?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 has suggested that targeting the gap junction protein connexin 43 (Cx43) holds promise for enhancing TMZ sensitivity in GBM. Dr. Gourdie's (co-Investigator) laboratory has developed a synthetic peptide, ACT1, which comprises the carboxy-terminus of Cx43 and has demonstrated therapeutic effects in promoting healing of chronic wounds. FirstString Research has licensed ACT1 for further development and clinical application, and has advanced Granexin(tm) Gel, the topical formulation of ACT1 peptide, through three successfully completed Phase 2 human clinical trials for scar reduction and the treatment of chronic wounds. In collaboration with the Sheng's (co-Investigator) laboratory, we observed that Cx43 expression inversely correlates to TMZ sensitivity and GBM patient survival, and demonstrated that ACT1 significantly increases TMZ sensitivity in vitro and in vivo, thus encouraging us to further investigate its therapeutic potential in sensitizing GBM tumors to TMZ. However, intracranial delivery of this peptide is limited by its relatively short half-life. Therefre, the overall objective of this application is to develop a novel delivery approach for ACT1 to treat GBM in vivo. The use of biodegradable nanoparticles for peptide delivery is a powerful approach due to its high biocompatibility and sustained peptide release. The rationale of this study is that ACT1-loaded nanoparticles (ACT1-NP) will efficiently deliver ACT1 into the brain by constantly and continuously supply GBM tumor cells with this peptide. Our hypothesis is that ACT1-NP will sensitize GBM to TMZ which will then be tested in two specific aims: 1) to engineer ACT1-NP and optimize controlled delivery of ACT1 in vitro, 2) to assess in vivo the therapeutic potential of ACT1-NP in tandem with TMZ treatment of brain tumors. We will first generate ACT1-NP in collaboration with Dr. Foster (co-Investigator) and his laboratory, using poly(lactic-co-glycolic acid) PLGA copolymer. After in vitro characterization of ACT1-NP and effect on human GBM cells, we will intracranially inject ACT1-NP into the brains of GBM mice followed by TMZ treatment. We will monitor the tumor growth using magnetic resonance imaging and analyze mice survival. These results will validate the therapeutic effect of ACT1 in vivo. We expect that this approach will efficiently deliver ACT1 in a sustained way, and sensitize GBM tumors to TMZ. The proposed research is significant because this innovative approach will not only allow us to develop novel combinational therapies for lethal GBM but also will lay foundation on potential clinical trials in newly diagnosed GBM patients in the near future. Finally our new ACT1-NP may be scalable to other CNS diseases that could benefit from Cx43 targeting.
Public Health Relevance Statement: Public Health Relevance: Glioblastoma is a very aggressive type of brain tumor and one of the most deadly diseases with no efficient therapy to cure it. The proposed research aims at developing a new combinational therapy to enhance the effectiveness of temozolomide, the front line chemotherapy for glioblastoma. Therefore, this work will have important impact on therapeutic intervention for glioblastoma and is relevant to public health and NIH's mission.
NIH Spending Category: Bioengineering; Brain Cancer; Brain Disorders; Cancer; Nanotechnology; Neurosciences; Orphan Drug; Rare Diseases
Project Terms: Adult; aggressive therapy; Alkylating Agents; Animals; Apoptosis; base; biomaterial compatibility; Brain; Brain Glioblastoma; Brain Neoplasms; Cell physiology; Cell Survival; Cells; Central Nervous System Diseases; chemotherapy; Chronic; Cicatrix; clinical application; Clinical Trials; Collaborations; Communication; Connexin 43; Connexins; copolymer; Cytotoxic Chemotherapy; Data; Development; Disease; DNA; Drug Delivery Systems; Drug Formulations; effective therapy; Effectiveness; Encapsulated; Engineering; Enzymes; Excision; Failure (biologic function); Fostering; Foundations; Future; Gel; Glioblastoma; Glioma; Glycolates; Goals; Grant; Half-Life; Healed; healing; Heterogeneity; Human; Image Analysis; Immunocompromised Host; implantation; improved; In Vitro; in vivo; Injection of therapeutic agent; innovation; Intervention; irradiation; Laboratories; Licensing; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; MGMT gene; migration; Mission; Monitor; Mus; nanoparticle; Nature; neoplastic cell; Newly Diagnosed; novel; novel strategies; novel therapeutic intervention; novel therapeutics; Operative Surgical Procedures; Outcome; outcome forecast; particle; Patients; Penetration; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase III Clinical Trials; Polymers; Population; prevent; Proteins; public health medicine (field); public health relevance; Radiation; Radiation therapy; Recurrence; Refractory; Regulation; repaired; Research; Research Institute; Research Personnel; Resistance; Site; Skin; Stem cells; Survival Analysis; synthetic peptide; Tail; temozolomide; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Toxic effect; Treatment Protocols; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; Tumor Tissue; United States Food and Drug Administration; uptake; Virginia; Work
