Chemotherapy In Mesothelioma Research Articles

The impact of Charcot-Leyden Crystal protein on mesothelioma chemotherapy: targeting eosinophils for enhanced chemosensitivity

In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma. The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells. Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment. This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour. Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.

Enhancing Drug Delivery Efficacy Through Bilayer Coating of Zirconium-Based Metal-Organic Frameworks: Sustained Release and Improved Chemical Stability and Cellular Uptake for Cancer Therapy.

The development of nanoparticle (NP)-based drug carriers has presented an exciting opportunity to address challenges in oncology. Among the 100,000 available possibilities, zirconium-based metal-organic frameworks (MOFs) have emerged as promising candidates in biomedical applications. Zr-MOFs can be easily synthesized as small-size NPs compatible with intravenous injection, whereas the ease of decorating their external surfaces with functional groups allows for targeted treatment. Despite these benefits, Zr-MOFs suffer degradation and aggregation in real, in vivo conditions, whereas the loaded drugs will suffer the burst effect-i.e., the fast release of drugs in less than 48 h. To tackle these issues, we developed a simple but effective bilayer coating strategy in a generic, two-step process. In this work, bilayer-coated MOF NU-901 remained well dispersed in biologically relevant fluids such as buffers and cell growth media. Additionally, the coating enhances the long-term stability of drug-loaded MOFs in water by simultaneously preventing sustained leakage of the drug and aggregation of the MOF particles. We evaluated our materials for the encapsulation and transport of pemetrexed, the standard-of-care chemotherapy in mesothelioma. The bilayer coating allowed for a slowed release of pemetrexed over 7 days, superior to the typical 48 h release found in bare MOFs. This slow release and the related performance were studied in vitro using both A549 lung cancer and 3T mesothelioma cells. Using high-resolution microscopy, we found the successful uptake of bilayer-coated MOFs by the cells with an accumulation in the lysosomes. The pemetrex-loaded NU-901 was indeed cytotoxic to 3T and A549 cancer cells. Finally, we demonstrated the general approach by extending the coating strategy using two additional lipids and four surfactants. This research highlights how a simple yet effective bilayer coating provides new insights into the design of promising MOF-based drug delivery systems.

P24.03 A Multicenter Randomized Phase III Trial of Dendritic Cell Maintenance Therapy After Chemotherapy in Mesothelioma; Denim Trial

P24.03 A Multicenter Randomized Phase III Trial of Dendritic Cell Maintenance Therapy After Chemotherapy in Mesothelioma; Denim Trial

In vivo formation of Cu(DDC)2 complex induced by nanomedicine for mesothelioma chemotherapy

The copper(II) diethyldithiocarbamate (Cu(DDC)2) complex exhibited excellent inhibition to cancer cells. The usual administration is intravenous injection for disulfram and oral for copper. A new strategy was reported to improve the administration efficiency of the Cu(DDC)2 drug. Poly(lactide-co-glycolide) (PLGA) nanoparticles were used to trap disulfram and copper gluconate separately, the two types of drug loaded nanoparticles were injected in mesothelioma-bearing nude mice via intraperitoneal injection. The in vivo formation of Cu(DDC)2 complex was induced by disulfiram and Cu2+ released from PLGA nanoparticles. This strategy avoided many obstacles in the use of Cu(DDC)2 complex as chemotherapeutic and exhibited excellent anticancer activity to mesothelioma.

Final Results of the Dream Trial: A Phase 2 Trial of Durvalumab with First-Line Chemotherapy in Mesothelioma with a Safety Run-In

Background: Cisplatin and pemetrexed chemotherapy provides modest survival benefits for malignant pleural mesothelioma (MPM). This study evaluated cisplatin and pemetrexed with, and followed by, the anti-PD-L1 (programmed death ligand-1) antibody durvalumab in advanced MPM. Methods: DREAM was a single-arm, multicentre open label phase 2 study in patients with treatment-naive advanced MPM. Eligible patients had Eastern Cooperative Oncology Group performance status 0 or 1 and measurable disease. The first six patients were treated on a two-cycle safety lead-in. All patients received cisplatin 75mg/m2, pemetrexed 500mg/m2, and durvalumab 1125mg fixed dose on day 1 of a three-weekly schedule to maximum six cycles chemotherapy. Change from cisplatin to carboplatin AUC5 was permitted. Durvalumab was continued to complete up to 12 months total treatment. The primary endpoint was progression-free survival at six months (PFS6); secondary outcomes included objective tumour response rate (RR), overall survival (OS), and adverse event (AE) rates. Findings: Fifty-four patients were registered and treated. Most were male (83%), with epithelioid subtype (83%), and a median age of 68 years. The proportion alive and progression-free at six months was 54%; median PFS was 6.9 months (95% CI 5.5–9.0). Median OS was 18.4 months (95% CI 13.1–24.8). RR according to modified RECIST for MPM was 48% (95% CI 36–61%), with partial responses in 26 (48%) and stable disease in 21 (37%) patients, respectively. AEs reflected the expected toxicities of combining chemotherapy and durvalumab. None of the five deaths during study treatment were attributed to durvalumab. There was no association between tumour expression of PD-L1 and PFS. Interpretation: This single-arm phase 2 trial demonstrated that the combination of durvalumab, cisplatin, and pemetrexed has promising activity and safety to warrant the conduct of a randomised phase 3 trial. Funding: AstraZeneca provided study drug and funding. Declaration of Interest: The other authors declared no conflicts of interest. Ethical Approval: DREAM conformed to ethical principles of the Declaration of Helsinki and the International Council on Harmonization guidelines on Good Clinical Practice. The protocol was approved by a central Human Research Ethics Committee (HREC), and all site HRECs. All patients provided written informed consent before any screening procedures. Patients confirmed eligible after screening were registered to the study.

Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma.

Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly(I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4cell lines. Efficacy of the combined treatment relied on cisplatin-induced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cell samples isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.

P1.06-22 Pathologic and Imaging Response Correlations in Patients Treated with Neoadjuvant Chemotherapy for Mesothelioma

P1.06-22 Pathologic and Imaging Response Correlations in Patients Treated with Neoadjuvant Chemotherapy for Mesothelioma

Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma

Introduction BRCA1 associated protein-1 (BAP1) is a key tumor driver in mesothelioma and a potential biomarker predicting response to several targeted therapies in clinical testing. Whether it also modulates response to cytotoxic chemotherapy is undetermined. This study used retrospective response analysis of BAP1 expression in archival tumor biopsies taken from patients in the MS01 trial (NCT00075699). We aimed to determine if BAP1 expression correlated with overall survival within the three treatment arms in this trial, namely active symptom control (ASC); ASC plus mitomycin, vinblastine and cisplatin (MVP); and ASC plus vinorelbine.Materials and methods We used immunohistochemical analysis of tumor samples from the MS01 trial to identify subgroups with and without nuclear BAP1 expression. We performed correlative analysis of clinical characteristics (age at diagnosis, sex and histological subtype) and overall survival within treatment arms with nuclear BAP1 expression.Results 89 tumor samples from the 409 patients originally in the trial were available for analysis. Of these, 60 samples harbored a positive internal control, in the form of positive staining of inflammatory cells for BAP1, and were carried forward for analysis. Correlative analysis suggested no significant association between loss of nuclear BAP1 expression and age at diagnosis, sex and histological subtype. Kaplan Meier survival analysis revealed a small, though non-significant, overall survival disadvantage associated with BAP1 expression in tumors from patients treated with vinorelbine.Discussion This exploratory analysis suggests BAP1 expression may modify response to vinorelbine in MPM, possibly due to prevention of mitotic microtubule formation. We suggest ongoing and planned clinical studies of vinorelbine in MPM assess BAP1 expression as a predictive biomarker of response.

ES03.04 Role of Chemotherapy in Mesothelioma with Minimal Bulk Disease

ES03.04 Role of Chemotherapy in Mesothelioma with Minimal Bulk Disease

MA12.07 gC1qR Expression is Independently Prognostic for Survival Benefit Following Chemotherapy in Mesothelioma

MA12.07 gC1qR Expression is Independently Prognostic for Survival Benefit Following Chemotherapy in Mesothelioma

OA08.02 DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result

OA08.02 DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result

Abstract 2448: Chemotherapy drug-induced AXL activation and cell survival signaling via reactive oxygen species that can be inhibited to enhance drug efficacy in mesothelioma

Abstract Cellular oxidative stress is characterized by elevated reactive oxygen species (ROS), and is a frequent phenotype of cancer cells. The consequences of ROS are complex, where ROS can promote or inhibit tumorigenesis. In mesothelioma, asbestos exposure to serous membranes induces ROS through iron content and chronic inflammation, and ROS promote cell survival signaling in mesothelioma. On the other hand, a current chemotherapy regime for mesothelioma consisting of a platinum and antifolate agent combination also induce ROS. Mesothelioma is notoriously chemotherapy-resistant, and we propose that ROS induced by cisplatin and pemetrexed may promote cell survival signaling pathways, which ultimately may contribute to chemotherapy resistance. In The Cancer Genome Atlas datasets, we found AXL kinase expression is relatively high in mesothelioma compared to other cancer samples. We showed that ROS induce the phosphorylation of AXL, which was blocked by the selective inhibitor BGB324 in VMC40 and P31 mesothelioma cells. We also showed that cisplatin and pemetrexed induce the phosphorylation of AXL and Akt, which was also blocked by BGB324 as well as by N-acetylcysteine antioxidant. AXL knockdown in these cells enhances sensitivity to cisplatin and pemetrexed. Similarly, AXL inhibitor BGB324 also enhances sensitivity to cisplatin and pemetrexed. Finally, higher synergy was observed when cells were pretreated with BGB324 before adding chemotherapy. These results demonstrate cisplatin and pemetrexed induce ROS that activate AXL, and blocking AXL activation enhances the efficacy of cisplatin and pemetrexed. These results suggest AXL inhibition may represent an effective strategy to enhance the efficacy of chemotherapy in mesothelioma. We further hypothesize AXL signaling may be part of an adaptive response to chemotherapeutic agents, providing transient resistance to cisplatin and pemetrexed that may ultimately contribute to acquired chemotherapy resistance. Citation Format: Derek B. Oien, Tamás Garay, Sarah Eckstein, Jeremy Chien. Chemotherapy drug-induced AXL activation and cell survival signaling via reactive oxygen species that can be inhibited to enhance drug efficacy in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2448.

DREAM: A phase II study of durvalumab with first line chemotherapy in mesothelioma—First results.

8503Background: DREAM is an open-label, single arm, multi-centre, phase II trial with a safety run in designed to determine the activity, safety and tolerability of durvalumab combined with cisplat...

Cisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy.

Reactive oxygen species (ROS) can promote or inhibit tumorigenesis. In mesothelioma, asbestos exposure to serous membranes induces ROS through iron content and chronic inflammation, and ROS promote cell survival signaling in mesothelioma. Moreover, a current chemotherapy regimen for mesothelioma consisting of a platinum and antifolate agent combination also induce ROS. Mesothelioma is notoriously chemotherapy-resistant, and we propose that ROS induced by cisplatin and pemetrexed may promote cell survival signaling pathways, which ultimately may contribute to chemotherapy resistance. In The Cancer Genome Atlas datasets, we found AXL kinase expression is relatively high in mesothelioma compared to other cancer samples. We showed that ROS induce the phosphorylation of AXL, which was blocked by the selective inhibitor BGB324 in VMC40 and P31 mesothelioma cells. We also showed that cisplatin and pemetrexed induce the phosphorylation of AXL and Akt, which was also blocked by BGB324 as well as by N-acetylcysteine antioxidant. AXL knockdown in these cells enhances sensitivity to cisplatin and pemetrexed. Similarly, AXL inhibitor BGB324 also enhances sensitivity to cisplatin and pemetrexed. Finally, higher synergy was observed when cells were pretreated with BGB324 before adding chemotherapy. These results demonstrate cisplatin and pemetrexed induce ROS that activate AXL, and blocking AXL activation enhances the efficacy of cisplatin and pemetrexed. These results suggest AXL inhibition combined with the current chemotherapy regimen may represent an effective strategy to enhance the efficacy of chemotherapy in mesothelioma. This is the first study, to our knowledge, on chemotherapy-induced activation of AXL and cell survival pathways associated with ROS signaling.

NU03.01 Supporting Patients Undergoing Radical Treatments EPD – MARS Study

NU03.01 Supporting Patients Undergoing Radical Treatments EPD – MARS Study

P2.06-025 DREAM - A Phase 2 Trial of DuRvalumab with First Line chEmotherApy in Mesothelioma with a Safety Run In: Topic: Mesothelioma and SCLC

P2.06-025 DREAM - A Phase 2 Trial of DuRvalumab with First Line chEmotherApy in Mesothelioma with a Safety Run In: Topic: Mesothelioma and SCLC

Invited Commentary

Invited Commentary

Novel Induction Therapies for Pleural Mesothelioma

Malignant mesothelioma is becoming increasingly common, and rates of diagnosis are expected to continue to increase in the coming years because of the extensive use of asbestos in industrialized countries and the long time interval between exposure and onset of disease. Although much research has been done on the optimal treatment for this disease, the overall prognosis remains grim. The main components of therapy are surgery, chemotherapy, and radiation therapy, but there is controversy in the literature about the optimal inclusion and sequencing of these treatments, as each has unique risk profiles. We have developed a new Surgery for Mesothelioma After Radiation Therapy protocol consisting of induction-accelerated hemithoracic radiation followed by extrapleural pneumonectomy. The rationale behind this protocol is to maximize both the tumoricidal and immunogenic potential of the radiotherapy while minimizing the radiation toxicity to the ipsilateral lung. Our initial trial demonstrated the feasibility of this approach and has shown encouraging results in patients with epithelial histology. In this article, we reviewed the current literature on induction chemotherapy for mesothelioma as well as described the Surgery for Mesothelioma After Radiation Therapy protocol and upcoming studies of novel induction therapies for mesothelioma.

Abstract 984: The role of TGF-alpha in the resistance to mesothelioma chemotherapy.

Abstract Background. Malignant mesothelioma (MM) is a cancer of the pleura caused mainly by the inhalation of asbestos fibers. The impact of chemotherapy on the outcome of patients with MM is still unclear. We hypothesized that unresponsiveness to chemotherapy is due to inadequate gene expression in tumor cells. We have previously shown that inhibitors of histones deacetylases (such as valproate, VPA) significantly increases the efficacy of compounds used in chemotherapy (Vandermeers et al, 2010, Clinical Cancer Research 15: 2818). A recent clinical trial on relapsing MM patients has shown that VPA in combination with doxorubicin improves response rates and quality of life (Scherpereel et al, 2011, European Respiratory Journal 37:129). Results. To study the mechanisms associated with the response to chemotherapy, we compared two types of cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Using Agilent microarrays and RT-qPCR, we observed that the basal expression level of TGFα was higher in "resistant" H28 compared to "sensitive" M14K cells. To evaluate the functional relevance of TGFα, we modulated its expression either by RNA interference or by transfection of a cDNA vector. A decrease of TGFα expression correlated with induction of apoptosis. Inversely, an inhibition of apoptosis occurred when TGFα was over-expressed. As TGFα is the ligand of EGFR, we tested the effect of gefitinib and erlotinib in combination with VPA+doxorubicin. Both EGFR inhibitors increased apoptosis induced by VPA+doxorubicin in H28 chemoresistant cells. Finally, the VPA+doxorubicin+erlotinib regimen prevented tumor growth in two mouse models (ZL34 in SCID and AB12 in Balb/c). Conclusions. Our data demonstrates that TGFα is involved in the chemoresistance to VPA+doxorubicin, a second-line regimen for MM. Although inefficient alone, tyrosine kinase inhibitors synergize to induce apoptosis in chemoresistant cells and prevent tumor growth in mouse models. Citation Format: Sathya Neelature Sriramareddy, Fabian Vandermeers, Chrisostome Costa, Céline Mascaux, Arnaud Scherpereel, Philippe Delvenne, Pascale Hubert, Luc L. Willems. The role of TGF-alpha in the resistance to mesothelioma chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 984. doi:10.1158/1538-7445.AM2013-984

CTLA-4 Blockade Expands Infiltrating T Cells and Inhibits Cancer Cell Repopulation during the Intervals of Chemotherapy in Murine Mesothelioma

Cancer immunotherapy has shown promising results when combined with chemotherapy. Blocking CTLA-4 signaling by monoclonal antibody between cycles of chemotherapy may inhibit cancer cell repopulation and enhance the antitumoral immune reaction, thus improve the efficacy of chemotherapy in mesothelioma. The impact of CTLA-4 blockade on the early stage of tumor development was evaluated in a subcutaneous murine mesothelioma model. CTLA-4 blocking antibody was administered following each cycle of chemotherapy, and monotherapy was included as controls. Antitumor effect was evaluated by tumor growth delay and survival of the animals. Tumor cell repopulation was quantified by bromodeoxyuridine incorporation and Ki67 by immunohistochemistry and/or flow cytometry. In vitro cell killing was determined by classic chromium-released assay, and reverse transcription PCR (RT-PCR) was carried out to determine the gene expression of associated cytokines. Anti-CTLA-4 monoclonal antibody was able to inhibit tumor growth at early stage of tumor development. Antitumor effect was achieved by administration of CTLA-4 blockade between cycles of chemotherapy. Tumor cell repopulation during the intervals of cisplatin was inhibited by CTLA-4 blockade. Anti-CTLA-4 therapy gave rise to an increased number of CD4 and CD8 T cells infiltrating the tumor. RT-PCR showed that the gene expression of interleukin IL-2, IFN-γ, granzyme B, and perforin increased in the tumor milieu. Blockade of CTLA-4 signaling showed effective anticancer effect, correlating with inhibiting cancer cell repopulation between cycles of chemotherapy and upregulating tumor-infiltrating T lymphocytes, cytokines, and cytolytic enzymes in a murine mesothelioma model.