Serum Macrophage Inhibitory Cytokine-1 Research Articles

Population Pharmacokinetic and Pharmacodynamic Analysis of Navtemadlin in Patients with Relapsed and Refractory (R/R) Myelofibrosis (MF) and Other Myeloid or Solid Tumor Malignancies

Background:Murine double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, is overexpressed in malignancies such as MF and Merkel cell carcinoma (MCC). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumors. Navtemadlin has been tested in 21- or 28-day treatment cycles, with 5 or 7 consecutive days of dosing per cycle. Navtemadlin elicits plasma concentration-dependent increases in serum macrophage inhibitory cytokine-1 (MIC-1). An increase in MIC-1 relative to baseline MIC-1 serum concentration is a key pharmacodynamic (PD) marker of response to navtemadlin treatment (Zhang et al. Xenobiotica 2022). A population pharmacokinetic (PK) model was developed, based on patients with R/R MF (N=113, NCT03662126); MCC (N=35, NCT03787602); solid tumors and multiple myeloma (ST/MM N=105, Gluck et al. Invest New Drugs 2019); R/R acute myeloid leukemia (AML, N=35, Erba et al. Blood Adv 2019); and healthy volunteers (HV, N=30, Wong et al. Clin Pharmacol Drug Dev 2022).The objectives wereto characterize navtemadlin PK and covariate effects and compare steady-state (SS) PK and PD across cancer types. Methods:A two-compartment PK model with first-order absorption and elimination was estimated using NONMEM ® (first-order conditional estimation with interaction). Four transit compartments captured absorption. Inter-subject variability was modeled as lognormal. A stepwise covariate search used forward addition (p<0.05) followed by backward elimination (p<0.01). Log-transformed SS MIC-1 ratio to baseline (fold ratio) was tested in a fixed-effects linear regression model with respect to SS exposures, with baseline MIC-1 as the covariate. The final population PK and MIC-1 models were evaluated by inspection of parameter tables, by overlaying model predictions with observed data, and by standard residual diagnostics. Results:The PK estimation used 5,282 concentrations from 318 subjects, including 1,415 concentrations in 113 patients with R/R MF. Tumor type affected absorption rate (median, 0.635/hr in MCC; slower vs other types), apparent clearance (median, 8.90 L/hr in MCC; lower vs other types), and apparent central volume (median, 64.4 L in MCC; similar to AML, but lower vs other types) (Table 1). Accordingly, simulated SS area under the curve (AUCss) differed across populations in the order MCC>AML>MF>ST/MM = HV (Figure 1). Covariate analysis indicated median AUC increased with the inflammation marker C-reactive protein, by 21% at 90 th percentile CRP, and with age, by 5% at 90 th percentile age of 75 y, compared to the median, 66 y. Men had 24% lower relative bioavailability than women. Taking navtemadlin with food slowed absorption by 10% but had no impact on AUCss. Other tested covariates, including body weight, creatinine clearance, aspartate transaminase, alanine transaminase, bilirubin, albumin, alpha 1-acid glycoprotein, race, UGT1A1 genotype, recent ruxolitinib treatment in MF, and CYP3A4 inducer/inhibitor concomitant medications, were not significant. Median MIC-1 fold ratio increased with navtemadlin AUCss. Higher baseline MIC-1 resulted in lower SS MIC-1 fold ratio. Median baseline MIC-1 differed by tumor type. In R/R MF, baseline MIC-1 was 2,297 ng/L and SS fold ratio of MIC-1 was 7.79 (N=91). In MCC, baseline MIC-1 was 1,718 ng/L and SS fold ratio of MIC-1 was 16.7 (N=29). In R/R MF, higher baseline spleen volume was also associated with lower SS MIC-1 fold ratio. Exposure-MIC-1 relationships in R/R MF and MCC were generally similar to other tumor types and HV populations (Allard et al. Hemasphere 2019; Zhang et al. Xenobiotica 2022). Conclusions:Tumor type influenced navtemadlin exposure with simulated exposure in R/R MF patients at the selected Phase 3 dose of 240 mg comparable to exposures in MCC patients at 180 mg, the selected Phase 2 dose for that indication. Cancer-associated inflammation and/or treatment history, as well as age and female sex, may increase navtemadlin exposure. The PD marker MIC-1 responds to navtemadlin in a concentration-dependent fashion. The overall SS fold change of MIC-1 PD responses was lower in disease states or subjects with higher baseline MIC-1. These studies demonstrate potent, dose-dependent PK/PD responses following p53 activation with the novel MDM2 inhibitor, navtemadlin, across diverse tumor types.

136 (PB126) - ALRN 6924 induces cell cycle arrest in bone marrow stem cells and hair follicles with dose-dependent degree and duration of effects after a single infusion in healthy volunteers

Background: ALRN-6924 is a cell-permeating, stabilized alpha-helical peptide that binds to endogenous p53 inhibitors MDMX and MDM2, thereby activating p53 and its transcriptional target p21 to cause cell cycle arrest (CCA). This effect is limited to cells with wild-type, functional p53. For cancer patients with tumors bearing mutated p53, ALRN-6924 treatment selectively induces CCA in normal cells, allowing chemotherapy to preferentially target p53-mutant cancer cells that are actively cycling. Materials and methods: A Phase 1 study in heathy volunteers is being conducted to evaluate ALRN-6924 pharmacokinetics (PK) and pharmacodynamics (PD). In Part 1 (37 subjects; Voors-Pette et al, ESMO 2021) it was shown that a 1-hour intravenous (IV) ALRN-6924 infusion was safe, well tolerated, and transiently upregulates p21 in human bone marrow (BM) cells with minimal signal for apoptosis. In Part 2, we aim to directly measure dose-dependent CCA in the BM as well as in hair follicles (HFs) in female subjects across a range of doses by 1-hour IV infusion and 3-minute bolus IV injection. ALRN-6924 was administered as a single IV infusion or bolus injection at 0 (placebo), 0.3, 0.6, or 0.9 mg/kg to cohorts of 3 to 5 subjects. Subjects were evaluated for safety and tolerability. Plasma and serum samples were obtained to determine PK and levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation. BM was sampled 12 hours post-dose to directly measure CCA by flow cytometry in CD34+, lineage-negative BM stem cells. Occipital scalp skin was sampled by 2 mm punch biopsy for p21 immunohistochemistry in HFs. Results: As of June 20, 2022, 42 subjects (ages 18–59; 100% female) were enrolled and evaluated in Part 2. Subjects experienced only mild, transient adverse events (AEs), with nausea/vomiting as the most frequent related AEs. The degree and duration of serum MIC-1 elevation was dose-dependent. At 12 hours post-dose, the proportion of cycling BM stem cells was significantly reduced at all dose levels, while blinded pathology review suggested ALRN-6924-dependent p21 induction in anagen-phase HFs. Safety profiles, PK and PD were similar for both bolus and infusion. Conclusions: ALRN-6924 shows a favorable safety profile for use as a chemoprotection agent. CCA measured in BM supports prevention of chemotherapy-induced neutropenia, thrombocytopenia, and anemia, while HF results support chemoprotection for alopecia. Administration by IV bolus may simplify dosing vs. the current 1-hr infusion clinical regimen. The dose-dependent degree and duration of effects support development of a universal treatment schedule for broad use across cancer indications and types of chemotherapy. Conflict of interest: Ownership: Manuel Aivado, Vojislav Vukovic, and Allen Annis are employees and shareholders of Aileron Therapeutics Advisory Board: Ulrich Steidl is a member of the Scientific Advisory Board of Aileron Therapeutics Other Substantive Relationships: Britta Will and Kevin Randall are consultants to Aileron Therapeutics

Clinical usefulness and acceleratory effect of macrophage inhibitory cytokine-1 on biliary tract cancer: an experimental biomarker analysis

BackgroundBiliary tract cancer (BTC) has a poor prognosis; therefore, useful biomarkers and treatments are needed. Serum levels of macrophage inhibitory cytokine-1 (MIC-1), a member of the TGF-β superfamily, are elevated in patients with pancreaticobiliary cancers. However, the effect of MIC-1 on BTC is unknown. Therefore, we investigated the effect of MIC-1 on BTC and assessed whether MIC-1 is a biomarker of or therapeutic target for BTC.MethodsMIC-1 expression in BTC cells was determined by performing histological immunostaining, tissue microarray (TMA), western blotting, and reverse transcription PCR (RT–PCR). Cell culture experiments were performed to investigate the effect of MIC-1 on BTC cell lines (HuCCT-1 and TFK-1). The relationships between serum MIC-1 levels and either the disease state or the serum level of the apoptosis marker M30 were retrospectively verified in 118 patients with pancreaticobiliary disease (individuals with benign disease served as a control group, n = 62; BTC, n = 56). The most efficient diagnostic marker for BTC was also investigated.ResultsMIC-1 expression was confirmed in BTC tissue specimens and was higher in BTC cells than in normal bile duct epithelial cells, as determined using TMA, western blotting and RT–PCR. In cell culture experiments, MIC-1 increased BTC cell proliferation and invasion by preventing apoptosis and inhibited the effect of gemcitabine. In serum analyses, serum MIC-1 levels showed a positive correlation with BTC progression and serum M30 levels. The ability to diagnose BTC at an early stage or at all stages was improved using the combination of MIC-1 and M30. The overall survival was significantly longer in BTC patients with serum MIC-1 < the median than in BTC patients with serum MIC-1 ≥ the median.ConclusionsMIC-1 is a useful diagnostic and prognostic biomarker and might be a potential therapeutic target for BTC.

A population pharmacokinetic-pharmacodynamic model of navtemadlin, its glucuronide metabolite (M1) and serum macrophage inhibitory cykokine-1 (MIC-1)

Navtemadlin is a potent, selective, orally available inhibitor of murine double minute 2 that restores p53 activity to induce apoptosis in TP53 wild-type malignancies. Using richly sampled pharmacokinetic (PK) and pharmacodynamic (PD) data from healthy volunteers, a population PK/PD model was developed. A population PK (PPK) model described the PK characteristics of navtemadlin and its major metabolite acyl glucuronide (M1) and quantified enterohepatic recirculation (EHR). Post hoc individual PK parameters from this model were coupled with PD data for serum macrophage inhibitory cytokine-1 (MIC-1, GDF15), a cytokine biomarker of p53 activation, to construct a population PK/PD model that described plasma concentration-driven MIC-1 excursions and enabled simulation of the extent and duration of navtemadlin PD effects. The median apparent clearance (CL/F) and apparent central volume (V2/F) of navtemadlin were 36.4 L/hr and 159 L. The typical maximum stimulatory effect (Smax) was close to the median maximum MIC-1 ratio to baseline of 7.29 in observed data. Simulation revealed a dose-dependent increase of MIC-1 with steady state attained in approximately 7 days, in a 7-day-on/21-day-off dose regimen. Elevated MIC-1 concentrations persist through 17–19 days, leaving about 9-11 PD-free days in a 28-day cycle.

Macrophage inhibitory cytokine-1 produced by melanoma cells contributes to melanoma tumor growth and metastasis in vivo by enhancing tumor vascularization.

Macrophage inhibitory cytokine-1 (MIC-1) has been reported to be elevated in various human cancers including melanoma; however, the function of MIC-1 in cancer remains unclear. In this study, we attempt to clarify the role of MIC-1 in tumor pathogenesis by employing the orthotopic B16F1 melanoma mouse model in which serum MIC-1 levels are positively correlated with tumor size. By stably transfecting a MIC-1 expression construct into B16F1 melanoma cells, we increased the expression and secretion levels of MIC-1. This increase in MIC-1 expression significantly enhanced the growth of tumors derived from B16F1 cells in vivo, despite not affecting in vitro cell growth. The elevated MIC-1 expression in B16F1 cells also resulted in lymph node metastasis in B16F1 tumor-bearing mice, significantly increasing mortality. Interestingly, among small melanoma tumors of similar size, tumors derived from the MIC-1-transfected B16F1 cells exhibited enhanced blood vessel formation compared with those of mock transfectant cells. Also, more MIC-1 was found in well-vascularized tumor regions than in poorly vascularized tumor regions. Moreover, conditioned medium (CM) of the MIC-1-transfected melanoma cells enhanced the angiogenic properties of endothelial cells more than CM of mock transfectant cells. Notably, hypoxic culture conditions forced parental B16F1 cells to secrete more endothelial cell-stimulating factors, among which the function of MIC-1 was confirmed by blocking the effects with an anti-MIC-1 antibody. Taken together, these results suggest that the MIC-1 produced by melanoma cells in response to oxygen deprivation promotes tumor vascularization during melanoma development in vivo, leading to enhanced tumor growth and metastasis.

Alrn-6924, a Dual Inhibitor of MDMX and MDM2, Transiently Induces Cell Cycle Arrest in Bone Marrow and Prevents Toxicity in Mouse Models of Acute Radiation Injury

Background: Myelosuppression is a common sequela of acute radiation injury due to sensitivity of proliferating bone marrow cells to ionizing radiation. ALRN-6924 is a clinical-stage, first-in-class, stabilized cell-permeating alpha-helical peptide drug that disrupts the interaction of the p53 tumor suppressor protein with its endogenous inhibitors, MDMX and MDM2, to induce transient, dose-dependent cell cycle arrest in p53-wild-type tissues. ALRN-6924 is being evaluated in clinical trials as a selective chemoprotection agent for patients with p53-mutant cancers to protect healthy normal cells from chemotherapy while not protecting p53-mutant cancer cells. We tested whether ALRN-6924 may similarly protect against radiation-induced toxicity in mouse models of acute radiation injury.Materials and methods: Activation of p21 (CDKN1A), a cell cycle regulator under transcriptional control of p53, was measured in formalin-fixed mouse bone marrow by immunohistochemistry analysis (IHC). Proliferation and apoptosis in bone marrow were measured by IHC of Ki67 and cleaved PARP, respectively. Cell cycle arrest was measured in the bone marrow of ALRN-6924-treated C57BL/6 mice by flow cytometry using EdU incorporation. Serum levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation, were measured by ELISA. As a model of radiation-induced toxicity, C57BL/6 mice (n=7/group) were treated with one or more intravenous 2.4 mg/kg doses of ALRN-6924 at 24, 16, 8, or 1 hour (or combinations thereof) or placebo prior to a 15 Gy shielded-body radiation dose and then monitored for body weight (BW) changes.Results: ALRN-6924 induced cell cycle arrest in mouse bone marrow with a maximum effect at 8 hrs post-dose. Repeated doses of ALRN-6924 every 8 hrs elevated p21 levels in bone marrow that correlated with reduced Ki67 positivity and increased serum MIC-1 levels. Treatment-dependent changes in cPARP expression in bone marrow were evident, but minimal in magnitude. In a nonlethal radiation exposure model, ALRN-6924 yielded significant protection from radiation-induced BW loss in a schedule-dependent manner. Placebo-treated mice showed 10% to 15% BW loss five days after irradiation, while mice receiving one or more ALRN-6924 doses 8 hrs prior to irradiation had an average of 4% BW loss (p=0.008, two-sided t test).Conclusions: ALRN-6924 mitigated toxicity in a mouse model of acute radiation injury. The observed radioprotection effect was correlated with cell cycle arrest in bone marrow after one or more doses of ALRN-6924. These results support further investigation of ALRN-6924 as a radioprotective agent. DisclosuresAnnis: Aileron Therapeutics, Inc.: Current Employment. Sutton: Aileron Therapeutics, Inc.: Consultancy; Kriya Therapeutics: Consultancy; First Light Pharmaceuticals: Consultancy; Cygnal Therapeutics: Consultancy. Aivado: Aileron Therapeutics, Inc.: Current Employment. Vukovic: Aileron Therapeutics, Inc.: Current Employment.

MP33-06 MACROPHAGE INHIBITORY CYTOKINE-1 INDUCED BY A HIGH-FAT DIET PROMOTES PROSTATE CANCER PROGRESSION BY STIMULATING TUMOR-PROMOTING CYTOKINE PRODUCTION FROM TUMOR STROMAL CELLS

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-06 MACROPHAGE INHIBITORY CYTOKINE-1 INDUCED BY A HIGH-FAT DIET PROMOTES PROSTATE CANCER PROGRESSION BY STIMULATING TUMOR-PROMOTING CYTOKINE PRODUCTION FROM TUMOR STROMAL CELLS Mingguo Huang, Shintaro Narita, Atsushi Koizumi, Taketoshi Nara, Kazuyuki Numakura, and Tomonori Habuchi Mingguo HuangMingguo Huang More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Atsushi KoizumiAtsushi Koizumi More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1 (MIC-1) activation. METHODS: We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated. RESULTS: HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor α-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy. CONCLUSIONS: HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression. Source of Funding: This work was supported by the Japan Society for the Promotion of Science (JSPS, Grant No.: 16H02679, 16K10992, 19K09663) and AMED-CREST, Japan Agency for Medical Research and Development (AMED) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e608-e608 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mingguo Huang More articles by this author Shintaro Narita More articles by this author Atsushi Koizumi More articles by this author Taketoshi Nara More articles by this author Kazuyuki Numakura More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Loading ...

Serum macrophage inhibitory cytokine-1 serves as a novel diagnostic biomarker of early-stage colorectal cancer

Background Patients with colorectal cancer usually have a poor prognosis because of the absence of suitable biomarkers for diagnosing asymptomatic patients. Here we determined the ability of MIC-1 to detect precancerous lesions and CRC in an asymptomatic cohort from CRC Screening Program. Methods We screened 2759 subjects with risk factors. Endoscopic and histopathological analyses revealed that 19 and 47 subjects had CRC or precancerous lesions. We randomly selected 24 subjects with normal colonoscopies as healthy controls. We used receiver operating characteristic curve analysis to evaluate the diagnostic efficacy of MIC-1 for CRC and precancerous lesions. Results The optimal thresholds of MIC-1 levels with precancerous lesions or CRC were 314.12 pg/mL (sensitivity, 91.50%; specificity, 54.20%) and 357.64 pg/mL (sensitivity, 82.40%; specificity, 70.80%). Moreover, MIC-1 levels distinguished precancerous lesions better than CEA, CA19-9, or CA24-2 (AUC: 0.760 vs. 0.529, 0.624, and 0.585) or CRC (AUCs: 0.821 vs. 0.743, 0.657, and 0.688) from the healthy controls. The combination of MIC-1, CEA, CA19-9, and CA24-2 showed the highest in sensitivity and specificity for CRC diagnosis (sensitivity, 94.10%; specificity, 87.50%). Conclusions Serum MIC-1 levels increased the sensitivity of detection of precancerous colorectal lesions and CRC and can be used to improve screening.

Macrophage inhibitory cytokine-1 induced by a high-fat diet promotes prostate cancer progression by stimulating tumor-promoting cytokine production from tumor stromal cells.

BackgroundRecent studies have indicated that a high‐fat diet (HFD) and/or HFD‐induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine‐1 (MIC‐1) activation.MethodsWe investigated the effects of HFD on PCa stromal microenvironment and MIC‐1 signaling activation using PC‐3M‐luc‐C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC‐1 signaling on human PCa stroma activation and progression were also investigated.ResultsHFD stimulated PCa cell growth and invasion as a result of upregulated MIC‐1 signaling and subsequently increased the secretion of interleukin (IL)‐8 and IL‐6 from prostate stromal fibroblasts in PC‐3M‐luc‐C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC‐1 production from PC‐3 cells and IL‐8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC‐1 was significantly correlated with human PCa stroma activation, high serum IL‐8, IL‐6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial‐derived neurotrophic factor receptor α‐like (GFRAL), a specific receptor of MIC‐1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy.ConclusionHFD‐mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC‐1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity‐induced PCa progression.

Effect of Food on MDM2 Inhibitor KRT-232 Pharmacokinetics and Macrophage Inhibitory Cytokine-1 (MIC-1) Response in Healthy Volunteers

Background: KRT-232 is a potent, selective, orally available, small-molecule drug that binds to mouse double minute 2 homolog (MDM2) and inhibits its interactions with tumor suppressor protein p53. KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia, and Merkel cell carcinoma. Increased serum MIC-1 (pg/mL) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with KRT-232 (Allard,HemaSphere, 2020;4:S1, Abstract EP519). The aim of this study was to assess the safety and effect of a high-fat meal on KRT-232 pharmacokinetics (PK) and MIC-1 PD of a new tablet formulation in healthy volunteers. This is the first characterization of a MDM2-inhibitor-induced MIC-1 response in healthy volunteers. Methods: KRT-232-105 was a single-center, open-label, 60-mg single-dose, 3-treatment, 4-period, and 3-sequence study with a partial replicate crossover design. Volunteers (N=30) were randomized to three treatment groups: A: new tablet, fasted (reference, dosed twice in Periods 2-4); B: new tablet, 30 min after a high-fat, high-calorie meal (test 1, dosed once in periods 2-4); C: current tablet, fasted (test 2, period 1 only). Plasma KRT-232, its acyl glucuronide metabolite (M1) and serum MIC-1 concentrations were measured over 0-96 h. Urine from group C was collected over 0-48 h. Doses were one week apart. All volunteers had aH pyloribreath test and were genotyped for UGT1A1*28 polymorphisms. Results: Volunteers were 43% female, 7% African American and 77% Hispanic/Latino. Mean age was 38.1 y (range, 18-54), and mean body mass index was 26.9 kg/m2 (range, 21.4-30.9). No deaths, serious adverse events (SAEs), or discontinuations were reported. Twenty-one treatment-emergent AEs (TEAEs) were observed in 13 (43%) volunteers; constipation was the most frequent AE, followed by headache. All TEAEs were grade 1 (n=17) or grade 2 (n=4: 1 headache event [possibly study drug-related] and 3 events of headache, influenza-like illness, and pharyngitis). Mean (SD) concentration-time plots of KRT-232 and M1 were similar across the 3 groups (Figure 1a and b). A second peak was observed, consistent with enterohepatic recirculation. With a meal (test 1), KRT-232 geometric least-squares mean (GLSM) maximum concentration (Cmax) was similar (431 and 442 ng/mL (GLSM ratio [90% CI], 103% [87.4-121]) and KRT-232 GLSM area under the curve (AUC0-t) decreased from 2858 to 2325 ng∙h/mL (GLSM ratio [90% CI], 81.4 [76.2-86.9]). Median time of Cmax (Tmax) was 2 h fasted and 3 h fed. Geometric mean half life (t1/2) was unchanged (17.0 vs 17.1 h). Under fasting conditions, the current tablet (C, test 2) vs new tablet (A, reference), KRT-232 GLSM Cmax decreased from 431 to 337 ng/mL (GLSM ratio [90% CI], 78.4% [72.0-85.3]) and KRT-232 GLSM AUC0-t had a possible small decrease (2858 and 2455 ng∙h/mL, GLSM ratio [90% CI], 85.9 [80.5-91.7]). Median Tmax (~2 h) and geometric mean t1/2 (17 h) were unchanged. The fraction of the KRT-232 dose in urine as KRT-232 and M1 was negligible at 0.0201% and 0.0220% of dose, respectively. KRT-232 is a carboxylic acid with pH-dependent solubility that increases with increasing pH.H pyloriinfection, which can increase stomach pH, did not have any discernable impact on KRT-232 PK. KRT-232 and M1 exposure in heterozygous UGT1A1*28 poor metabolizers (6/7 TA repeats, N=16) was generally comparable to exposure in wild-type (WT) UGT1A1*28 (6/6 TA repeats, N=12) subjects. MIC-1 concentrations in serum were variable and followed the PK time course with a median Tmax lag of ~8-12 h. Group A: Mean Cmax 2115 pg/mL, C0 (Baseline) 170 pg/mL, AUC0-T 89267 pg*h/mL and mean t1/2 27 h. MIC-1 Cmax and AUC were generally comparable over 96 h across groups (Figure 1c).Figure 1dshows the statistically significant correlation between KRT-232 AUC0-t and MIC-1 AUC0-t. Conclusions: Based on generally comparable PK, KRT-232 can be administered with or without food, and no dose adjustment is warranted with a new tablet formulation. KRT-232 PK was not affected byH pylori, inferring that higher gastric pH did not alter absorption of KRT-232. KRT-232 exposure in UGT1A1*28 heterozygous poor metabolizers was generally comparable to WT UGT1A1*28 wild type healthy volunteers. The 60-mg KRT-232 dose elicited a reproducible and robust MIC-1 response that correlated with KRT-232 exposure, indicating MDM2-p53 target engagement. Disclosures Wong: Kartos Therapeutics:Current Employment;AbbVie Biotherapeutics:Ended employment in the past 24 months.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Lee:Kartos Therapeutics:Current Employment.Harris:Gilead Sciences:Current equity holder in publicly-traded company;Kartos Therapeutics:Current Employment, Current equity holder in private company;BeiGene:Ended employment in the past 24 months;Clovis:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Simard:Certara:Current Employment;AltaScience:Ended employment in the past 24 months.Wang:Certara:Current Employment.Rubets:Certara:Current Employment.Allard:Certara:Consultancy, Ended employment in the past 24 months;CytomX Therapeutics:Ended employment in the past 24 months;Telios Pharma:Current Employment, Current equity holder in private company.Podoll:IV/PO, LLC:Consultancy.O'Reilly:Celerion:Current Employment.Slatter:Amgen:Divested equity in a private or publicly-traded company in the past 24 months;Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor.

Circulatory MIC-1 as a Determinant of Prostate Cancer Racial Disparity.

Simple SummaryAfrican American men are diagnosed with more aggressive prostate cancer and have worse outcomes than Caucasians. This study examined the role of MIC-1 as a risk factor and demonstrated a conceptual observation for the differential level of MIC-1 in circulation (serum and urine) and tumor tissues from prostate cancer patients of racial disparity. The circulatory MIC-1 levels in serum and urine are significantly higher in prostate cancer patients of African American ethnicity, with higher sensitivity and specificity than Caucasians. The validation of circulatory MIC-1 in a larger cohort of patients may help identify high-risk prostate cancer patients and develop race-oriented therapies to reduce the observed cancer outcome gaps between the races.In this study, we investigated the potential of MIC-1 (macrophage inhibitory cytokine-1) on the severity of prostate cancer between African American men and Caucasians. Differences between the races were examined using Mann–Whitney tests for continuous variables and Fisher’s exact tests for categorical variables. Pearson’s correlation coefficient was used to identify associations between continuous measures across all samples and within each race. Analysis of variance, including clinical parameters, was used to identify differences in serum and urine MIC-1 levels between races. We found significant differences between the two races for age (p = 0.01), Gleason scores (p = 0.01), and stage of disease (p = 0.03). African American men in the study had higher Gleason scores (mean = 6.9) than Caucasians (mean = 6.5), during earlier stages of the disease. In Caucasian men with prostate cancer, serum MIC-1 expression was positively associated with age (r = 0.7, p < 0.01). However, African American men had highly expressed MIC-1 and high Gleason scores (r = 0.16, p = 0.3). Interestingly, the urine MIC-1 level was significantly higher in African American men with prostate cancer than in Caucasian patients. It appeared to be more sensitive and specific for African Americans (AUC = 0.85 vs. 0.56). Thus, high circulatory MIC-1 in prostate cancer patients may indicate MIC-1 as a potential biomarker to improve the diagnostic ability of an aggressive stage of prostate cancer in African American men. However, a larger cohort of sample analysis is required to validate these observations.

Phase Ib study of a novel, small-molecule MDM2 inhibitor APG-115 combined with pembrolizumab in U.S. patients with metastatic solid tumors.

3512 Background: APG-115 activates p53-mediated apoptosis in tumor cells retaining wild-type TP53. It also functions as a host immune modulator and enhances antitumor activities when combined with PD-1 blockade preclinically. MDM2 amplification is associated with hyperprogression in patients treated with checkpoint inhibitors. Methods: The Phase Ib / II study was designed to evaluate APG-115 combined with pembrolizumab in patients with metastatic solid tumors (NCT03611868). APG-115 was administered orally every other day for 2 weeks, at dose ranging from 50 mg – 200 mg, with pembrolizumab at 200 mg IV on Day 1 of a 21-day cycle. Study objectives were to assess safety including dose-limiting toxicity (DLT), serious adverse events (SAEs), treatment-related AEs (TRAEs), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed by RECIST v1.1), to determine recommended phase 2 dose (RP2D). Results: As of December 25, 2019, the enrollment of phase 1b study was completed. Total 19 patients had been treated in four APG-115 cohorts: 50 mg (n = 3), 100 mg (n = 3), 150 mg (n = 6), and 200 mg (n = 7). No DLT was observed, The TRAEs (≥15%) were nausea (47.4%), fatigue (36.8%), decreased platelet count (26.3%), and decreased appetite (21.1%), as well as diarrhea, vomiting, decreased neutrophil or white blood cell count, and hypothyroidism in 15.8% each. Grade &gt; 3 TRAEs included decreased neutrophil and thrombocytopenia in 15.8% each. Two SAEs were treatment related: G3 febrile neutropenia and G3 adrenal insufficiency. No new safety finding from combination with Pembrolizumab. The RP2D of APG-115 was 150 mg. One patient with ovarian cancer has a CR lasting for 15 months, 2 patients had PR for 8-9 months: one NSCLC failed IO therapy, another with appendix cancer, and 7 had SD for 1.5-7 months. The objective response rate was 15.8%, and the disease control rate (DCR) was 52.6%. PK data indicated an approximately dose-proportional increase in APG-115 exposure over the range of 50-200 mg on Day 1. PD-PK analyses showed that serum macrophage inhibitory cytokine-1 (MIC-1) increase was time and dose dependent, the MIC-1 elevation correlated with APG-115 exposure, indicating p53 activation in these patients. Conclusions: APG-115 in combination with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in several tumor types. The phase II study is ongoing in the cancer patients with specific bio-marker profiling. Clinical trial information: NCT03611868 .

Phase I study results of APG-115, a MDM2-p53 antagonist in Chinese patients with advanced liposarcoma and other solid tumors.

11542 Background: APG-115 is a potent, small-molecule MDM2 inhibitor and immune modulator with promising antitumor activities in various tumors, especially those wild-type TP53 with MDM2 amplification ( TP53wt+MDM2 amp). To better delineate safety, optimal dosage, and potential target population, we report updated results. Methods: Patients with advanced liposarcoma and other solid tumors received APG-115 (100-200 mg) orally every other day for 21 days of a 28-day cycle. The primary endpoints were safety and tolerability. Efficacy (assessed by RECIST v1.1), pharmacokinetics (PK) and pharmacodynamics (PD) have also been analyzed. Results: Enrollment of this Phase I study (CTR20170975) was completed. As of January 7, 2020, 21 patients (14 liposarcomas, 2 synovial sarcomas, 2 adenoid cystic carcinomas, 1 chondrosarcoma, 1 osteosarcoma, 1 rhabdomyosarcoma) were treated in 3 dose levels of APG-115: 100 mg (n = 11), 150 mg (n = 8) and 200 mg (n = 2). The median number of cycles of APG-115 was 2 (0; 6). Two DLTs were observed at 200 mg, thrombocytopenia and febrile neutropenia. The most common treatment-emergent adverse events (TEAEs) (≥20%) included leukopenia, thrombocytopenia, neutropenia, anemia, increased blood creatinine, hypercholesterolemia, hypertriglyceridemia, hypoalbuminemia, vomiting, and nausea. The incidence of TEAEs was much lower at 100 mg. Serious AEs occurred in 5 patients (23.8%) which were assessed as possibly drug related by investigators. In 20 efficacy-evaluable patients, there was 1 patient with a partial response, 12 patients with stable disease, and 7 patients with progressive disease, yielding a disease control rate (CR, PR, SD) of 61.9%. Among the 13 patients (9 liposarcomas) who benefited, 11 had TP53wt and 7 had TP53wt+MDM2 amp, including one liposarcoma patient (150 mg) who had a PR, she was kept-up over 10 months, even though the treatment was discontinued for over 5 months, indicating the host immune modulatory effects of APG-115. Another patient with liposarcoma (100 mg, TP53wt+MDM2 amp) had 28.5% tumor shrinkage at cycle 4 and remained on treatment. PK results showed an approximately dose-proportional increase in exposure on Day 1. PK-PD analyses showed the serum macrophage inhibitory cytokine-1 (MIC-1) increased with increased APG-115 exposure. Conclusions: The phase I data have demonstrated that APG-115 monotherapy was well tolerated, with minimal toxicity at 100mg (RP2D), and conferred encouraging anti-tumor activities in patients with liposarcomas. Clinical trial information: CTR20170975 .

Abstract A086: Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S.

Abstract Keywords: MDM2; Immuno-oncology; PD-1 Background APG-115 is an orally active small-molecule MDM2 inhibitor that potently binds MDM2 protein, restores TP53 function, and activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T cells, enhanced CD4+ T cell activation, and increased PD-L1 expression on tumor cells. Enhanced antitumor activity was demonstrated in syngeneic tumor models after APG-115 combined with PD-1 blockade. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression in the patients treated with check point inhibitors. Keywords: MDM2; Immuno-oncology; PD-1 In general, by targeting MDM2-p53 pathway, APG-115 in combination with PD-1/PD-L1 blockade may provide a novel strategy to reverse immunosuppression and/or enhance antitumor immunity in the cancer patients who were either failed to standard therapies or resistant to IO therapies. Methods This dose escalation study (NCT03611868) combines APG-115 with pembrolizumab for the treatment of patients with metastatic solid tumors. Four dose levels of APG-115 have been tested: 50, 100, 150, and 200mg. APG-115 is administrated orally every other day (QOD) for consecutive 2 weeks of a 21-day-cycle with pembrolizumab at 200mg IV on day1 of a 21-day-cycle. Results Through June 15, 2019, a total of 14 patients have been treated in 4 cohorts of APG-115 in combination with pembrolizumab IV q3weeks. No cycle 1 DLTs have been observed up to and including 200 mg APG-115 at total doses of APG115 that are equivalent to the single agent MTD of APG-115 alone. Eleven patients experienced at least 1 TEAE. The most common TRAEs (≥10%) were nausea (42.9%), neutrophil count decreased (21.4%), vomiting (14.3%), decreased appetite (14.3%), diarrhea (14.3%), platelet count decreased (14.3%), white blood cell count decreased (14.3%), and fatigue (14.3%). Four patients experienced at least 1 grade 3 or higher TRAE beyond course 1 including neutrophil count decreased (21.4%). Five SAEs occurred in 3 patients, but only one grade 3 febrile neutropenia was treatment related. One patient with advanced ovarian cancer with a germline ATM mutation, refractory to 6 prior lines of therapy, has a sustained “confirmed CR” that continues beyond 12 cycles at the 100mg cohort. A patient with advanced NSCLC in 100mg cohort has received “confirmed PR” (still ongoing) after failed prior 5 lines of therapies including 3 months’ nivolumab treatment; 5 patients had SD after two cycle treatments, 2 of them ongoing. PK analyses indicates an approximately dose proportional increase in exposure across dose levels from 50 to 100 mg with plasma concentrations that exceed those that portend MDM2 inhibition. Preliminary pharmacodynamic (PD) results showed that the serum macrophage inhibitory cytokine-1 (MIC-1) levels are elevated in the APG-115 treated patients, suggesting a potential p53 activation in patients. Conclusion APG-115 in combination with pembrolizumab is well tolerated. The MTD has not been exceeded at full doses of APG-115. Promising anti-tumor effects have been seen in several tumor types when in combination with pembrolizumab. Expansion cohorts in molecularly selected patients is planned. Citation Format: Anthony W Tolcher, Raghad Karim, Yuefen Tang, Jiao Ji, Hengbang Wang, Lichuang Meng, Angela Kaiser, Jennifer Coe, Eric Liang, Christina Rosas, Dajun Yang, Yifan Zhai. Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A086. doi:10.1158/1535-7163.TARG-19-A086

Clinical application of combined detection of serum macrophage inhibitory cytokine-1, carcinoembryonic antigen and carbohydrate antigens for the diagnosis and prognosis of colorectal cancer in the elderly

Objective To explore the application value of combined detection of serum macrophage inhibitory cytokine-1(MIC-1), carcinoembryonic antigen(CEA)and carbohydrate antigens in the diagnosis and prognosis of elderly patients with colorectal cancer.172 elderly patients with colorectal cancer were selected retrospectively as the observation group, 175 elderly patients with benign colorectal lesions were enrolled as the benign lesion group and 166 healthy elderly subjects as the control group. Methods The levels of MIC-1, CEA, carbohydrate antigens of 199(CA199), 724(CA724), 242(CA242), 125(CA125), and 50(CA50)were compared among the three groups, and the diagnostic efficacy was calculated.The difference in the above-mentioned indicators between patients with different stages and prognosis in the observation group were compared. Results Levels of MIC-1, CEA, CA199, CA242, CA724, CA125 and CA50 were higher in the observation group than in the benign lesion group and the control group, and the above indexes were higher in the benign lesion group than in the control group.The sensitivity, positive predictive value and negative predictive value of MIC-1 were the highest in single index test(68.6%, 72.8% and 84.6%, respectively). The specificity of CA199 was the highest(91.2%). The combined detections greatly improved sensitivity, positive predictive value and negative predictive value(89.0%, 79.3% and 94.1%, respectively). In the observation group, levels of MIC-1, CEA, CA199, CA242, CA724, CA125 and CA50 in the elderly colorectal cancer patients were higher in stage Ⅲ and Ⅳ than in stage Ⅰ and Ⅱ.The levels of MIC-1, CEA, CA199, CA242, CA724, CA125 and CA50 in elderly patients with recurrence and metastasis of colorectal cancer were higher than those in patients without recurrence and metastasis. Conclusions Combined detection of multiple indicators can improve the sensitivity of diagnosis, and is more conducive to the early diagnosis of elderly patients with colorectal cancer. Key words: Colorectal neoplasms; Macrophage migration-inhibitory factors; Carcinoembryonic antigen; Antigens, tumor-associated, carbohydrate

Macrophage inhibitory cytokine-1 versus carbohydrate antigen 19-9 as a biomarker for diagnosis of pancreatic cancer: A PRISMA-compliant meta-analysis of diagnostic accuracy studies.

Background:Because of the high malignant degree of pancreatic cancer (PC), the early diagnosis of PC is of great concern. Macrophage inhibitory cytokine-1 (MIC-1) was reported to be a potential diagnostic biomarker, but its diagnostic value is indeterminate. Therefore, we performed this meta-analysis to compare it to carbohydrate antigen 19–9 (CA19–9), the most frequently used serum biomarker in PC.Material and Methods:After a systematic review of the relevant studies, the pooled diagnostic indices, including sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), diagnostic odds ratio (DOR), summary receiver operating characteristic curve (sROC), and area under the SROC curve (AUC) were used to evaluate the diagnostic value of MIC-1 and CA19–9 for PC. These indices were pooled with random-effects models. We explored the heterogeneity by meta-regression.Results:Fourteen studies comprising a total of 2826 subjects were included in our meta-analysis. The summary estimates for MIC-1 and CA19–9 are listed as follows: sensitivity, 80% [95% confidence interval (CI) 78–82] versus 71% (95% CI 68–73); specificity, 85% (95% CI 83–87) versus 88% (95% CI 86–90); DOR, 24.57 (95% CI 14.00–43.10) versus 17.65 (95% CI 11.65–26.76); area under sROC (AUC), 0.8945 versus 0.8322; PLR, 5.18 (95% CI 3.24–8.26) versus 5.34 (95% CI 3.78–7.54); and NLR, 0.23 (95% CI 0.19–0.29) versus 0.32 (95% CI 0.28–0.37).Conclusion:These data demonstrate that serum MIC-1 has a comparable diagnostic accuracy to CA19–9 for PC.

Abstract A082: A phase I study of the MDM2 antagonist RO6839921, a pegylated intravenous prodrug of idasanutlin, in patients with AML

Abstract Background: Activation of the p53 pathway by inhibiting MDM2 has been proposed as a novel strategy for cancer therapy. We previously reported the phase 1 results in solid tumor patients (pts) of RO6839921, a small-molecule pegylated IV prodrug of the MDM2 antagonist idasanutlin (active principle = AP), which was developed with the goal of reducing exposure variability to improve the therapeutic index. We report here on the safety, PK, PD, and activity in AML pts. Methods: This was an open-label phase I monotherapy study evaluating RO6839921 in R/R AML pts on a 5-day dosing schedule. Primary objectives were to identify dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD, DLT rate ≤ 33%). Secondary objectives were to assess PK, PD, and preliminary activity. Maximum escalation increments followed a Modified Fibonacci sequence. TP53 mutational status was assessed by next-generation sequencing from bone marrow samples. Serum MIC-1 (macrophage inhibitory cytokine-1), a p53 transcriptional target, was analyzed by Elecsys® ECL as a PD marker of p53 activation. Results: 26 DLT-evaluable pts were treated at doses between 120-300 mg AP. The MTD was 250 mg with DLTs reported at 250 mg (2/8 pts, 25%) and 300 mg (2/5 pts, 40%) (table). Related AEs ≥ G3 in &amp;gt;5% of pts included febrile neutropenia (3/26, 11.5%), epistaxis and platelet count decreased (both 2/26, 7.7%). Related AEs of all grades observed in &amp;gt; 20% pts were diarrhea, nausea, vomiting, decreased appetite, and fatigue. PK analyses showed rapid and near-complete conversion of prodrug to AP and dose-proportional exposure across the doses tested (table). Variability ranged from 30-47% (22-54% for idasanutlin). 11/26 pts had evidence of antileukemic activity (CR, CRi/MLFS, PR, HI/SD) for a disease control rate of 42%, with a composite CR rate of 7.7% (1 CR, 1 CRi/MLFS; 2/26); TP53 was evaluable in 24 pts; 21 (87.5%) were wild type and 3 mutant (12.5%). 10/11 pts with activity were wild type and 1 did not have a sample. p53 activation was demonstrated by MIC-1 induction in serum and was associated with AP exposure. Conclusions: RO6839921 shows a PK profile similar to idasanutlin. The MTD of 250 mg AP qd x 5 days has a manageable safety profile in R/R AML at ~25% of the idasanutlin dose identified for development in this population. Single-agent antileukemic activity is observed in 42% pts overall, including 4 of 8 pts (50%) at the MTD. NCT02098967. Arm B Cohort(n)Dose(mg AP)Prior AML induction regimens (median and range)ELN risk at initial diagnosis (Favorable, Int-1, Int-2, Adverse)TP53 status (Wild Type, Mutant, or Not Evaluable)PK (AP on D5)DLT eventsAnti-leukemicactivity*FI-1I-2AdvCmax (µg/ml)AUC0-24 (hr*µg/ml)Cohort 1 (n = 6)1202 (0-4)00155 WT, 1 NE18 ± 690 ± 30none2 HI/SDCohort 2 (n = 7)2001 (1-4)13215 WT / 1 MT / 1 NE32 ± 3164 ± 41none1 PR, 2 HI/SDCohort 3 (n = 5)3002 (0-3)01133 WT / 2 MT42 ± 8335 ± 93G4 QTcF prolongation, G3 colitis1 CRi/MLFS, 1 HI/SDCohort 4MTD(n = 8)2501 (0-2)13138 WT43 ± 9 (n=3)278 ± 72 (n=3)G3 stomatitis, G3 diarrhea1 CR, 1 PR, 2 HI/SDTotal(n = 26)11 (42%) Citation Format: Karen Yee, Geoffrey Uy, Sarit Assouline, Carolyn D. Britten, Jianguo Zhi, Steven Blotner, William Pierceall, Brian Higgins, Lin-Chi Chen. A phase I study of the MDM2 antagonist RO6839921, a pegylated intravenous prodrug of idasanutlin, in patients with AML [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A082.

The value of macrophage inhibitory cytokine-1 level in differentiating benign from malignant solitary pulmonary nodules.

Macrophage inhibitory cytokine-1 (MIC-1), a transforming growth factor-β superfamily cytokine, is involved in tumor pathogenesis, and its measurement can be used as a clinical tool for the diagnosis of a wide range of cancers. The aim of this study was to explore the diagnostic value of serum MIC-1 in patients with solitary pulmonary nodules (SPNs). Serum specimens from 158 malignant SPN patients, 110 benign SPN patients, along with 120 healthy volunteers. The levels of serum MIC-1 were measured by sandwich enzyme-linked immunosorbent assay. Serum levels of MIC-1 in malignant SPN patients were significantly higher than those in benign SPN patients (P < .01), or those in healthy volunteers (P < .01). With a cutoff of 685.8 pg/ml, the sensitivity and specificity of MIC-1 in differentiating between malignant SPN patients and benign SPN patients, and between malignant SPN patients and healthy volunteers was, 56.3% and 92.7%, and 65.8% and 96.7%, respectively. An area under the curve (AUC) for malignant SPN resulting from MIC-1, which was significantly better than any other tumor markers tested including carbohydrate antigens 12-5 (CA125), and carcinoembryonic antigen (CEA). In conclusion, measurement of serum MIC-1 levels could be considered as a diagnostic biomarker for malignant SPN patients.

The efficacy of biliary and serum macrophage inhibitory cytokine-1 for diagnosing biliary tract cancer

The serum macrophage inhibitory cytokine-1 (MIC-1) levels are elevated in some inflammatory conditions and cancers. We thus compared the levels of biliary and serum MIC-1 and conventional tumour markers between 23 biliary tract cancer (BTC) patients (malignant group) and 29 benign biliary disease patients (benign group) and found that all markers were significantly elevated in the malignant group. The levels of two markers were higher in early BTC (Stage I/II, n = 15) than in the benign group: biliary MIC-1 [12 (0–2153) vs. 678 (0–4429) pg/ml, P < 0.01] and serum CA19–9 [13 (2–15,682) vs. 45.1 (2–10,478) U/ml, P = 0.02]. A receiver operating characteristic curve analysis revealed that the area under the curve for biliary MIC-1 was greater than that for serum CA19-9 (0.77 vs. 0.73). The cut-off value for biliary MIC-1 in diagnosing early BTC was 581.6 pg/ml, and this value yielded a sensitivity, specificity and accuracy of 71.4%, 82.8%, and 79.1%, respectively. The sensitivity of biliary MIC-1 for diagnosing early BTC was superior to that of biliary cytology (71.4% vs. 8.33%, P < 0.01), and the combination of serum MIC-1 with CA19-9 (cut-off value = 4021.2 pg/ml, 42.4 U/ml) was useful for screening BTC (sensitivity = 82.6%, specificity = 72.4%). In conclusion, biliary MIC-1 can effectively diagnose early BTC.

Expression of macrophage inhibitory cytokine-1 in early gastric cancer cases treated using endoscopic mucosal resection and the correlation with prognosis.

The expression of macrophage inhibitory cytokine-1 (MIC-1) of early gastric cancer treated using endoscopic mucosal resection (EMR) and its correlation with prognosis were investigated. One hundred and forty-seven patients with early gastric cancer (less than 20 mm in diameter) were recruited and assigned into an observation group (75 cases) or a control group (72 cases), according to treatment. The control group was treated with a radical resection by the conventional laparotomy approach and the observation group was treated by EMR. Differences in operative outcomes and prognosis were compared between the two groups. Complete lesion resection rates of the two groups were 100%. The amount of bleeding, operation time and postoperative complication rates in the observation group were each significantly lower than those in the control group (P<0.05). The serum MIC-1 levels in the two groups were reduced, with the observation group being significantly lower than that of the control group (P<0.05). The progression-free survival was significantly prolonged and the recurrence rate was significantly lower in the observation group compared to the control group, with the difference being statistically significant (P<0.05). In conclusion, EMR treatment of early gastric cancer was observed to be safe and effective in this study and can reduce the expression level of serum MIC-1 after the operation. EMR can also increase the survival period and reduce the recurrence rate, and MIC-1 can be used as an important index to predict the prognosis of the disease.