Mutation of Bcr-Abl is an important mechanism by which chronic myelogenous leukemia (CML) cells become resistant to Gleevec. The T315I mutation is clinically significant since CML cells harboring this mutation are insensitive to Gleevec and other Bcr-Abl-targeted drugs. Identification of new agents capable of effectively killing CML cells with T315I mutation would have important therapeutic implications in Gleevecresistant CML. Here, we showed that b-phenylethyl isothiocyanate (PEITC), a natural compound found in vegetables, is effective in killing CML cells expressing T315I BCR-ABL. Treatment of leukemia cell lines harboring wild-type or mutant Bcr-Abl with 10 lM PEITC resulted in an elevated ROS stress and a redox-mediated degradation of the BCR-ABL protein, leading to massive death of the leukemia cells. Antioxidant NAC attenuated the PEITC-induced oxidative stress in CML cells and prevented the degradation of BCR-ABL, caspase-3 activation and cell death. We further showed that the ROS-induced degradation of BCR-ABL was mediated partially by caspase-3 and the proteasome pathway. The ability of PEITC to effectively kill T315I-positive CML cells was further confirmed using primary leukemia cells isolated from CML patients. Our results suggest that PEITC is a promising compound capable of killing Gleevec-resistant CML cells through a ROS-mediated mechanism and warrants further investigations.

Background Atezolizumab is an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody that blocks the binding of PD-L1 to PD-1 and B7.1 receptors, thereby restoring tumor-specific immunity. TNBC is characterized by PD-L1 expression on tumor-infiltrating immune cells (IC), high levels of tumor-infiltrating lymphocytes (TILs), and a higher mutation rate compared with other breast cancers suggesting a therapeutic opportunity for atezolizumab. Atezolizumab alone and in combination with nab-paclitaxel is well tolerated, with promising clinical activity in metastatic TNBC. Furthermore, cytotoxic chemotherapies like nab-paclitaxel can enhance anti-tumor immune responses via neoantigen release. Taken together, this supports the investigation of atezolizumab in combination with nab-paclitaxel in early-stage TNBC. IMpassion031 is a global Phase III, double-blind, randomized, multicenter, placebo-controlled study being conducted to evaluate the efficacy and safety of neoadjuvant treatment with nab-paclitaxel → doxorubicin + cyclophosphamide and either atezolizumab or placebo in invasive stage II/III early TNBC. The selection and sequence of chemotherapy has been chosen to maximize the opportunity for a robust immune response. Methods: Eligible patients are those with previously untreated, central laboratory–confirmed invasive TNBC with primary tumor size > 2 cm and ECOG PS 0-1. Exclusion criteria include history of invasive breast cancer, stage IV disease, bilateral breast cancer, prior systemic therapy for the treatment or prevention of breast cancer, prior immunotherapy and a history of autoimmune disease. Approximately 204 patients will be randomized 1:1 to receive atezolizumab (840 mg q2w) or placebo with nab-paclitaxel (125 mg/m2 qw) for 12 weeks. Subsequent atezolizumab (840 mg q2w) or placebo with doxorubicin (60 mg/m2 q2w) + cyclophosphamide (600 mg/m2 q2w) will be given for 4 cycles prior to surgery. Post-surgery, patients will be unblinded. Patients in the atezolizumab arm will continue to receive atezolizumab (1200 mg q3w × 11 doses) post-surgery. Stratification factors include stage II vs III TNBC at diagnosis and PD-L1 expression on tumor-infiltrating IC (IC0 < 1% vs IC1/2/3 ≥ 1% with the VENTANA SP142 IHC assay). The primary endpoint is pathologic complete response (pCR); key secondary endpoints include pCR according to PD-L1 IC status, patient-reported outcomes, event-free survival and overall survival. Tumor samples will be taken at baseline, on treatment (optional), at surgery and post-recurrence for the assessment of biomarkers associated with treatment response and immune escape. (NCT pending). Citation Format: Mittendorf E, Barrios CH, Harbeck N, Miles D, Saji S, Zhang H, Duc A-N, Rafii S, Lai C. IMpassion031: A phase III study comparing neoadjuvant atezolizumab vs placebo in combination with nab-paclitaxel–based chemotherapy in early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-03.