Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer.

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The “epithelial barrier hypothesis” proposes that genetic predisposition to epithelial barrier damage, exposure to various epithelial barrier–damaging agents and chronic periepithelial inflammation are responsible for the development of allergic and autoimmune diseases. Particularly, the introduction of more than 200,000 new chemicals to our daily lives since the 1960s has played a major role in the pandemic increase of these diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defence against external factors. A leaky epithelial barrier initiates the translocation of the microbiome from the surface of affected tissues to interepithelial and even deeper subepithelial areas. In tissues with a defective epithelial barrier, colonization of opportunistic pathogens, decreased microbiota biodiversity, local inflammation, and impaired regeneration and remodelling takes place. A dysregulated immune response against commensals and opportunistic pathogens starts. Migration of inflammatory cells to other tissues and their contribution to tissue injury and inflammation in the affected tissues are key events in the development and exacerbation of many chronic inflammatory diseases. Understanding the underlying factors that affect the integrity of epithelial barriers is essential to find preventive measures or effective treatments to restore its function. The aim of this review is to assess the origins of allergic and autoimmune diseases within the framework of the epithelial barrier hypothesis.

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BRCA1 and BRCA2 are involved in control of DNA repair by homologous recombination (HR). Germline mutations in these genes substantially increase lifetime risk of developing breast, ovarian and other cancers. BRCA-deficient tumors show increased sensitivity to therapies that target defective HR. Sporadic tumors lacking germline BRCA mutations but sharing the molecular features of BRCA-mutant tumors may respond to these types of therapies as well. PARP inhibitors represent a form of targeted therapy for HR-deficient tumors that have been approved in ovarian cancer and are being tested in clinical trials in breast cancer, metastatic castration-resistant prostate cancer, and glioblastoma. Our lab has previously identified a small molecule called ONC201 in a screen for compounds capable of inducing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Our lab has previously reported that ONC201 induces an integrated stress response that involves ATF4/CHOP and inactivates pro-survival kinases Akt and ERK. The latter leads to decreased phosphorylation of transcription factor FOXO3a, its nuclear translocation, and induction of transcription of the target gene TRAIL. A first-in-human clinical trial showed that the compound is well tolerated, achieves a therapeutic pharmacokinetic profile, exhibits biological activity. It has since entered multiple phase I/II trials. ONC201 has anti-proliferative and pro-apoptotic effects in a wide range of tumor types including BRCA-deficient breast and ovarian cancers (n=10), with GI50 values in the low micromolar range. Treatment with ONC201 induces surface TRAIL and inhibits Akt activity in BRCA deficient breast and ovarian cancers. PARP inhibitors have been previously shown to upregulate DR5 through transcription factor CHOP, sensitizing solid tumors to TRAIL. Resistance to PARP inhibitors can occur through PI3K/Akt pathway activation, and PI3K/MEK blockade improves their anti-tumor effects. We observed synergy between ONC201 and PARP inhibitors olaparib and rucaparib in BRCA-deficient breast and ovarian cancer cell lines in cell viability assays with combination indices (CI) ranging from 0.4 - 0.8. Robust synergy was also observed in prostate cancer and glioblastoma cells. The mechanisms of the observed synergy are currently under investigation. These results indicate that ONC201 possesses single agent activity in BRCA-deficient cancer cells and that the combination of ONC201 with PARP inhibitors represents a promising synergistic therapeutic approach that could be exploited in multiple solid tumors. Citation Format: Marie D. Baumeister, Ozan C. Küçükkase, Varun V. Prabhu, David T. Dicker, Josh E. Allen, Wafik S. El-Deiry. ONC201 shows efficacy in BRCA-deficient cancer cells and synergy with PARP inhibitors in glioblastoma, breast, prostate, and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3212. doi:10.1158/1538-7445.AM2017-3212