to modulate nearby tissues or biomolecules without killing the cells. This proposal leverages image-guided strategies and nanoscale engineering to develop Targeted Photo- Activable Multi-Inhibitor Liposome (TPMIL) that co-delivers PDP, Top1 inhibitors, and tetracycline antibiotics in the appropriate sequence with consideration of their mechanistic interactions. In addition to co-packaging Top1 inhibitors and antibiotics, TPMIL is surface modified with antibody-photosensitizer conjugates to target epidermal growth factor receptor, which is frequently amplified in pancreatic and ovarian cancer. Using a novel hyperspectral fluorescence microendoscope imaging system, we will longitudinally monitor photosensitizer delivery and changes in ABC transporter expression to improve PDP and chemosensitization in vivo (Aim 1). The mechanistic interactions between Top1 inhibitors and tetracycline antibiotics will be investigated in vivo, with and without PDP (Aim 2). Biomarkers predictive of chemosensitization will also be identified. TPMILs will be customized to target ovarian and pancreatic cancer cells while co-delivering photosensitizers, Top1 inhibitors, and tetracycline antibiotics (Aim 3). The safety and therapeutic efficacy of TPMIL will be determined in PDX mouse models (Aim 4). We have demonstrated the clinical feasibility of PDP in patients with locally advanced pancreatic cancer. For metastatic ovarian cancer, we envision a simple and feasible modification to the standard clinical framework. TPMILs will be delivered intraperitoneally after surgical debulking of ovarian tumors, and then light activated to trigger PDP and the release of chemotherapy and antibiotics. The knowledge gained may play a transformative role in the development of improved therapeutic regimens that are tailored to the molecular profile of advanced pancreatic and ovarian cancer in individual patients.


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 = $567,763 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	5	3/12/2025	NON-COMPETING CONTINUATION	$567,763
														Subtotal = $567,763

Issue Date FY: 2024 ( Subtotal = $606,372 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$31,914
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	4	3/1/2024	NON-COMPETING CONTINUATION	$574,458
														Subtotal = $606,372

Issue Date FY: 2023 ( Subtotal = $648,382 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	3	3/16/2023	NON-COMPETING CONTINUATION	$648,382
														Subtotal = $648,382

Issue Date FY: 2022 ( Subtotal = $659,460 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	2	3/17/2022	NON-COMPETING CONTINUATION	$593,511
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	001	2	7/15/2022	NON-COMPETING CONTINUATION	$65,949
														Subtotal = $659,460

Issue Date FY: 2021 ( Subtotal = $673,220 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cancer Treatment Research	000	1	3/16/2021	NEW	$673,220
														Subtotal = $673,220

Grand Total All Awards = $3,155,197

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Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines using Targeted Photo-Activable Multi-Inhibitor Liposome

Award Number: R01CA260340

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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