Graduate Thesis Or Dissertation
 

Development of Novel Therapeutic Approach for Ewing’s Sarcoma Treatment

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/dz010x45d

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  • Ewing sarcoma (EwS) is the second most highly malignant tumor that arises mainly from bone and surrounding soft tissue of adolescent and young adult patients. Despite the advances in Ewing sarcoma treatment that today include a combination of five chemotherapeutic agents, surgery, and/or radiotherapy, these therapies have demonstrated limited improvement in overall survival of patients with localized or metastatic disease. The currently used combination of chemotherapy drugs is associated with severe side effects such as nephrotoxicity and cardiotoxicity. To date, there is no standard treatment protocol for metastatic Ewing sarcoma and thus multiple clinical and preclinical trials have focused on introducing new targeted molecules and combining them with current therapies for improving overall outcomes. EWS/FLI fusion protein, which is not expressed in untransformed cells, is considered the main oncogenic driver of Ewing sarcoma disease. EWS/FLI fusion protein is an ideal target for therapy; however, it is still undruggable because of the absence of intrinsic enzyme activity and disordered protein nature. To date, there are no molecularly targeted EwS therapies that have been approved by the FDA. As a result, researchers have broadened drug screening in their attempts to identify highly selective molecules toward EwS cells and improve treatment outcomes. At the initial step, we have employed phenotypic, high-throughput screening (HTS) and identified a selective and potent molecule (ML111) for Ewing sarcoma treatment. This compound exhibited selectivity and high potency toward the panel of EwS cells. However, upon exposure to liver enzymes, ML111 exhibited rapid metabolism which may hinder its translation as a potential therapy. Also, solubility and stability of most new molecules, including ML111, are the major barriers preventing translation to clinical trials. To overcome these obstacles, we employed nanoparticle formulation, as it has been shown to enhance solubility and improve stability. Nanomaterial-based delivery platforms can facilitate prolonged blood circulation with desirable drug release profiles and increased accumulation within tumors by controlling the size and charge of the nanoparticle. Therefore, we have encapsulated the hydrophobic molecule ML111 (350-fold solubility enhancement) in a nontoxic PEG-PCL polymeric nanoparticle with suitable characteristics for drug delivery. Use of the polymeric nanoparticle formulation (ML111-NP) has provided compelling evidence of enhanced accumulation within EwS xenograft models following intravenous administration. We concluded that polymeric nanoparticles improved the solubility of ML111 and accommodated suitable drug delivery in EwS treatment. ML111-NP is a potential EwS agent with significant antitumor activity. However, it did not completely inhibit tumor growth. The current treatment of EwS is based on combination therapy and is associated with complicated toxicities. Therefore, we investigate the synergistic effect of combinatorial therapy of ML111 with current chemotherapy to further improve antitumor activity while minimizing toxicities. Administration of vincristine with ML111-NP in combinatorial therapy led to significant cell viability reduction and extended anti-tumor activity in an orthotopic model of EwS while minimizing toxicity at or below MTD of vincristine. Overall, ML111 (new agent) and its delivery system demonstrated superior antitumor activity in multiple mouse models of EwS, which suggests its potential as a new single therapy or combinatorial therapy for enhancing efficacy and reducing toxicity in pursuit of improved patient outcomes
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  • Intellectual Property (patent, etc.)
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  • 2021-03-04 to 2023-04-05

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