Publications by authors named "Seung Woo Chung"

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers.

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Biomaterials are implanted in millions of individuals worldwide each year. Both naturally derived and synthetic biomaterials induce a foreign body reaction that often culminates in fibrotic encapsulation and reduced functional lifespan. In ophthalmology, glaucoma drainage implants (GDIs) are implanted in the eye to reduce intraocular pressure (IOP) in order to prevent glaucoma progression and vision loss.

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While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect.

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In conventional chemotherapy, maximum tolerated dose approach is considered as a first-line medication for cancer treatment in clinics. In contrast to the conventional chemotherapy which has heavy tumor burdens arising from high dose treatment, metronomic chemotherapy (MCT) engages relatively low dose without drug-free breaks, and is recognized as a promising strategy for a long-term management of the disease. Although doxorubicin (DOX), an anthracycline anti-cancer drug, showed a potential of maintenance effect in vitro, further study on in vivo-relevant concentration to achieve tumor suppression with no toxicity is required to apply the MCT in clinicals.

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Therapy-induced senescence (TIS), a common outcome of current cancer therapy, is a known cause of late recurrence and metastasis and thus its eradication is crucial for therapy success. In this study, we introduced a conceptually novel strategy combining radiation-induced apoptosis-targeted chemotherapy (RIATC) with an effective glycolysis inhibitor, 2-deoxy-d-glucose (2DG) to target TIS. RIATC releases cytotoxic payload by amplification, continually increasing TIS, and this can be targeted by 2DG that stimulates an intrinsic apoptotic pathway in senescent cells, the senolysis; the senolytic 2DG also sensitizes cancer cells to chemo/radiation treatment.

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Triple-negative breast cancer (TNBC) is characterized by its highly heterogeneous microenvironment and propensity for aggressive behavior, both of which represent, along with poor prognosis and high incidence of relapse, the main challenges of curing the disease. Although recent progress in targeted chemotherapy combinations has shown promising outcomes, conventional targeted chemotherapeutic approaches have relied on exploiting the expression of certain molecules or proteins overexpressed on cancer cells as drug targets, which have demonstrated limited clinical benefit against metastatic cancers. Here, we describe a tumoral caspase-3 mediated peptide-doxorubicin conjugates (PDC) switch therapy that adopts two different caspase-3 cleavable PDCs, RGDEVD-DOX (TPD1) and EMC-KGDEVD-DOX (MPD1), for targeting metastatic triple-negative breast cancer (mTNBC).

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Growth factors (GF) regulate normal development to cancer progression. GFs interact with extracellular matrix (ECM) biomolecules, such as heparin sulfate (HS) glycosaminoglycan (GAG), to enhance their stability and angiogenic signaling. Biomaterials that modulate GF activity by mimicking interactions observed in the native ECM could be designed as an effective treatment strategy.

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Despite recent breakthroughs in the development of direct KRAS inhibitors and modulators, no drugs targeting pan-KRAS mutant cancers are clinically available. Here, we report a novel strategy to treat pan-KRAS cancers using a caspase-3 cleavable peptide-drug conjugate that exploits enhanced albumin metabolism in KRAS altered cancers to deliver a cytotoxic agent that can induce a widespread bystander killing effect in tumor cells. Increased albumin metabolism in KRAS mutant cancer cells induced apoptosis via the intracellular uptake of albumin-bound MPD1.

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Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8 T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.

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Cyclin D3 regulates the G1/S transition and is frequently overexpressed in several cancer types including breast cancer, where it promotes tumor progression. Here we show that a cytoskeletal protein keratin 19 (K19) physically interacts with a serine/threonine kinase GSK3β and prevents GSK3β-dependent degradation of cyclin D3. The absence of K19 allowed active GSK3β to accumulate in the nucleus and degrade cyclin D3.

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Immunotherapy has emerged as an unprecedented hope for the treatment of notoriously refractory cancers. Numerous investigational drugs and immunotherapy-including combination regimens are under preclinical and clinical investigation. However, only a small patient subpopulation across different types of cancer responds to the therapy due to the presence of several mechanisms of resistance.

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Purpose: Here, this study verifies that cancer-associated thrombosis (CAT) accelerates hypoxia, which is detrimental to the tumor immune microenvironment by limiting tumor perfusion. Therefore, we designed an oral anticoagulant therapy to improve the immunosuppressive tumor microenvironment and potentiate the efficacy of immunotherapy by alleviating tumor hypoxia.

Experimental Design: A novel oral anticoagulant (STP3725) was developed to consistently prevent CAT formation.

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The selective cytotoxicity of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) to cancer cells but not to normal cells makes it an attractive candidate for cancer therapeutics. However, the disadvantages of TRAIL such as physicochemical instability and short half-life limit its further clinical applications. In this study, TRAIL was encapsulated into a novel anti-angiogenic nanocomplex for both improved drug distribution at the tumor site and enhanced anti-tumor efficacy.

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The selective targeting of cytotoxic agents to a tumor has shown limited success by difficulties in identifying the appropriate target molecules, and more importantly, by the phenotypically dynamic nature of the tumor cells and intratumoral heterogeneity. In an attempt to overcome these issues and efficiently deliver cytotoxic drugs to the tumor, we previously reported a strategy termed radiation-induced apoptosis-targeted chemotherapy (RIATC), which utilizes the radiotherapy for intentionally triggering the caspase-3 and in situ amplification of tumor apoptosis by caspase-3 activated prodrug. Herein, we propose an advanced form of RIATC prodrug, AP1-DEVD-S-DOX, that could more actively target to the ligands of radiation-induced tumor cells, which could accumulate more prodrugs, thereby allowing more effective in situ activation and amplification of tumor apoptosis, comparing to RIATC.

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Despite its central role in tumor progression and treatment resistance, poor vascularization that necessitates penetration of therapeutics through tumor extracellular matrix (ECM) constitutes a significant challenge to managing tumor hypoxia via conventional systemic treatment regimens. In addition, methods to target hypoxic tumor cells are lacking. Here, we discovered that human ferritin nanocages (FTn) possess an intrinsic ability to preferentially engage with hypoxic tumor tissues, in addition to normoxic tumor areas.

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Despite the emergence of advanced therapeutics such as targeted therapy and immunotherapy in the modern oncology, cytotoxic chemotherapy still remains as the first-line treatment option in a wide range of cancers attributing to its potency. Many endeavors have been made to overcome the toxicity issues of cytotoxic chemotherapy by improving the specific delivery to the tumor, with active tumor targeting being one of the most popular approaches. However, such an approach has been challenged by the intratumor heterogeneity and the lack of valid molecular target in many types of cancer.

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Metronomic chemotherapy, which is defined as a low-dose and frequent administration of cytotoxic drugs without drug-free breaks, has been recently emerged as an alternative to traditional MTD therapy and has shown therapeutic benefit in breast cancer patients in numbers of clinical studies. Unlike MTD, metronomic chemotherapy acts by multiple mechanisms including antiangiogenic effect and immunomodulation, but the direct cytotoxic effect only playing a minor role due to the lowered dose. In this light, within the limits of p53-deficient breast cancer, we demonstrate the enhanced anticancer effect of metronomic chemotherapy using doxorubicin when combined with Chk1 inhibitor MK-8776 by specifically augmenting the direct cytotoxic effect on cancer cells.

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Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target-positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin αvβ3 and releases cytotoxins upon entering cells or by caspase-3.

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Chemotherapy have commonly been used in maximum tolerated dose to completely eradicate the cancer. However, such treatments often failed due to the complex and dynamic nature of cancer. Therefore, it has been suggested that cancer should be treated as a chronic disease, controlling its growth by providing continuous therapeutic pressure for long-term.

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Clinical studies have found that the incidence of cancer metastasis through the lymphatic vessels are 3-5 times higher than that through the blood vessels. These findings suggest the potency of anti-lymphangiogenic therapy in reducing the incidence of cancer metastasis. Previously, we reported LHbisD4, which is the conjugate of low molecular weight heparin (LMWH) and four bis-deoxycholates as a potent anti-angiogenic drug with less toxicity and orally active property.

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Metronomic chemotherapy has translated into favorable toxicity profile and capable of delaying tumor progression. Despite its promise, conventional injectable chemotherapeutics are not meaningful to use as metronomic due to the necessity of frequent administration for personalized therapy in long-term cancer treatments. This study aims to exploit the benefits of the oral application of carboplatin as metronomic therapy for non-small cell lung cancer (NSCLC).

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Existence of the genomically and epigenomically diverse subclones in a tumor severely limits the therapeutic efficacy of targeted agents. To overcome such a limitation, we prepared a novel targeted prodrug, EMC-DEVD-S-DOX, which comprises two important features: radiation-induced apoptosis targeting and albumin-binding properties. In particular, the prodrug binds circulating albumin after intravenous administration and then activated by caspase-3, which is upregulated from apoptotic cells that responded to radiotherapy.

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Controlled and site-specific regulation of growth factor signaling remains a major challenge for current antiangiogenic therapies, as these antiangiogenic agents target normal vasculature as well tumor vasculature. In this article, we identified the prion-like protein doppel as a potential therapeutic target for tumor angiogenesis. We investigated the interactions between doppel and VEGFR2 and evaluated whether blocking the doppel/VEGFR2 axis suppresses the process of angiogenesis.

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Context: As a class of angiogenesis inhibitors, heparin conjugates have shown significant effectiveness in several studies.

Objectives: The purpose of our current study is to evaluate the effectiveness and safety of infusing the conjugate of low molecular weight heparin and taurocholate (LHT7), which has been developed as a potent angiogenesis inhibitor.

Methods: To evaluate its safety, the method of intravenous infusion was compared with its i.

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