In this article, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with CT guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. Purpose: Recent studies suggest that ultrahigh-dose-rate, "FLASH," electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. Methods and Materials: Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation.

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The c-Myc oncogene (MYC) drives malignant progression, but also induces robust anabolic and proliferative programs leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. We have uncovered an essential role for the transcription factor ATF4 in survival following MYC activation. MYC upregulates ATF4 by activating GCN2 kinase through uncharged tRNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC target genes, primarily those regulating amino acid and protein synthesis, including 4E-BP1, a negative regulator of translation. 4E-BP1 is essential to balance protein synthesis, relieving MYC-induced proteotoxic stress. 4E-BP1 activity is negatively regulated by mTORC1-dependent phosphorylation and inhibition of mTORC1 signaling rescues ATF4 deficient cells from MYC-induced ER stress. Acute deletion of ATF4 significantly delays MYC-driven tumor progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC-activity, ensuring enhanced translation rates are compatible with survival and tumor progression.

Oral vancomycin treatment enhances the direct and abscopal antitumor effects of hypofractionated RT in preclinical melanoma and lung/cervical tumor models. Given the role of the gut microbiota in modulating immune cells that are also known to be involved in the response to RT, we examined whether the microbiota-regulated systemic immune response contributes to the RT-mediated anticancer immune response. The effects of oral vancomycin treatment are localized and impact the gut microbiota directly without any known systemic effects (21-23). Vancomycin (mostly targeting gram-positive bacteria) or a neomycin/metronidazole (Neo/Met) regimen (mostly targeting gram-negative bacteria

A variety of cell intrinsic or extrinsic stresses evoke perturbations in the folding environment of the endoplasmic reticulum (ER), collectively known as ER stress. Adaptation to stress and reestablishment of ER homeostasis is achieved by activation of an integrated signal transduction pathway called the unfolded protein response (UPR). Both ER stress and UPR activation have been implicated in a variety of human cancers. Although at early stages, or physiological conditions of ER stress, the UPR generally promotes survival, when the stress becomes more stringent or prolonged, its role can switch to a pro-cell death one. Here, we discuss historical and recent evidence supporting an involvement of the UPR in malignancy, describe the main mechanisms by which how tumor cells overcome ER stress to promote their survival, tumor progression and metastasis and discuss the current state of efforts to develop therapeutic approaches of targeting the UPR.