Pancreatic cancer has a poor prognosis due to its aggressive nature and ability to metastasize at an early stage. Currently, its management is still a challenge because this neoplasm is resistant to conventional treatment approaches, among which is chemo‐radiotherapy (CRT), due to the abundant stromal compartment involved in the mechanism of hypoxia. Hyperthermia, among other effects, counteracts hypoxia by promoting blood perfusion and thereby can enhance the therapeutic effect of radiotherapy (RT). Therefore, the establishment of integrated treatments would be a promising strategy for the management of pancreatic carcinoma. Here, the effects of joint radiotherapy/hyperthermia (RT/HT) on optimized chick embryo chorioallantoic membrane (CAM) pancreatic tumor models are investigated. This model enables a thorough assessment of the tumor‐arresting effect of the combined approach as well as the quantitative evaluation of hypoxia and cell cycle‐associated mechanisms by both gene expression analysis and histology. The analysis of the lower CAM allows to investigate the variation of the metastatic behaviors of the cancer cells associated with the treatments. Overall, this study provides a potentially effective combined strategy for the non‐invasive management of pancreatic carcinoma.
Chemotherapy (CT) is the standard care for advanced pancreatic ductal adenocarcinoma (PDAC); however, with limited efficacy. Hyperthermia (HT) treatment has been suggested as a sensitizer to improve outcomes. However, the direct effect of the HT and CT combination is not fully understood. Therefore, we aim to assess the direct cytotoxic effect of HT in PDAC cells as monotherapy or in combination with chemotherapeutics. Different temperatures (37-, 40.5-, 41-, and 41.5 °C) and durations (6-, 12-, and 24 h) were tested in PDAC cell lines (BxPC-3, Capan-1, Capan-2, PANC-1, and MIA-PaCa-2). Different concentrations of gemcitabine, 5-fluorouracil, and cisplatin were also tested in these conditions. The impact on cell metabolic activity was determined by an MTS assay. Enhancement of chemosensitivity was assessed by a reduction in half-maximal inhibitory concentration (IC50). HT and chemotherapeutics interactions were classified as antagonistic, additive, or synergistic using the combination index. HT inhibited cell proliferation in a cell type, temperature, and duration-dependent manner. The induction of apoptosis was seen after 6 h of HT treatment, eventually followed by secondary necrosis. The HT and CT combination led to an IC50 reduction of the tested CT. At 12 h of HT, this effect was between 25 to 90% and reached a 95% reduction at 24 h. The additive or synergistic effect was demonstrated in all cell lines and chemotherapeutics, although, again, this depended on cell type, duration, and temperature. HT is cytotoxic and enhances the therapeutic effectiveness of gemcitabine, 5-fluorouracil, and cisplatin on PDAC cells. This result was further confirmed by the decrease in the expression of RRM2, TS, and ERCC1 in BxPC-3 and Capan-2 cells. These observations warrant further study in specific subsets of PDAC patients to improve their clinical outcomes.
Hyperthermia, the procedure of raising the temperature of a part of the entire body above normal for a defined period of time, is applied alone or as an adjunctive treatment to various established cancer treatment modalities such as radiotherapy and chemotherapy. Whole-Body Hyperthermia (WBHT), in contrast to local or regional hyperthermia, represents the only hyperthermia modality available for patients with disseminated malignancies. The biological rationale for the treatment of malignant disease by heat is driven by a number of reasons; a) the survival of cells depends on the temperature and duration of heating in a predictable and repeatable way; b) the tumor cell environment (such as hypoxia, poor nutrition, and low pH) that negatively influences the tumor cell killing by ionizing radiation and some chemotherapy regimens, is beneficially influenced by heat therapy; c) the differential sensitivity of normal and tumor cells to heat is dependent on cell type and environmental conditions; d) heat treatment enhances the biological effect of both radiation and chemotherapy agents. The biological rationale is based on a direct cell-killing effect at temperatures in the range of 41– 42°C. A systematic review of van der Horst et al, 2018, addressed clinical trials that used local or whole-body hyperthermia treatment (at variable temperatures) in pancreatic cancer patients. In those described trials, the weighted estimate of the treated population median overall survival was 11.7 compared to 5.6 for the control cohorts. In addition, locoregional hyperthermia (42-44°C) clinical trials showed that the weighted estimate median overall survival of the treated population was 15 months compared to 9 months in control cohorts. The MATTERS trial is a first in-human clinical investigation in advanced solid cancer patients or pancreatic adenocarcinoma patients (TxNxM1). The justification of the design is based on evaluation of pre-clinical data and clinical evaluation of clinical data, safety and/or performance of similar devices/therapies. The study is a mono-centric, non-randomized trial in which the safety and preliminary efficacy of whole-body hyperthermia will be evidenced. Well designed and performed early-stage correlative studies have the potential to strongly influence further clinical development of oncology clinical trials, and correlative data obtained from early stage trials has the potential to provide important guidance on the design and ultimate success of later stage trials. Blood samples will be collected for analysis of immunological panels (e.g. cytokines, chemokines), exosome research, RNA expression profiles. Urine will be collected for analysis of exosome research. The samples will be collected during different timepoints (before, during and after treatment). Citation Format: Ivana Gorbaslieva, Dana Mustafa, Robin Colenbier, Marc Peeters, Dirk Ysebaert, Vera Saldien, Luigi Brancato, Oleg Rudenko, Johan Van den Bossche, John Paul Bogers. First in-human, safety and preliminary efficacy study of (neo)adjuvant, model-based, whole-body hyperthermia treatment in advanced solid cancer patients or stage IV (TxNxM1) metastatic pancreatic adenocarcinoma patients: Liquid biopsies [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A023.
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