bims-mesote 2021-11-07 papers

Issue of 2021–11–07
six papers selected by
Laura Mannarino, Humanitas Research

Cureus. 2021 Sep;13(9): e18380

The Rarest of the Rare: A Case of BAP1-Mutated Primary Peritoneal Mesothelioma.

Aanchal Gupta, Alisa Vasileva, Sukesh Manthri.

Malignant mesotheliomas (MM), as described are rare tumors that are mostly associated with occupational exposure to asbestos. They most commonly occur in the pleura. Other unfamiliar sites where they can occur are the peritoneum, pericardium, and tunica vaginalis. There is no significant correlation between the amount and duration of asbestos exposure to mesothelioma development as reported by various studies over the years. Apart from the environmental exposure, the development of malignant mesothelioma has been linked to a mutation in the BAP1 gene, which can predispose the patient to develop other malignancies associated with BAP1 mutation. We report a case of a 43-year-old man without any significant risk factors, who presented with a complaint of abdominal discomfort and was found to have malignant peritoneal mesothelioma (MPM). With a known familial history of mesothelioma and melanoma, our patient underwent genetic testing which revealed a mutation in BAP1, affirming the strong association with the development of MPM. Young patients who develop malignant mesothelioma without risk factors for MM should have germline testing for BAP1. This case report is unique and highlights a familial variant of mesothelioma, even rare with peritoneal mesothelioma in our patient.

Keywords: asbestos; bap1; genetic testing; malignant peritoneal mesothelioma; mesothelioma

DOI: https://doi.org/10.7759/cureus.18380

J Exp Clin Cancer Res. 2021 Nov 02. 40(1): 344

Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma.

Mario Cioce, Claudia Canino, Harvey Pass, Giovanni Blandino, Sabrina Strano, Vito Michele Fazio.

Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed.
METHODS: Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells.
RESULTS: We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug.
CONCLUSIONS: AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.

Keywords: ALDH; Arachidonic acid; Chemoresistance; MPM; Malignant pleural mesothelioma; NFkB; Spheroids; cPLA2

DOI: https://doi.org/10.1186/s13046-021-02118-y

Sci Rep. 2021 Nov 01. 11(1): 21357

Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort.

Susana Cedres, Juan-David Assaf, Patricia Iranzo, Ana Callejo, Nuria Pardo, Alejandro Navarro, Alex Martinez-Marti, David Marmolejo, Alejandra Rezqallah, Caterina Carbonell, Joan Frigola, Ramon Amat, Anna Pedrola, Rodrigo Dienstmann, Enriqueta Felip.

CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall d'Hebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the Kaplan-Meier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2-24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4-3.4; p < 0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0-2.3; p = 0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFS = 0.09, p of interaction OS = 0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy.

DOI: https://doi.org/10.1038/s41598-021-00831-4

J Radiat Res. 2021 Nov 05. pii: rrab090. [Epub ahead of print]

Anticancer agent α-sulfoquinovosyl-acylpropanediol enhances the radiosensitivity of human malignant mesothelioma in nude mouse models.

Eiko Inamasu, Tomoshi Tsuchiya, Motohiro Yamauchi, Kodai Nishi, Katsuya Matsuda, Fumio Sugawara, Kengo Sakaguchi, Ryoichi Mori, Keitaro Matsumoto, Takuro Miyazaki, Go Hatachi, Ryoichiro Doi, Hironosuke Watanabe, Koichi Tomoshige, Naoki Matsuda, Yoshikazu Higami, Isao Shimokawa, Masahiro Nakashima, Takeshi Nagayasu.

Malignant pleural mesothelioma (MPM) is a highly malignant disease that develops after asbestos exposure. Although the number of MPM cases is predicted to increase, no effective standard therapies have been established. The novel radiosensitizer α-sulfoquinovosyl-acylpropanediol (SQAP) enhances the effects of γ-radiation in human lung and prostate cancer cell lines and in animal models. In this study, we explored the radiosensitizing effect of SQAP and its mechanisms in MPM. The human MPM cell lines MSTO-211H and MESO-4 were implanted subcutaneously into the backs and thoracic cavities of immunodeficient KSN/Slc mice, then 2 mg/kg SQAP was intravenously administered with or without irradiation with a total body dose of 8 Gy. In both the orthotopic and ectopic xenograft murine models, the combination of irradiation plus SQAP delayed the implanted human MSTO-211H tumor growth. The analysis of the changes in the relative tumor volume of the MSTO-211H indicated a statistically significant difference after 8 Gy total body combined with 2 mg/kg SQAP, compared to both the untreated control (P = 0.0127) and the radiation treatment alone (P = 0.0171). After the treatment in each case, immunostaining of the harvested tumors revealed decreased cell proliferation, increased apoptosis and normalization of tumor blood vessels in the SQAP- and irradiation-treated group. Furthermore, hypoxia-inducible factor (HIF) 1 mRNA and protein expression were decreased, indicating reoxygenation in this group. In conclusion, SQAP improved hypoxic conditions in tumor tissue and may elicit a radiosensitizing effect in malignant mesothelioma models.

Keywords: hypoxia-inducible factor (HIF); malignant pleural mesothelioma (MPM); radiosensitizer; sulfoquinovosyl-acylpropanediol (SQAP)

DOI: https://doi.org/10.1093/jrr/rrab090

Cancer Discov. 2021 Nov;11(11): 2674-2676

New Immunotherapy Combinations Enter the Battlefield of Malignant Mesothelioma.

Mihaela Aldea, Jose Carlos Benitez, Nathalie Chaput, Benjamin Besse.

Chimeric antigen receptor (CAR) T cells targeting mesothelin plus pembrolizumab, and atezolizumab plus bevacizumab, have recently shown clinical efficacy in phase I trials in malignant pleural and peritoneal mesothelioma. Despite being tested in a highly selected patient population and requiring a complex engineering that can hardly be upscaled, CAR T cells combined with pembrolizumab bring the first proof of efficacy in cold solid tumors with low genomic heterogeneity, while atezolizumab-bevacizumab offers an easy-to-use combination of antiangiogenics and immunotherapy in an orphan disease.See related article by Raghav et al., p. 2738.See related article by Adusumilli et al., p. 2748.

DOI: https://doi.org/10.1158/2159-8290.CD-21-1046

J Immunother. 2021 Nov 01.

Treatment of Platinum Nonresponsive Metastatic Malignant Peritoneal Mesothelioma With Combination Chemoimmunotherapy.

Michael B Foote, Jinru Shia, Marjorie G Zauderer, Garrett M Nash, Andrea Cercek.

Malignant peritoneal mesothelioma is a rare cancer associated with minimal durable disease control with chemotherapy and poor overall survival. The efficacy of combined cytotoxic chemotherapy and immune checkpoint inhibitors (ICIs) in malignant peritoneal mesothelioma has not previously been studied. We describe the clinical course of 2 patients with metastatic peritoneal mesothelioma who both relapsed with platinum nonresponsive disease after initial cytoreductive surgery and chemotherapy. In both cases, addition of pembrolizumab to platinum and pemetrexed treatment resulted in a substantial partial and a near complete disease response. Notably, both patients possessed tumors without validated biomarkers of ICI response, including low tumor mutational burden and negative programmed death ligand-1. The unique genomic landscape of each patient may have enabled increased tumor immunorecognition and ICI efficacy. In addition, chemotherapy priming of the tumor microenvironment may have improved ICI response. This report supports future research to characterize the benefit of combination chemotherapy and ICI in peritoneal mesothelioma.

DOI: https://doi.org/10.1097/CJI.0000000000000399