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Background: This trial investigated the efficacy and safety of salvage boron neutron capture therapy (BNCT) combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for recurrent head and neck cancer after prior radiotherapy (RT). Methods: BNCT was administered using an intravenous boronophenylalanine–fructose complex (500 mg/kg) in a single fraction; multifractionated IG-IMRT was administered 28 days after BNCT. For BNCT, the mucosa served as the dose-limiting organ. For IG-IMRT, the clinical target volume (CTV) and the planning target volume (PTV) were generated according to the post-BNCT gross tumor volume (GTV) with chosen margins. Results: This trial enrolled 14 patients, and 12 patients received combined treatment. The median BNCT average dose for the GTV was 21.6 Gy-Eq, and the median IG-IMRT dose for the PTV was 46.8 Gy/26 fractions. After a median (range) follow-up period of 11.8 (3.6 to 53.2) months, five patients had a complete response and four had a partial response. One patient had grade 4 laryngeal edema; another patient had a grade 4 hemorrhage. Most tumor progression occurred within or adjacent to the CTV. The 1-year overall survival and local progression-free survival rates were 56% and 21%, respectively. Conclusion: Despite the high response rate (64%) of this trial, there was a high incidence of in-field and marginal failure with this approach. Future studies combining BNCT with modalities other than radiation may be tried.

Simple Summary Glioblastoma (GBM) is the most lethal type of brain cancer. It is well known that the malignancy of cancers is dependent not only on the oncogenic properties of the tumor cells, but also on the composition of the tumor microenvironment, which includes macrophages of the immune system. The prevalence of M2 type macrophages usually promotes tumor progression as opposed to tumor-suppressing function of M1 type macrophages. In our previous studies, we identified Musashi-1 (MSI1) RNA-binding protein as a principal oncogenic factor in GBM. In this study, in a pursuit of finding secreted factors that may alter tumor microenvironment in GBM, we identified MIF1 cytokine to be positively regulated by MSI1. Moreover, we found that MSI1-mediated MIF1 secretion promotes differentiation of macrophages into pro-oncogenic M2 phenotype. The oncogenic role of MSI1/MIF1/M2 macrophage regulatory axis was also confirmed in GBM mouse models, which makes it a promising target for novel drug discovery. Abstract Glioblastoma (GBM) is the most malignant brain tumor which is characterized by high proliferation and migration capacity. The poor survival rate has been attributed to limitations of the current standard therapies. The search for novel biological targets that can effectively hamper tumor progression remains extremely challenging. Previous studies indicated that tumor-associated macrophages (TAMs) are the abundant elements in the tumor microenvironment that are closely implicated in glioma progression and tumor pathogenesis. M2 type TAMs are immunosuppressive and promote GBM proliferation. RNA-binding protein Musashi-1 (MSI1) has recently been identified as a marker of neural stem/progenitor cells, and its high expression has been shown to correlate with the growth of GBM. Nevertheless, the relationship between MSI1 and TAMs in GBM is still unknown. Thus, in our present study, we aimed to investigate the molecular interplay between MSI1 and TAMs in contributing to GBM tumorigenesis. Our data revealed that the secretion of macrophage inhibitory factor 1 (MIF1) is significantly upregulated by MSI1 overexpression in vitro. Importantly, M2 surface markers of THP-1-derived macrophages were induced by recombinant MIF1 and reduced by using MIF1 inhibitor (S,R)-3-(4-hHydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1). Furthermore, GBM tumor model data suggested that the tumor growth, MIF1 expression and M2 macrophage population were significantly downregulated when MSI1 expression was silenced in vivo. Collectively, our findings identified a novel role of MSI1 in the secretion of MIF1 and the consequent polarization of macrophages into the M2 phenotype in promoting GBM tumor progression.

Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N-mustard, play an important role in cancer drug development. BO-1051 is a new 9-anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC(50) in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future.