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Mayura Meerang
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.03 - Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma (Now Available) (ID 2349)
15:45 - 17:15 | Presenting Author(s): Mayura Meerang
- Abstract
- Presentation
Background
Loss of the tumor suppressor NF2 is frequent in malignant pleural mesothelioma (MPM). NF2 suppresses tumorigenesis in part by inhibiting Cullin4 ubiquitin ligase (CUL4) complex. Here we aimed to evaluate an importance of CUL4 in MPM.
Method
We evaluated the expression of CUL4A and CUL4B in tissue microarrays using immunohistochemistry. We tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation, in 13 cell lines and 3 primary cells in 2D and 3D culture. Four groups of SCID mice haboring intraperitoneal (ip.) pevonedistat sensitive (MSTO211H) or resistant (ACC-Meso1) cell lines were treated with pevonedistat (50 mg/kg; ip.) on a 5day on/5day off schedule for 3 cycles. Treatment efficacy was assessed by means of overall survival.
Result
CUL4B expression was associated with clinical outcomes (figure 1). Five MPM cell lines (38%) were highly sensitive to pevonedistat (IC50<500 nM). This remained true in 3D spheroid culture. The treatment induced S/G2 cell cycle arrest and accumulation of cells undergoing DNA re-replication (containing >4N DNA content) known to be mediated by p21 and CDT1 accumulation. Indeed the accumulation of p21 and CDT1 was more pronounced in pevonedistat sensitive cell lines after the treatment. Two of primary cells (67%) were sensitive to pevonedistat and also showed higher CDT1 accumulation following the treatment compared to the resistant cells. In vivo, pevonedistat treatment significantly prolonged survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth (phosphorylated histoneH3 positive) in pevonedistat sensitive tumor but increased apoptosis (cleaved–caspase3 positive) in pevonedistat resistant tumor.
Conclusion
High CUL4B expression may play a role in MPM progression. Inhibition of cullins by pevonedistat induced growth arrest and DNA re-replication strongly in a subset of MPM. The major mechanism seems to be mediated by p21 and CDT1 accumulation in vitro. Investigation of mechanisms in vivo is ongoing.
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P1.06 - Mesothelioma (ID 169)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.06-15 - Safety of Irradiation Combined with Intracavitary Cisplatin-Fibrin After Lung-Sparing Surgery in a Rat Model of Mesothelioma (ID 2372)
09:45 - 18:00 | Author(s): Mayura Meerang
- Abstract
Background
To investigate feasibility and toxicity of new localized therapeutic treatment combinations for malignant pleural mesothelioma (MPM), we performed lung-sparing surgery followed by cisplatin-fibrin application and hemithoracic irradiation in an orthotopic immunocompetent rat model of MPM.
Method
Male F344 rats (n=9) were implanted sub-pleurally (parietal pleura) with 1 million rat mesothelioma cells (IL45-luciferase). Formed tumor nodules confirmed by IVIS bioluminescence imaging (BLI) were resected on day 9 after implantation. Following resection, animals were treated with local-intracavitary cisplatin-fibrin or placebo (NaCl-fibrin). Three days later, CT guided local irradiation of the former tumor region, resembling IMRT in human patients, was performed. Irradiation was given in a single high dose application using the image-guided stereotactic small animal irradiation X-RAD SmART (small animal radiotherapy) and image guided biological irradiator PXi (precision X-Ray) with precise localization.
Treatment schemes after tumor resection were as followed:
i) Intracavitary cisplatin-fibrin application (n=2)
ii) Irradiation with 10 Gy (n=2)
iii) Irradiation with 20 Gy (n=1)
iv) Intracavitary cisplatin-fibrin plus 10 Gy radiotherapy (n=2)
v) Intracavitary cisplatin-fibrin plus 20 Gy radiotherapy (n=2)
Wellbeing of the animals was monitored daily until the predefined termination criteria were reached. Particular attention was given to possible irradiation toxicity related pulmonary side effects and weight loss.
Result
We successfully treated 1-2 animals per group according to the methods above. The irradiation was performed after visualization of the tumor with BLI- and CT-imaging to ensure an individual treatment plan. None of the animals, whether with radiotherapy alone or in combination with cisplatin-fibrin application, showed any signs of pulmonary side effects. In addition, none had reduced pulmonary functions, measured by increased breathing or the appearance of blue or white colored ear/extremities/eyes assuming desaturation. Furthermore, neither significant body weight loss of ≥ 15%, deterioration of body conditioning score nor of the activity score were observed in the immediate post-interventional phase. In all animals, termination endpoint was reached because of tumor relapse.
Conclusion
In this pilot study, we have shown that irradiation alone and in combination with local intracavitary cisplatin-fibrin application in rats is safe and feasible up to a dosage of 20 Gy. The efficacy of the various treatment schemes and a possible radio-sensitizing effect by intracavitary cisplatin is currently being evaluated in the same animal model.
