Thursday, November 21, 2024 11/21/2024

Targeted drug delivery system to overcome blood-brain barrier and therapeutic resistance to current standard of care in Glioblastoma

Award Number: R01CA269607
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract: The uniform lethality of glioblastoma (GBM) with a survival of less than 2 years despite best available therapy is attributed to treatment resistance due to DNA repair mechanisms that drive disease relapse and tumor heterogeneity. One prognostic factor identified as a reliable biomarker for GBM sensitivity to temozolomide (TMZ) and radiotherapy (RT) is the overexpression of O6-methylguanine-methyl- transferase (MGMT) enzyme. Patients with active MGMT were found to receive little benefit from TMZ and RT and represent a group of great unmet need with no treatment options that significantly improve survival. Recently, several preclinical and clinical studies suggest that alcohol aversion drug, disulfiram (DSF), inhibited MGMT and improved the efficacy of TMZ in GBM when combined with copper (Cu). However, phase II trial showed that there was no survival benefit from oral Cu/DSF. Nevertheless, the major limitation of oral Cu/DSF has been delivery of fragile DSF within the in vivo system. We have developed 2-hydroxypropyl beta cyclodextrin (HPßCD) encapsulating Cu complex of DSF metabolite, diethyldithiocarbamic acid (DDC), Cu(DDC)2 delivery system that addresses major drawbacks of the Cu(DDC)2: easy degradation in the blood and non-specific interactions with cells and serum proteins and lack of tissue specific delivery. HPßCD providing stability of Cu(DDC)2 is identified. In vitro cell culture study revealed that HPßCD-Cu(DDC)2 inhibited MGMT through the ubiquitin-proteasome pathway. Inhibition of MGMT activity in cell cultures vastly increased the alkylation-induced DNA double-strand breaks, cytotoxicity, and the levels of apoptotic markers like -H2AX, JNK-P and cleavage of PARP-1. Preliminary intravenous delivery of HPßCD- Cu(DDC)2 in combination with TMZ in an MGMT-positive patient derived orthotopic xenograft (PDOX) model demonstrated tumor size regression with prolonged survival. HPßCD-Cu(DDC)2 targets MGMT-145-cysteine and its unique cytotoxic mechanism circumvents MGMT-mediated chemo- and radiation resistance. The present work aimed at the development and application of HPßCD-Cu(DDC)2 for targeted delivery of drug to GBM. Chlorotoxin (CTX), a peptide reported to bind selectively to glioma cells while showing no affinity for non- neoplastic cells, will covalently be coupled to functionalized HPßCD encapsulating Cu(DDC)2. We have shown that PDOXs without MGMT expression are sensitive to RT. Therefore, we hypothesize that the combination of GBM targeting CTX-HPßCD-Cu(DDC)2 with TMZ and RT will overcome TMZ+RT resistance and show synergistic cytotoxic effect in PDOXs which will be monitored by MRI studies. Our objectives of the proposed research are A) To incorporate targeting ligand CTX with HPßCD-Cu(DDC)2 to obtain an active brain drug delivery system, B) To determine the efficacy and safety of oral DSF/Cu versus intravenous CTX-HPßCD- Cu(DDC)2 alone or in combination with TMZ in PDOX, and C) To determine the efficacy and safety of CTX- HPßCD-Cu(DDC)2 in combination with TMZ and fractionated radiation in MGMT upregulated PDOX models.


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 = $496,815 )
2024	2024	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	003	2	8/28/2024	NON-COMPETING CONTINUATION	-$429,106
2024	2024	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	2	3/19/2024	NON-COMPETING CONTINUATION	$452,949
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	002	3	8/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$447,809
2024	2024	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$25,163
														Subtotal = $496,815

Issue Date FY: 2023 ( Subtotal = $499,464 )
2023	2023	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	1	3/20/2023	NEW	$499,464
														Subtotal = $499,464

Grand Total All Awards = $996,279

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Targeted drug delivery system to overcome blood-brain barrier and therapeutic resistance to current standard of care in Glioblastoma

Award Number: R01CA269607

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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