Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer.

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor.

ANGPTL4 accelerates KRAS-Induced acinar to ductal metaplasia and pancreatic carcinogenesis.

Oncogenic KRAS induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), and drives pancreatic ductal adenocarcinoma (PDAC). Angiopoietin-like 4 (ANGPTL4) is known to be involved in the regulation of cancer growth and metastasis. However, whether ANGPTL4 affects KRAS-mediated ADM and early PDAC intervention remains unknown.

The Pathogenesis of , Host Defense Mechanisms, and the Development of AFMP4 Antigen as a Vaccine.

is one of the ubiquitous fungi with airborne conidia, which accounts for most aspergillosis cases. In immunocompetent hosts, the inhaled conidia are rapidly eliminated. However, immunocompromised or immunodeficient hosts are particularly vulnerable to most infections and invasive aspergillosis (IA), with mortality from 50% to 95%.

Intracellular KRAS-specific antibody enhances the anti-tumor efficacy of gemcitabine in pancreatic cancer by inducing endosomal escape.

KRAS mutation is associated with the progression and growth of pancreatic cancer and contributes to chemo-resistance, which poses a significant clinical challenge in pancreatic cancer. Here, we developed a RT22-ep59 antibody (Ab) that directly targets the intracellularly activated GTP-bound form of oncogenic KRAS mutants after it is internalized into cytosol by endocytosis through tumor-associated receptor of extracellular epithelial cell adhesion molecule (EpCAM) and investigated its synergistic anticancer effects in the presence of gemcitabine in pancreatic cancer. We first observed that RT22-ep59 specifically recognized tumor-associated EpCAM and reached the cytosol by endosomal escape.

ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a.

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin-like 4 (ANGPTL4) as one of the most significantly upregulated genes.

PBT-6, a Novel PI3KC2γ Inhibitor in Rheumatoid Arthritis.

Phosphoinositide 3-kinase (PI3K) is considered as a promising therapeutic target for rheumatoid arthritis (RA) because of its involvement in inflammatory processes. However, limited studies have reported the involvement of PI3KC2γ in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2γ as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6.

An Integrative Data Mining and Omics-Based Translational Model for the Identification and Validation of Oncogenic Biomarkers of Pancreatic Cancer.

Substantial alterations at the multi-omics level of pancreatic cancer (PC) impede the possibility to diagnose and treat patients in early stages. Herein, we conducted an integrative omics-based translational analysis, utilizing next-generation sequencing, transcriptome meta-analysis, and immunohistochemistry, combined with statistical learning, to validate multiplex biomarker candidates for the diagnosis, prognosis, and management of PC. Experiment-based validation was conducted and supportive evidence for the essentiality of the candidates in PC were found at gene expression or protein level by practical biochemical methods.

HS-173 as a novel inducer of RIP3-dependent necroptosis in lung cancer.

Necroptosis is a form of regulated necrotic cell death mediated by receptor-interacting kinase 3 (RIP3). Recently, necroptosis has gained attention as a novel alternative therapy to target cancer cells. In this study, we screened several chemotherapeutics used in preclinical and clinical studies, and identified a drug HS-173 that induces RIP3-mediated necroptosis.

KRAS targeting antibody synergizes anti-cancer activity of gemcitabine against pancreatic cancer.

Pancreatic cancer exhibits an oncogenic KRAS mutation rate of ∼90%. Despite research and drug development efforts focused on KRAS, no targeted therapy has been clinically approved for the treatment of pancreatic cancer with KRAS mutation. Also, the efficacy of gemcitabine is poor due to rapidly acquired resistance.

Melatonin Synergizes with Sorafenib to Suppress Pancreatic Cancer via Melatonin Receptor and PDGFR-β/STAT3 Pathway.

Background/aims: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors with poor prognosis. Conventional chemotherapies including gemcitabine have failed owing to weak response and side effects. Hence novel treatment regimens are urgently needed to improve the therapeutic efficacy.

Artemisia Capillaris leaves inhibit cell proliferation and induce apoptosis in hepatocellular carcinoma.

Background: Natural product is one of the most important sources of drugs used in pharmaceutical therapeutics. Artemisia capillaris has been traditionally used as a hepatoprotective and anti-inflammatory agent. In this study, we extracted an ethanol fraction (LAC117) from the dried leaves of Artemisia capillaris and identified its anticancer activity and mechanism of action against hepatocellular carcinoma (HCC).

A novel tropomyosin-related kinase A inhibitor, KK5101 to treat pancreatic cancer.

Tropomyosin-related kinase A (TrkA) plays important roles in tumor cell growth and survival signaling and contributes to chemo-resistance in pancreatic cancer. Therefore, we developed KK5101, a novel TrkA target inhibitor and assessed its anti-cancer effects and investigated underlying mechanism of action in pancreatic cancer. KK5101 was characterized to inhibit TrkA selectively and potently by protein binding assay.

Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer.

Activation of PI3K/AKT pathway occurs frequently in tumors and is correlated with radioresistance. The PI3K/AKT pathway can be an important target for improvement of radiotherapy. Although adding of chemotherapy to radiation therapy regimen enhances survival in patients with locally advanced pancreatic cancer, more effective therapies for increasing radiosensitivity are urgently needed.

Systematic assessment of cervical cancer initiation and progression uncovers genetic panels for deep learning-based early diagnosis and proposes novel diagnostic and prognostic biomarkers.

Although many outstanding achievements in the management of cervical cancer (CxCa) have obtained, it still imposes a major burden which has prompted scientists to discover and validate new CxCa biomarkers to improve the diagnostic and prognostic assessment of CxCa. In this study, eight different gene expression data sets containing 202 cancer, 115 cervical intraepithelial neoplasia (CIN), and 105 normal samples were utilized for an integrative systems biology assessment in a multi-stage carcinogenesis manner. Deep learning-based diagnostic models were established based on the genetic panels of intrinsic genes of cervical carcinogenesis as well as on the unbiased variable selection approach.

Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery.

Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors.

Oncolytic adenovirus expressing relaxin (YDC002) enhances therapeutic efficacy of gemcitabine against pancreatic cancer.

Pancreatic cancer is a highly lethal disease for which limited therapeutic options are available. Pancreatic cancer exhibits a pronounced collagen-rich stromal reaction, which induces chemoresistance by inhibiting drug diffusion into the tumor. Complementary treatment with oncolytic virus such as an oncolytic adenovirus expressing relaxin (YDC002) is an innovative treatment option for combating chemoresistant pancreatic cancer.

HS-173, a novel PI3K inhibitor suppresses EMT and metastasis in pancreatic cancer.

Pancreatic cancer is one of the most aggressive solid malignancies prone to metastasis. Epithelial-mesenchymal transition (EMT) contributes to cancer invasiveness and drug resistance. In this study, we investigated whether HS-173, a novel PI3K inhibitor blocked the process of EMT in pancreatic cancer.

Optimization and biological evaluation of aminopyrimidine-based IκB kinase β inhibitors with potent anti-inflammatory effects.

Targeting IκB kinase β (IKKβ) can be a promising strategy in the development of a therapeutic treatment of inflammatory diseases because IKKβ is well-recognized as a key mediator of the NF-κB signaling pathway. In this study, we have successfully developed a structure-activity relationship (SAR) profile of the aminopyrimidine-based IKKβ inhibitors through the structure-based design strategy to improve the physicochemical properties and cellular activity in terms of the anti-inflammatory effects. Representative compounds exhibited desirable activity in nitric oxide (NO) reduction by inhibiting the synthesis of inducible nitric oxide synthase (iNOS), and strongly inhibited the expression of pro-inflammatory cytokines (IL-1α, IL-6, and TNF-α).

CD-200 induces apoptosis and inhibits Bcr-Abl signaling in imatinib-resistant chronic myeloid leukemia with T315I mutation.

Chronic myeloid leukemia (CML) is characterized by a constitutively active Bcr-Abl tyrosine kinase. Although Imatinib has been proven to be an effective drug against CML, its resistance has been observed with disease relapse due to T315I predominant point mutation. Liriodendron tulipifera L.

HS-543 induces apoptosis of Imatinib-resistant chronic myelogenous leukemia with T315I mutation.

Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT).

Recombinant ESAT-6-like proteins provoke protective immune responses against invasive Staphylococcus aureus disease in a murine model.

Staphylococcus aureus is a common pathogen found in the community and in hospitals. Most notably, methicillin-resistant S. aureus is resistant to many antibiotics, which is a growing public health concern.

Crizotinib exhibits antitumor activity by targeting ALK signaling not c-MET in pancreatic cancer.

Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action.

Anticancer activity of HS-527, a novel inhibitor targeting PI3-kinase in human pancreatic cancer cells.

Pancreatic cancer is known to have low 5-year survival rate and poor response to treatment. In this study, we synthesized HS-527, a new PI3-kinase inhibitor, and investigated not only its anticancer activity, but also its mechanism of action in pancreatic cancer cells. HS-527 had higher specificity for PI3K than other kinases and inhibited PI3K/Akt signaling pathway by down-regulating Akt and P70S6K.

HS-104, a PI3K inhibitor, enhances the anticancer efficacy of gemcitabine in pancreatic cancer.

Gemcitabine has limited clinical benefits for pancreatic cancer patients. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is important in cell proliferation and survival, and is frequently dysregulated in pancreatic cancer. To obtain insights into novel therapeutic strategies for treating pancreatic cancer, we investigated whether HS-104, a novel PI3K inhibitor, in combination with gemcitabine would show a synergistic effect in pancreatic cancer.