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Novel therapeutic approach in treatment of glioblastoma using sustained delivery of Connxin43 carboxy-terminal peptide encapsulated in biodegradable nanoparticles in combination with temozolomide

Award Number: R44CA195937
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Novel therapeutic approach in treatment of glioblastoma using sustained delivery of Connxin43 carboxy-terminal peptide encapsulated in biodegradable nanoparticles in combination with temozolomide - PROJECT SUMMARY Glioblastoma (GBM) is an incurable cancer even with aggressive therapies such as surgical resection followed by radiotherapy and chemotherapy using temozolomide (TMZ). Efforts to improve surgical resection or the efficacy of irradiation are limited by the potential damage these interventions cause to the brain. In contrast, sensitizing GBM to TMZ is an appealing strategy because TMZ has excellent brain penetration and a low toxicity profile. Recent research suggests that targeting the gap junction protein connexin 43 (Cx43) holds promise for enhancing TMZ sensitivity in GBM. A synthetic peptide, aCT1, which comprises the carboxy- terminus of Cx43, and has demonstrated therapeutic efficacy in promoting healing of acute and chronic wounds, has been developed in order to explore the potential of targeting Cx43 and overcoming TMZ resistance in GBM. FirstString Research has currently advanced Granexin® gel, the topical formulation of aCT1 peptide, through three Phase 2 human clinical trials for scar reduction and the treatment of chronic wounds. Preliminary data demonstrated that Cx43 expression inversely correlates with TMZ sensitivity and GBM patient survival, and demonstrated that aCT1 significantly increases TMZ sensitivity in vitro and in vivo, thus encouraging further investigation into its therapeutic potential in sensitizing GBM tumors to TMZ. During the Phase I SBIR, to facilitate efficient and targeted drug delivery, a controlled and sustained biodegradable aCT1 nanoparticle system of therapeutic delivery was developed and validated in vitro and in vivo models of GBM. Biodegradable aCT1-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed, optimized and validated, specifically with characteristics necessary for targeted convection-enhanced delivery (CED) in GBM patients (FDA approved copolymer; <150nm +\- 40 in diameter, controlled and sustained aCT1 release profile). The objective of this Phase II SBIR proposal is to translate the success of our Phase I data through more extensive pre-clinical development. Aim I will involve intracranial injection of aCT1-NPs into the brains of GBM mice followed by TMZ treatment and mechanism of action studies. We will monitor tumor growth using MRI and analyze mouse survival. Aim II will validate the efficacy and safety of combinatorial aCT1-NP and TMZ treatment in a veterinary clinical trial in high-grade spontaneous canine gliomas. Canine gliomas have many of the characteristics of human tumors, thus permitting precise extrapolation of efficacy and safety data from canine therapy studies to human trials. We will enroll companion dogs with spontaneous tumors into a specific protocol involving CED of aCT1-NPs in association with TMZ. Efficacy evaluation will involve comprehensive neuroimaging response assessment, neurobiobehavioral evaluation, and survival. Safety analyses will involve adverse event reporting and toxicokinetic analyses. Successful completion of these aims will validate CED delivery of aCT1-NP as a novel combinational therapy for lethal GBM and will lay foundation for potential clinical trials in newly diagnosed GBM patients in the near future.


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: 2022 ( Subtotal = -$48,241 )
2022	2020	XEQUEL BIO, INC.	1501 BELLE ISLE AVE STE 220	MOUNT PLEASANT	SC	29464	CHARLESTON	USA	Cancer Treatment Research	000	3	2/4/2022	SUPPLEMENT FOR EXPANSION	-$48,241
														Subtotal = -$48,241

Issue Date FY: 2020 ( Subtotal = $100,000 )
2020	2020	FIRSTSTRING RESEARCH, INC	300 WEST COLEMAN BOULEVARD SUITE 203	MOUNT PLEASANT	SC	29464	CHARLESTON	USA	Cancer Treatment Research	002	3	9/14/2020	SUPPLEMENT FOR EXPANSION	$100,000
2020	2019	FIRSTSTRING RESEARCH, INC	300 WEST COLEMAN BOULEVARD SUITE 203	MOUNT PLEASANT	SC	29464	CHARLESTON	USA	Cancer Treatment Research	000	3	12/20/2019	NON-COMPETING CONTINUATION	$0
2020	2018	FIRSTSTRING RESEARCH, INC	300 WEST COLEMAN BOULEVARD SUITE 203	MOUNT PLEASANT	SC	29464	CHARLESTON	USA	Cancer Treatment Research	001	2	12/23/2019	COMPETING CONTINUATION	$0
														Subtotal = $100,000

Issue Date FY: 2019 ( Subtotal = $655,532 )
2019	2019	FIRSTSTRING RESEARCH, INC	300 WEST COLEMAN BOULEVARD SUITE 203	MOUNT PLEASANT	SC	29464	CHARLESTON	USA	Cancer Treatment Research	000	3	8/28/2019	NON-COMPETING CONTINUATION	$655,532
														Subtotal = $655,532

Issue Date FY: 2018 ( Subtotal = $841,361 )
2018	2018	FIRSTSTRING RESEARCH, INC	300 WEST COLEMAN BOULEVARD SUITE 203	MOUNT PLEASANT	SC	29464	CHARLESTON	USA	Cancer Treatment Research	001	2	9/7/2018	COMPETING CONTINUATION	$0
2018	2018	FIRSTSTRING RESEARCH, INC	300 WEST COLEMAN BOULEVARD SUITE 203	MOUNT PLEASANT	SC	29464	CHARLESTON	USA	Cancer Treatment Research	000	2	9/6/2018	COMPETING CONTINUATION	$841,361
														Subtotal = $841,361

Grand Total All Awards = $1,548,652

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Novel therapeutic approach in treatment of glioblastoma using sustained delivery of Connxin43 carboxy-terminal peptide encapsulated in biodegradable nanoparticles in combination with temozolomide

Award Number: R44CA195937

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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