Search

Chiglitazar (Carfloglitazar) is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes. In this randomized phase 3 trial, we compared the efficacy and safety of chiglitazar with sitagliptin in patients with type 2 diabetes who had insufficient glycemic control despite a strict diet and exercise regimen. Eligible patients were randomized (1:1:1) to receive chiglitazar 32 mg (n = 245), chiglitazar 48 mg (n = 246), or sitagliptin 100 mg (n = 248) once daily for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin A1C (HbA1c) from baseline at week 24 with the non-inferiority of chiglitazar over sitagliptin. Both chiglitazar and sitagliptin significantly reduced HbA1c at week 24 with values of −1.40%, −1.47%, and −1.39% for chiglitazar 32 mg, chiglitazar 48 mg, and sitagliptin 100 mg, respectively. Chiglitazar 32 and 48 mg were both non-inferior to sitagliptin 100 mg, with mean differences of −0.04% (95% confidential interval (CI) −0.22 to 0.15) and −0.08% (95% CI −0.27 to 0.10), respectively. Compared with sitagliptin, greater reduction in fasting and 2-h postprandial plasma glucose and fasting insulin was observed with chiglitazar. Overall adverse event rates were similar between the groups. A small increase in mild edema in the chiglitazar 48 mg group and slight weight gain in both chiglitazar groups were reported. The overall results demonstrated that chiglitazar possesses good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions, thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

Chiglitazar (Carfloglitazar) is a novel non-thiazolidinedione (TZD) structured peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies. This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone. Eligible patients were randomly assigned to receive chiglitazar 32 mg (n = 167), chiglitazar 48 mg (n = 166), or placebo (n = 202) once daily. The primary endpoint was the change in glycosylated hemoglobin A1c (HbA1c) at week 24 with superiority of chiglitazar over placebo. The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA1c, and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were −0.87% (95% confidential interval (CI): −1.10 to −0.65; P

Objective Chidamide is an oral histone deacetylase subtype-selective inhibitor approved for relapsed or refractory peripheral T-cell lymphoma (PTCL). This phase 1b study evaluated the safety, pharmacokinetics, and preliminary efficacy of chidamide in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) for treatment-naive PTCL patients. Methods This study was an open-label, multicenter trial composed of dose escalation and dose expansion. Patients received CHOP for six 21-d cycles and chidamide on d 1, 4, 8 and 11 in each cycle. Four dose levels of chidamide (20, 25, 30 and 35 mg) were evaluated. The primary objective was to evaluate the safety and tolerability of the combination regimen. Results A total of 30 patients were evaluated in this study: 15 in the dose-escalation part and 15 in the dose-expansion part. In the dose-escalation study, three patients were enrolled in the 35 mg chidamide cohort. One had dose-limiting toxicity with grade 3 vascular access complications, and one had grade 2 neutropenia with a sustained temperature >38 °C. Dose escalation was stopped at this chidamide dose level. The most common (≥10%) grade 3 or 4 adverse events (AEs) were leukopenia (90.0%), neutropenia (83.3%), vomiting (13.3%), thrombocytopenia (10.0%) and febrile neutropenia (10.0%). No significant changes in chidamide pharmacokinetic properties were observed before and after combination treatment. The objective response rate for the 28 patients evaluable for preliminary efficacy was 89.3% (25/28), with 16 (57.1%) achieving complete response or unconfirmed complete response. The estimated median progression-free survival was 14.0 months. In summary, we chose chidamide 30 mg as the recommended dose for phase 2. Conclusions The addition of chidamide to standard CHOP chemotherapy was tolerable with promising preliminary efficacy in previously untreated PTCL patients, which supports further clinical studies with this combination regimen for the frontline treatment of PTCL.

Objective The recurrence or progression under endocrine therapy in hormone receptor-positive (HR+) advanced breast cancer (ABC) remained a critical clinical challenge. Chidamide is an oral subtype-selective histone deacetylase (HDAC) inhibitor with multiple functions in tumor growth inhibition and microenvironment modulation via epigenetic reprogramming. The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of chidamide in combination with exemestane in HR+ ABC patients. Methods Eligible patients were postmenopausal women with HR+ ABC recurrent or progressed to at least one endocrine therapy. Blood samples were obtained in the run-in period and the first day of combination treatment for PK analysis. In combination treatment, patients were given exemestane 25 mg daily and chidamide 30 mg twice a week (BIW) until progression of disease or intolerable toxicities. A treatment cycle was defined as 4 weeks. Safety, PK parameters, and preliminary efficacy were evaluated. Results A total of 20 patients were enrolled between July and December, 2015. The median number of treatments cycle was 5.2 (20.8 weeks) with 2 patients still on treatment at the data cut-off date of October, 2017. The treatment-related adverse events (AE) ≥ grade 3 in more than 2 patients were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). The plasma exposure of exemestane was consistent in the presence or absence of chidamide. A slight increase in chidamide exposure was noted in the presence of exemestane, probably due to the inter- and intra-patient variations. The best response in 16 evaluable patients was assessed by Response Evaluation Criteria in Solid Tumors (RECIST), including 4 patients with partial response, 10 patients with stable disease. The median progression-free survival (PFS) was 7.6 months. Conclusions The combination of chidamide with exemestane was generally well tolerated with promising preliminary efficacy in HR+ ABC patients. The overall results from this study encourage further pivotal trial in this patient population.

Chiglitazar, a novel PPARα/γ/δ pan-agonist, showed favorable effects on glycemic control and lipid modulation with well tolerated safety profile in phase 2 trials. This trial aimed to compare the efficacy and safety of chiglitazar with DPP-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with diet and exercise (ClinicalTrials.gov NCT02173457). Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or sitagliptin 100 mg once daily. The primary endpoint was change in HbA1c from baseline at week 24, with a non-inferiority of each chiglitazar dose versus sitagliptin. Analysis was done in all randomized patients who received at least one dose of study drug (n=739). Chiglitazar showed comparable HbA1c lowering effect compared with sitagliptin at 24 weeks (LS mean difference -0.04% [95% CI -0.22 to 0.15] and -0.08% [95% CI -0.27 to 0.10] for 32 mg and 48 mg, respectively), along with different trends in secondary endpoints. Overall adverse events were comparable across study groups. The incidences of weight gain and edema were generally low but relatively higher in chiglitazar 48 mg. In conclusion, chiglitazar showed non-inferior effect compared with sitagliptin on HbA1c reduction with well tolerated safety profile. Disclosure W. Jia: None. J. Ma: None. H. Miao: None. C. Wang: None. X. Wang: None. Q. Li: None. W. Lu: None. J. Yang: None. L. Zhang: None. J. Yang: None. G. Wang: None. X. Zhang: None. M. Zhang: None. L. Sun: None. X. Yu: None. J. Du: None. B. Shi: None. C. Xiao: None. D. Zhu: None. H. Liu: None. L. Zhong: None. C. Xu: None. Q. Xu: None. G. Liang: None. Y. Zhang: None. G. Li: None. M. Gu: None. J. Liu: None. Z. Ning: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. Funding Ministry of Science and Technology of the People´s Republic of China (2013ZX09401301)

Chiglitazar showed favorable effect on glycemic control and lipid modulation with well tolerated safety profile in phase 2 trials. This trial aimed to further compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes inadequately controlled with lifestyle interventions (ClinicalTrials.gov NCT02121717). Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or placebo once daily. After 24-week treatment, patients in placebo group were randomly assigned to receive chiglitazar 32 mg or 48 mg, while others remained on the planned treatment till to 52 weeks. The primary endpoint was change in HbA1c at week 24 with superiority of each chiglitazar dose versus placebo. Analysis was done in all randomized patients who received at least one dose of study drug (n= 535). Chiglitazar was superior to placebo in HbA1c reduction at 24 weeks (LS mean difference -0.87% [95% CI -1.10 to -0.65] and -1.05% [95% CI -1.29 to -0.81] for 32 mg and 48 mg, respectively) and achieved sustainable effect till to 52 weeks. Overall adverse events were comparable across groups. The incidences of weight gain, edema, and hypoglycemia were relatively higher in chiglitazar groups. Chiglitazar showed superior and sustainable HbA1c lowering effect with well tolerated safety profile in patients with type 2 diabetes. Disclosure L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. W. Song: None. H. Fang: None. W. Li: None. J. Geng: None. Y. Xu: None. Y. Wang: None. L. Guo: None. H. Cai: None. T. Yang: None. H. Li: None. G. Yang: None. Q. Li: None. K. Liu: None. S. Li: None. Y. Liu: None. F. Shi: None. X. Li: None. X. Gao: None. Q. Ji: None. H. Tian: None. Q. Su: None. Z. Zhou: None. W. Wang: None. Z. Zhou: None. X. Li: None. Y. Xu: None. Z. Ning: None. X. Lu: None. W. Jia: None. Funding Ministry of Science and Technology of the People´s Republic of China (2013ZX09401301)

Rheumatoid arthritis (RA) is a representative autoimmune disease characterized by chronic inflammation and joint destruction. Although biological inhibitors such as TNF-α and IL-6 antibodies have achieved success in clinical therapy, small molecule inhibitors against the Janus kinases (JAKs) involved in the signaling pathways of various cytokine receptors have gained more attraction as safe and efficacious options. In this study, we identified CS12192 as a novel selective JAK3/JAK1/TBK1 inhibitor and investigated its pharmacological effects on the experimental arthritis models in rat and mouse. We found that CS12192 showed a more selective inhibitory activity on JAK3, and to a less extent on JAK1 and TBK1, that were verified by decreased activation of p-STATs and p-IRF3 as well as down-regulation of IFN gene expression in the cultured cells with relevant stimuli. Furthermore, oral treatment with CS12192 dose-dependently ameliorated the disease severity, hind paw swelling, body weight loss, and bone destruction in rat models of adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In a mouse CIA model, CS12192 also attenuated the disease severity, which was correlated with the suppressed CD4+ T cell activation and Th17 function, as well as the reduced cytokine levels in sera and pro-inflammatory cytokine and chemokine gene expression in joint tissue. Corroboratively, RANKL-induced osteoclast formation was inhibited by CS12192. Thus, these results suggest that CS12192 as a novel selective JAK inhibitor has therapeutic potential for the treatment of RA and may provide a new strategy for the control of autoimmune diseases.

Long non-coding RNAs (lncRNAs) are functional components of the human genome. Recent studies have demonstrated that lncRNAs play essential roles in tumorigenesis, and are involved in cell proliferation, apoptosis, migration and invasion in several types of tumor, including lung cancer. However, the clinical relevance of lncRNA expression in lung cancer remains unknown. The aim of the present study was to investigate the expression pattern of RFPL3 antisense (RFPL3S) and its associations with clinicopathological characteristics in patients with lung cancer. Whether RFPL3S can act as a potential prognostic biomarker for lung cancer was also investigated. RFPL3S expression in tumor samples and cells was assessed using the Oncomine database and the Cancer Cell Line Encyclopedia, respectively. Based on Kaplan-Meier Plotter analyses, the prognostic values of RFPL3S were further evaluated. It was revealed that RFPL3S was highly expressed in lung cancer tissues when compared with normal tissues and was significantly associated with pN factor, pTNM stage and Ki-67 labeling index. In the survival analyses, increased RFPL3S expression was associated with poor survival and was inversely associated with first progression in all patients. These results indicate that RFPL3S may be of clinical significance and may act as a prognostic biomarker in lung cancer.

Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase inhibitor. In an exploratory study, the combination of tucidinostat with exemestane showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone receptor-positive breast cancer. To build on these findings, we aimed to assess the efficacy and safety of this combination in a randomised trial in a larger population of postmenopausal patients with advanced, hormone receptor-positive breast cancer.We did the randomised, double-blind, placebo-controlled, phase 3 ACE trial at 22 specialist cancer centres in China. Eligible patients were postmenopausal women (aged ≥60 years or aged60 years if their serum follicle-stimulating hormone and oestradiol concentrations were within postmenopausal ranges) with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate haematological and biochemical parameters. Endocrine therapy did not have to be the most recent therapy before randomisation, but recurrence or progression after the most recent therapy was a prerequisite. Patients were randomly assigned (2:1) by a dynamic randomisation scheme via an interactive web-response system to receive 30 mg oral tucidinostat or placebo twice weekly. All patients in both groups also received 25 mg oral exemestane daily. Randomisation was stratified according to the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy analyses were done in the full analysis set population, comprising all patients who received at least one dose of any study treatment, and safety analyses were done in all patients who received at least one dose of any study treatment and for whom at least one safety case report form was available. This study is registered with ClinicalTrials.gov, number NCT02482753. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing.Between July 20, 2015, and June 26, 2017, 365 patients were enrolled and randomly assigned, 244 to the tucidinostat group and 121 to the placebo group. The median duration of follow-up was 13·9 months (IQR 9·8-17·5). Investigator-assessed median progression-free survival was 7·4 months (95% CI 5·5-9·2) in the tucidinostat group and 3·8 months (3·7-5·5) in the placebo group (HR 0·75 [95% CI 0·58-0·98]; p=0·033). The most common grade 3 or 4 adverse events in either group were neutropenia (124 [51%] of 244 patients in the tucidinostat group vs three [2%] of 121 patients in the placebo group), thrombocytopenia (67 [27%] vs three [2%]), and leucopenia (46 [19%] vs three [2%]). Serious adverse events of any cause occurred in 51 (21%) of 244 patients in the tucidinostat group and seven (6%) of 121 patients in the placebo group. No treatment-related deaths were reported.Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3-4 haematological adverse events were more common in the tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients.Chipscreen Biosciences.

Background Chiauranib is a novel orally active multi-target inhibitor that simultaneously inhibits the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα, and c-Kit), mitosis-related kinase Aurora B, and chronic inflammation-related kinase CSF-1R. This phase I dose-escalation study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor activity of chiauranib in patients with refractory advanced solid tumor and lymphoma. Methods Eighteen patients were treated with continuous dosing of chiauranib from 10 to 65 mg once daily in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Pharmacokinetic profile of plasma chiauranib was analyzed in both single and multiple dose studies. Results Dose-limiting toxicity (DLT) as of grade 3 hypertension occurred in two patients at 65 mg/day, and one dose level below as MTD was 50 mg/day. The most common treatment-related adverse events included fatigue (61.1%), proteinuria (44.4%), hematuria (38.9%), hypothyroidism (38.9%), hypertriglyceridemia (33.3%), and hypertension (33.3%). A linear and dose-dependent pharmacokinetic profile of chiauranib was characterized with rapid absorption and slow elimination feature in both single and multiple dose studies. The accumulative exposure of chiauranib reached the steady state within 8 days and was approximately increased by twofold as those in the single dose study. No complete or partial response was observed, and 12 patients (66.7%) achieved stable disease (SD). Conclusions Chiauranib demonstrated an acceptable safety and favorable pharmacokinetic profile with potential antitumor activity. Several phase Ib/II clinical studies are currently under further investigation. Trial registration NCT, NCT02122809. Registered 25 April 2014

Background: Chidamide is an oral subtype-selective histone deacetylase (HDAC) inhibitor that demonstrated encouraging anti-tumour activity when combined with exemestane in hormone-receptor (HR)-positive advanced breast cancer patients. The current study aimed to assess the efficacy and safety of chidamide plus exemestane in postmenopausal patients with advanced, HR-positive breast cancer. Methods: In this phase 3 trial, we compared chidamide and exemestane versus placebo and exemestane in 365 postmenopausal patients (randomised as a 2:1 ratio) with HR-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had relapsed or progressed after previous endocrine therapy. The primary end point was progression-free survival, as assessed by the investigators. Secondary end points included overall survival, objective response, clinical benefit rate, and safety. Findings: The median progression-free survival on the basis of investigator assessment was 7·4 months (95% CI 5·5-9·2) in the chidamide group versus 3·8 months (95% CI 3·7-5·5) in the placebo group (HR 0·75, 95% CI 0·58-0·98; p=0.034). The median progression-free survival was 9.2 months and 3.8 months, respectively, according to central assessment (HR 0·71, 95% CI 0·53-0·96; p=0.024). Objective response rates were 18% and 9% (p=0·026), and clinical benefit rates were 47% and 36% (p=0·034) in the chidamide group and placebo group, respectively. The most common grade 3 or 4 adverse events in the chidamide group were neutropenia (51% vs. 3% in the placebo group), thrombocytopenia (27% vs. 3%), and leucopenia (19% vs. 3%). Serious adverse events occurred in 51 (21%) patients in the chidamide group and 7 (6%) patients in the placebo group. No treatment related death was reported. Interpretation: This is the first phase 3 trial to demonstrate that a selective HDAC inhibitor plus endocrine blockade improves progression-free survival in patients with HR-positive advanced breast cancer progressing after prior endocrine therapy. Trial Registration Number: This study is registered with ClinicalTrials.gov, number NCT02482753. Funding: Chipscreen Biosciences Declaration of Interest: ZN and XP are employees of Chipscreen Biosciences Ltd. The other authors declare no competing interests. Ethical Approval: The Ethics Committee at each participating centre approved the study which was conducted in accordance with the principles of Good Clinical Practice, the Declaration of Helsinki and the regulations of China.

Background: Chiglitazar is a novel PPARα/γ/δ pan-agonist with moderate transcriptional activities. Phase 2 studies demonstrated that chiglitazar had significant effects on glycemic control and lipid modulation in patients with type 2 diabetes. The current CMAP study aimed to assess the efficacy and safety of chiglitazar compared with placebo in type 2 diabetes patients who had not previously received anti-diabetic treatment. Methods: This study was a double-blind and placebo-controlled phase 3 trial conducted at 26 centres in China. Eligible patients were 18-70 years old, type 2 diabetes with HbA1c ≥7*5% and ≤10*0% and without previous anti-diabetic treatment. Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or placebo once daily. The primary endpoint was change in HbA1c at week 24 with superiority of chiglitazar to placebo. Findings: Between June 17, 2014, and Oct 13, 2016, 535 patients were randomly assigned to receive chiglitazar 32 mg (n=167), 48 mg (n=166), or placebo (n=202). In the primary LOCF analysis in the full-analysispopulation, both chiglitazar doses were superior to placebo for HbA1c reduction at week 24, with the mean differences between chiglitazar 32 mg or 48 mg versus placebo were -0*87% [95% CI -1*10 to -0*65] or -1*05% [- 1*29 to -0*81], respectively. Overall frequency of adverse events and study discontinuation attributable to adverse events were similar among groups. Serious adverse events were reported for seven (3%) in the placebo group, four (2%) in the chiglitazar 32 mg group, and eight (5%) in the chiglitazar 48 mg group. A small increased mild edema events and body weight gain was reported in the chiglitazar dose groups. Interpretation: The PPAR pan-agonist chiglitazar had significant and clinically relevant improvements in glycaemic control in patients with type 2 diabetes, with no unexpected safety findings. Trial Registration: This study is registered with clinicaltrials.gov number NCT02121717. Funding Statement: Chipscreen Biosciences. This study was partly supported by grants from Chinese National and Provincial Major Project for New Drug Innovation (National: 2008ZX09101-002, 2013ZX09401301; Provincial: 2011A080501010) and Shenzhen Municipal Major Project (2010-1746). Declaration of Interests: ZN, HC, DP, HY and XL are employees of Chipscreen Biosciences Ltd. The other authors declare no competing interests. Ethics Approval Statement: The study complied with the Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by institutional review boards and independent ethics committees for participating centers. All participants provided written informed consent.

// Zhi-Qiang Ning 1, * , Hai-lin Lu 1, * , Chao Chen 1, * , Lin Wang 2, * , Wei Cai 1 , Yan Li 1 , Ting-hua Cao 1 , Jing Zhu 1 , Yong-Qian Shu 3, 4 , Hua Shen 3, 4 1 Department of Oncology, The First People's Hospital of Wujiang District, Suzhou, 215200, China 2 Institute of Medcine, University of Zhengzhou, Henan Province, 450000, China 3 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China 4 Collaborative Innovation Center for Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China * These authors contributed equally to this work Correspondence to: Hua Shen, email: medshenhua@126.com Yong-Qian Shu, email: shuyongqian1999@126.com Keywords: miRNA-30e, chemosensitivity, gefitinib, HOXA1, lung cancer Received: May 28, 2016 Accepted: December 06, 2016 Published: December 15, 2016 ABSTRACT MicroRNAs (miRNAs) play critical roles in variousbiological processes,including malignancy. Here, we demonstrated that miR-30e levels were markedly reduced in human lung carcinoma specimens in comparisonwith adjacent normal tissues.In addition, miR-30eamounts were starkly lower in the resistant PC9/gefitinib (PC9G) cancer cells compared with PC9 cells. Meanwhile, miR-30eoverexpression inPC9G cells resulted in reduced cell proliferation and migration,reversing drug resistance to gefitinib.Conversely,miR-30e silencing in PC9 cells increased proliferation as well as migration, and conferred resistance to gefitinib.Moreover, HOXA1, which was identified asa new miR-30etarget, plays important roles in regulating cell fate, early developmental patterns and organogenesis.Importantly, miR-30ealso inhibited PC9G growth in vivo . Taken together, these findings demonstrated that miR-30eshould be considered a tumor suppressor miRNA, which could be used in treatinghuman lung cancer.

Purpose The present review aimed to assess the role of exosomal miRNAs in cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancer cells. The roles of exosomal miRNAs and miRNA dysregulation in CAF formation and activation were summarized. Methods All relevant publications were retrieved from the PubMed database, with key words such as CAFs, CAF, stromal fibroblasts, cancer-associated fibroblasts, miRNA, exosomal, exosome, and similar terms. Results Recent studies have revealed that CAFs, NFs, and cancer cells can secrete exosomal miRNAs to affect each other. Dysregulation of miRNAs and exosomal miRNAs influence the formation and activation of CAFs. Furthermore, miRNA dysregulation in CAFs is considered to be associated with a secretory phenotype change, tumor invasion, tumor migration and metastasis, drug resistance, and poor prognosis. Conclusions Finding of exosomal miRNA secretion provides novel insights into communication among CAFs, NFs, and cancer cells. MicroRNA dysregulation is also involved in the whole processes of CAF formation and function. Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells.

Shikonin is a kind of naphthoquinone compound found mainly in Lithospermum erythrorhizon Sieb,et Zucc. Previous studies have shown that Shikonin has anti-tumor, anti-inflammatory and extensive pharmacological effects. According to new studies, Shikonin could also modulate the immune system function, but the effect to NK (nature killer) cells is yet unknown.To investigate the effect and mechanism of Shikonin on NK cells proliferation and cytotoxicity to colon cancer cell line (Caco-2).The proliferation and cytotoxicity of NK cells cultured with Shikonin were detected with CCK-8 assay. The expressions of perforin, GranB and IFN-γ were examined with FCM. The content of TNF-alpha was disclosed with ELISA kit. p-ERK1/2 and p-Akt expression of NK cells were detected with western blot.With CCK-8 assay, it is found that Shikonin could significantly enhance NK cells proliferation and cytotoxicity to colon cancer cells. With FCM assay, it is found that Shikonin could improve the expression of perforin and GranB in a dose-dependent manner. Shikonin had no effect on TNF-alpha and IFN-γ expression. In mechanism, the study shows that Shikonin could enhance the expression of p-ERK1/2 and p-Akt.Shikonin enhances NK cells proliferation and cytotoxicity via the improvement of perforin, GranB, p-ERK1/2 and p-Akt expression.

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

Tumorigenesis is maintained through a complex interplay of multiple cellular biological processes and is regulated to some extent by epigenetic control of gene expression. Targeting one signaling pathway or biological function in cancer treatment often results in compensatory modulation of others, such as off-target drivers of cell survival. As a result, overall survival of cancer patients is still far from satisfactory. Epigenetic-modulating agents can concurrently target multiple aberrant or compensatory signaling pathways found in cancer cells. However, existing epigenetic-modulating agents in cancer treatment have not yet fully translated into survival benefits beyond hematological tumors. In this article, we present a historical rationale for use of chidamide (CS055/Epidaza), an orally active and subtype-selective histone deacetylase (HDAC) inhibitor of the benzamide chemical class. This compound was discovered and successfully developed as mono-therapy for relapsed and refractory peripheral T cell lymphoma (PTCL) in China. We discuss the evidence supporting chidamide as a durable epigenetic modulator that allows cellular reprogramming with little cytotoxicity in cancer treatments.

Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC₅₀ = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.

1 The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipidlowering effect is mediated through its activation of PPARa. 2 Chiglitazar is a PPARa/g dual agonist. 3 The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4 Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5 Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARa, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6 These data suggest that PPARa/g coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARg agonists.

e12543 Background: Chidamide (CHI) is a novel benzamide type of subtype-selective histone deacetylase inhibitor approved in China for refractory and relapsed peripheral T-cell lymphoma with a dosage of 30 mg PO twice a week. A randomized, double blind and placebo-controlled phase 3 clinical trial of CHI plus exemestane (EXE) is currently ongoing in patients (pts) with hormone receptor-positive (HR+) advanced breast cancer (ABC). This abstract reports the results from the pilot study preceded the phase 3 trial. Methods: Eligible pts were postmenopausal women recurrent or progressed to at least one endocrine therapy. In the run-in period for pharmacokinetic (PK) analysis, pts received EXE 25 mg on day (D) 1 and CHI 30 mg on D 2. From D 5 pts started combination treatment having EXE 25 mg daily and CHI 30 mg twice a week until progression of disease (PD) or intolerable toxicities. A treatment cycle was defined as 28 days. Safety, PK parameters and preliminary efficacy were assessed. Results: 20 pts with HR+ and HER-2 negative were enrolled between Jul and Dec, 2015. Median duration of treatment was 5 cycles (range 0-16), with 4 pts still on treatment. 3 pts discontinued due to adverse events (AE). Drug-related AEs ≥ grade 3 in 2 or more pts were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). Similar plasma exposure of EXE was observed in the absence and presence of CHI ( 73 ± 27 vs. 80 ± 29 ng·hr/mL). A potential increased plasma exposure of CHI was noted in the presence of EXE compared with CHI alone ( 2232 ± 973 vs 1787 ± 946 ng·hr/mL), apparently related to the inter-patient variations in CHI plasma concentrations. Best response in 18 pts was assessed by RECIST, including 3 pts with partial response, 12 pts with stable disease and 3 pts with PD. Median progression free survival was 7.6 months. Conclusions: The combination of CHI and EXE was generally well tolerated. Most AEs were related to the CHI single-agent treatment that are generally manageable. Encouraging antitumor activity was observed. The overall results from this pilot trial enabled the next-stage clinical development of this combination regimen in HR+ ABC pts. Clinical trial information: NCT02482753.

Lipid accumulation in nonadipose tissues is increasingly linked to the development of type 2 diabetes in obese individuals. We report here the design, synthesis, and evaluation of a series of novel PPARalpha selective activators containing 1,3-dicarbonyl moieties. Structure-activity relationship studies led to the identification of PPARalpha selective activators (compounds 10, 14, 17, 18, and 21) with stronger potency and efficacy to activate PPARalpha over PPARgamma and PPARdelta. Experiments in vivo showed that compounds 10, 14, and 17 had blood glucose lowering effect in diabetic db/db mouse model after two weeks oral dosing. The data strongly support further testing of these lead compounds in other relevant disease animal models to evaluate their potential therapeutic benefits.