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Title: SGT-53: A Tumor-Targeting Nanomedicine for TP53 Gene Therapy That Renders Glioblastomas Less Resistant to Temozolomide
Authors: Joe B. Harford1, Sang Soo Kim1,2, Kathleen F. Pirollo2, Antonina Rait2 and Esther H. Chang2
Affiliations: 1SynerGene Therapeutics, Inc.;
2Georgetown University Medical Center Washington, DC
Abstract: Glioblastomas (GBM) are among the most deadly of cancers with median patient survival of under 15 months and a 5-year survival rate of less than 5%. Standard-of-care treatment for GBM includes surgery (when possible), radiotherapy, and chemotherapy using temozolomide, a DNA- alkylating agent that triggers apoptosis. Inherent or acquired TMZ resistance contributes to pooroutcomes for GBM patients and has been linked to higher levels of the DNA repair enzyme, O6 -methylguanine-DNA-methyltransferase (MGMT), that reverses the damage caused by TMZ. Attempts have been made to relieve TMZ resistance by reducing MGMT by various means. The tumor suppressor p53 is a pleiotropic transcription factor with capacity to alter expression of hundreds of genes and affect multiple cellular pathways. Among p53-regulated genes is MGMT. When functional p53 pathways are defective as they are in many GBM tumors, MGMT levels tend to be high, and tumor cells are more resistant to TMZ. We are developing SGT-53, an investigational nanomedicine for TP53 gene therapy that is now in Phase II clinical trials. In SGT-53, a plasmid encoding normal human p53 is encapsulated within a cationic liposome, the surface of which is decorated with a single-chain antibody fragment recognizing the transferrin receptor (TfR). This nanocomplex actively crosses the blood-brain barrier (BBB) by TfR-mediated transcytosis of brain capillary endothelial cells. Once in the brain parenchyma, the nanocomplexes are preferentially taken up by brain cancer cells, which overexpress TfR. As a result of TfR-targeted delivery of the TP53 gene, normal human p53 is expressed in brain tumors. In animal models of human GBM, SGT-53 displays anti-tumor activity, but this activity of the nanomedicine as monotherapy is sub-optimal. However, the p53 emanating from SGT-53 results in: a) reduced levels of MGMT; b) higher levels of p21, a protein linked to cell cycle arrest; and c) enhanced apoptosis. These data suggested that SGT-53 would sensitize tumors to DNA-targeting chemotherapeutics like TMZ. Indeed, we have shown that TMZ combined with SGT-53 is markedly more effective than TMZ alone in curtailing tumor growth in murine xenograft models of human GBM. As a result, the combination therapy provided a clear survival benefit to mice bearing intracranial human GBM including tumors that are intrinsically TMZ-resistant. Cancer stem-like cells (CSCs) have been implicated in recurrence and treatment resistance in many human cancers including GBM. We have demonstrated that SGT-53 targets both CSCs and bulk tumor. Expression of exogenous p53 in the CSCs enhances their apoptotic death. Collectively, our data indicate that SGT-53 mitigates TMZ-resistance in murine models for human GBM and suggest that adding SGT-53 to TMZ-based standard-of-care for GBM could produce a more effective therapeutic regimen. We also have independent data showing that SGT-53 also augments the anti-tumor efficacy of radiotherapy and of immunotherapy based on immune checkpoint inhibition. Thus, TP53 gene therapy appears to sensitize tumor cells to a variety of other therapeutic modalities. Under an expanded access IND, two pediatric patients with CNS malignancies have been treated with SGT-53 plus chemotherapy and radiotherapy with tumor responses observed. Additional assessment of TP53 gene therapy as a component of combination treatment regimens for GBM is clearly warranted.
Title: Cell-and cell membrane-based cancer therapies and future aspects for immunomodulation
Authors: Serkan Yaman1,2,#, Uday Chintapula1,2,#, Edgar Rodriguez1, Kytai T. Nguyen1,2,*
Affiliations: 1Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76010, USA.
2Joint Bioengineering program, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
#Yaman. S. & Chintapula. U contributed equally to this work.
*Corresponding author: Dr. Kytai Nguyen, Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76010, USA.
Abstract: Nanotechnology-based drug delivery platforms have been developed over the last two decades due to their favorable features in terms of improved drug bioavailability and efficient targeting. Despite recent advancement in these platforms, this approach still falls short to meet the complexity of diseases such as avoiding systemic side effects, manipulating biological interactions and overcoming drug resistance, which hinders the therapeutic effects of these drug delivery systems in vivo. To address these issues, various strategies have been developed including the use of engineered cells and/or cell membrane coated drug delivery nanocarriers. Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions, targeting and homing of either engineered cells or cell membrane coated nanocarriers to the sites of interests. In this context, we comprehensively discuss various cell- and cell membrane-based drug delivery approaches towards cancer therapy, the therapeutic potential of these strategies and the limitations associated with engineered cells and cell-membrane-associated drug nanocarriers. Finally, we review various cell types and cell membrane receptors for their potentials in targeting, immunomodulation and overcoming drug resistance towards cancer.