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Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer

Award Number: R01CA240703
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer - SUMMARY The overall objective of the proposed project is to harness a newly discovered, active transendothelial transport pathway, the caveolae pumping system, to provide an effective solution to the delivery and toxicity problem of chemotherapeutics in metastatic breast cancer treatment. We propose to develop novel antibody- drug conjugates (ADCs) that exploit our newly discovered endothelial cell (EC) caveolae targeting system in order to improve the delivery and targeting of modern chemotherapeutics. We have established that EC caveolae in preclinical models can rapidly and specifically pump Annexin A1 (AnnA1) antibodies and attached cargo across the vascular endothelial barrier directly into solid tumors. Based on this discovery, we propose to design novel EC caveolae-targeted ADCs that may revolutionize treatments for metastatic breast cancer. We have created a robust delivery platform by arming hAnnA1 with amatoxins, a class of ultra-potent toxins that can effectively kill both rapidly dividing and dormant tumor cells. These include α-Amanitin, a toxin derived from the “death cap” mushroom and Chaetocin, an anti-proliferative, broad-spectrum toxin derived from the filamentous fungus Chaetomiun sp. Our main hypothesis is that caveolae-targeted antibody-drug conjugates (CTAs), will dramatically increase delivery of ultra-potent toxins specifically into tumors, thereby requiring much lower dosages and dramatically enhancing efficacy of cancer treatment. This hypothesis will be tested by the following specific aims: In Aim 1, we will design and characterize novel hAnnA1-toxin CTAs. We will optimize their physicochemical properties, stability, release kinetics in the tumor interstitium, and binding affinity towards the human Annexin A1 protein. In Aim 2, we will evaluate therapeutic efficacy, drug delivery and off-target effects of candidate CTAs in human tumor models of breast cancer using intravital microscopy (IVM). In Aim 3, we will examine the therapeutic efficacy of the select CTAs in metastatic tumor models and in patient-derived xenograft (PDX) models. We will also prepare a foundation for clinical testing, where successful targeted therapeutics will be selected as candidates for future Phase 1 safety trial. Tumor targeting, delivery and accumulation of these novel therapies will be assessed in rodents using x-ray/CT imaging, IVM, and histology. The long-term goal is to translate our key basic discoveries into a unique, innovative delivery platform that may vastly improve treatments for solid cancers.


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	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	5	4/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $680,774 )
2023	2023	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	5	6/29/2023	NON-COMPETING CONTINUATION	$680,774
														Subtotal = $680,774

Issue Date FY: 2022 ( Subtotal = $694,745 )
2022	2022	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	4	6/27/2022	NON-COMPETING CONTINUATION	$694,745
														Subtotal = $694,745

Issue Date FY: 2021 ( Subtotal = $722,712 )
2021	2021	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	3	6/28/2021	NON-COMPETING CONTINUATION	$722,712
														Subtotal = $722,712

Issue Date FY: 2020 ( Subtotal = $735,974 )
2020	2020	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	2	6/18/2020	NON-COMPETING CONTINUATION	$735,974
														Subtotal = $735,974

Issue Date FY: 2019 ( Subtotal = $749,235 )
2019	2019	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	1	6/13/2019	NEW	$749,235
														Subtotal = $749,235

Grand Total All Awards = $3,583,440

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Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer

Award Number: R01CA240703

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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