The plant decapeptide OSIP108 can alleviate mitochondrial dysfunction induced by cisplatin in human cells

We investigated the effect of the Arabidopsis thaliana-derived decapeptide OSIP108 on human cell tolerance to the chemotherapeutic agent cisplatin (Cp), which induces apoptosis and mitochondrial dysfunction. We found that OSIP108 increases the tolerance of HepG2 cells to Cp and prevents Cp-induced changes in basic cellular metabolism. More specifically, we demonstrate that OSIP108 reduces Cp-induced inhibition of respiration, decreases glycolysis and prevents Cp-uptake in HepG2 cells. Apart from its protective action against Cp in human cells, OSIP108 also increases the yeast Saccharomyces cerevisiae tolerance to Cp. A limited yeast-based study of OSIP108 analogs showed that cyclization does not severely affect its activity, which was further confirmed in HepG2 cells. Furthermore, the similarity in the activity of the D-stereoisomer (mirror image) form of OSIP108 with the L stereoisomer suggests that its mode of action does not involve binding to a stereospecific receptor. In addition, as OSIP108 decreases Cp uptake in HepG2 cells and the anti-Cp activity of OSIP108 analogs without free cysteine is reduced, OSIP108 seems to protect against Cp-induced toxicity only partly via complexation. Taken together, our data indicate that OSIP108 and its cyclic derivatives can protect against Cp-induced toxicity and, thus, show potential as treatment options for mitochondrial dysfunction- and apoptosis-related conditions

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E–mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224. opens in new tab; EudraCT number, 2015-005805-35. opens in new tab.

Colon cancer subtypes: Concordance, effect on survival and selection of the most representative preclinical models

Multiple gene-expression-based subtypes have been proposed for the molecular subdivision of colon cancer in the last decade. We aimed to cross-validate these classifiers to explore their concordance and their power to predict survival. A gene-chip-based database comprising 2,166 samples from 12 independent datasets was set up. A total of 22 different molecular subtypes were re-trained including the CCHS, CIN25, CMS, ColoGuideEx, ColoGuidePro, CRCassigner, MDA114, Meta163, ODXcolon, Oncodefender, TCA19, and V7RHS classifiers as well as subtypes established by Budinska, Chang, DeSousa, Marisa, Merlos, Popovici, Schetter, Yuen, and Watanabe (first authors). Correlation with survival was assessed by Cox proportional hazards regression for each classifier using relapse-free survival data. The highest efficacy at predicting survival in stage 2-3 patients was achieved by Yuen (p = 3.9e-05, HR = 2.9), Marisa (p = 2.6e-05, HR = 2.6) and Chang (p = 9e-09, HR = 2.35). Finally, 61 colon cancer cell lines from four independent studies were assigned to the closest molecular subtype. © 2016 The Author(s)

Een 21-jarige Somaliër met spier- en gewrichtspijn en aanhoudende koorts

status: publishe

Extended criteria for liver transplantation in hepatocellular carcinoma. A retrospective, multicentric validation study in Belgium.

BACKGROUND: Recent studies indicate that a group of patients with cirrhosis receiving a liver transplantation for hepatocellular cancer (HCC) beyond the Milan Criteria (MC) can achieve a similar outcome compared to patients within these criteria. This study aims to investigate the value of the Asan critera (AC), up-to-7 criteria (UT7), French alpha-foetoprotein (AFP) model and Metroticket 2.0 (MT2.0) model compared to the MC. METHODS: 526 patients transplanted for non-metastatic HCC were analyzed. Patient groups within and beyond MC and extended criteria were determined according to radiological assessment and AFP value at listing. RESULTS: Overall survival (OS) and recurrence (RR) rates were similar between patients within MC and all extended criteria. Five-year OS within MC was 71.3% compared to 70.9% for AC, 71.4% for UT7, 69.7% for AFP-model and 71.0% for MT2.0 criteria. Five-year RR within MC was 12.3% compared to 13.5% for AC, 13.0% for UT7, 14.3% for AFP-model and 13.2% for MT2.0 criteria. Patients beyond MC but within the extended criteria had tendency towards higher recurrence. CONCLUSIONS: All validated extended criteria (AC, UT7, AFP-model and MT2.0) could be proposed as alternatives to the MC with similar outcome. Prospective data are awaited to assess recurrence beyond MC

Extended criteria for liver transplantation in hepatocellular carcinoma. A retrospective, multicentric validation study in Belgium

Background: Recent studies indicate that a group of patients with cirrhosis receiving a liver transplantation for hepatocellular cancer (HCC) beyond the Milan Criteria (MC) can achieve a similar outcome compared to patients within these criteria. This study aims to investigate the value of the Asan critera (AC), up-to-7 criteria (UT7), French alpha-foetoprotein (AFP) model and Metroticket 2.0 (MT2.0) model compared to the MC. Methods: 526 patients transplanted for non-metastatic HCC were analyzed. Patient groups within and beyond MC and extended criteria were determined according to radiological assessment and AFP value at listing. Results: Overall survival (OS) and recurrence (RR) rates were similar between patients within MC and all extended criteria. Five-year OS within MC was 71.3% compared to 70.9% for AC, 71.4% for UT7, 69.7% for AFP-model and 71.0% for MT2.0 criteria. Five-year RR within MC was 12.3% compared to 13.5% for AC, 13.0% for UT7, 14.3% for AFP-model and 13.2% for MT2.0 criteria. Patients beyond MC but within the extended criteria had tendency towards higher recurrence. Conclusions: All validated extended criteria (AC, UT7, AFP-model and MT2.0) could be proposed as alternatives to the MC with similar outcome. Prospective data are awaited to assess recurrence beyond MC

The plant decapeptide OSIP108 can alleviate mitochondrial dysfunction induced by cisplatin in human cells

We investigated the effect of the Arabidopsis thaliana-derived decapeptide OSIP108 on human cell tolerance to the chemotherapeutic agent cisplatin (Cp), which induces apoptosis and mitochondrial dysfunction. We found that OSIP108 increases the tolerance of HepG2 cells to Cp and prevents Cp-induced changes in basic cellular metabolism. More specifically, we demonstrate that OSIP108 reduces Cp-induced inhibition of respiration, decreases glycolysis and prevents Cp-uptake in HepG2 cells. Apart from its protective action against Cp in human cells, OSIP108 also increases the yeast Saccharomyces cerevisiae tolerance to Cp. A limited yeast-based study of OSIP108 analogs showed that cyclization does not severely affect its activity, which was further confirmed in HepG2 cells. Furthermore, the similarity in the activity of the D-stereoisomer (mirror image) form of OSIP108 with the L-stereoisomer suggests that its mode of action does not involve binding to a stereospecific receptor. In addition, as OSIP108 decreases Cp uptake in HepG2 cells and the anti-Cp activity of OSIP108 analogs without free cysteine is reduced, OSIP108 seems to protect against Cp-induced toxicity only partly via complexation. Taken together, our data indicate that OSIP108 and its cyclic derivatives can protect against Cp-induced toxicity and, thus, show potential as treatment options for mitochondrial dysfunction- and apoptosis-related conditions.status: publishe

Phase 2 study results of murlentamab, a monoclonal antibody targeting the Anti-Mullerian-Hormone-Receptor II (AMHRII), acting through Tumor-Associated Macrophage engagement in advanced/metastatic colorectal cancers

Introduction: Membranous expression of AMHRII is present in about 80% of colorectal adenocarcinomas. Murlentamab is a glycoengineered mAb binding with high affinity both AMHRII on the tumor cell membrane and CD16 via its low-fucose Fc on macrophages, inducing phagocytosis. Murlentamab reprograms TAMs, restoring their antitumoral functions, also resulting in cytotoxic T lymphocyte activation. Methods: Patients with pretreated advanced/metastatic colorectal adenocarcinoma, measurable disease, performance status ≤1, adequate organ function, baseline tumor biopsy, and agreeing to a subsequent biopsy under treatment, received murlentamab single agent (SA) or in combination with trifluridine/tipiracil (FTD/TPI) in two parallel non-randomized cohorts. Antitumor activity (objective response by RECIST 1.1, Tumor Growth Rate (TGR), progression-free survival (PFS), overall survival), pharmacodynamics (circulating immune cells and tumor microenvironment) and safety were to be assessed in 30 patients (15 in each cohort) evaluable for efficacy (having completed at least two 28-day cycles of treatment and with at least one tumor assessment under treatment). Results: Thirty-nine heavily pretreated patients were enrolled and received murlentamab, SA or in combination with FTD/TPI. Fourteen patients in SA and 15 patients in combination with FTD/TPI (after a median of 4 and 2 prior therapy lines, respectively) were evaluable for efficacy. No objective responses were observed. A 1.7-fold and 3.6-fold TGR decrease was observed with murlentamab SA and murlentamab combined with FTD/TPI, respectively. In the murlentamab SA cohort, 21% (3/14) of patients were progression-free at 2 months. In combination with FTD/TPI, 53% (8/15), 40% (6/15) and 31% (4/13) of patients were progression-free at 2, 4 and 6 months, respectively. Among patients with more than 20% AMHRII-positive tumor cells, 5/6 and 3/4 patients were stabilized at 4 and 6 months, respectively. In contrast, the 7 patients progressing at their first tumor evaluation (2 months) had less than 20% of AMHRII-positive tumor cells. In the 7 paired biopsies analyzed, tumor microenvironment immune activation (staining positive area increase) under murlentamab was observed: CD16 in 6/7 tumors reflecting macrophage activation; granzymeB/CD16 co-localisation in 5/7 tumors reflecting phagocytosis. In the paired biopsies from 2 patients stabilized at 4 months in combination with FTD/TPI, CD86 on antigen presenting cells and CD8 on T cell increased, reflecting activation. In the peripheral blood (samples from 20 patients analyzed), a significant activation of monocytes (CD69+) and neutrophils (CD64+) was observed under murlentamab SA and in combination with FTD/TPI. No serious adverse events related to murlentamab were reported. All 36 reported murlentamab toxicities experienced by 10 patients in combination with FTD/TPI cohort were G1-2, the most common being: decreased appetite (9 events), vomiting, nausea, constipation and asthenia (3 events each). No overlapping toxicities were observed when combining murlentamab with FTD/TPI. Conclusion: This pilot study suggests longer than expected PFS for murlentamab and FTD/TPI in advanced mCRC, especially in patients with high AMHRII expression. Immune activation of the macrophage / cytotoxic T cell cascade was observed in tumor microenvironment as well as in peripheral blood. These results together with murlentamab’s innovative immunological mode of action support its further development in combination with standard chemotherapies and/or immunological agents in colorectal cancers