ABSTRACT: A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-overexpressing solid tumor malignancies
Project description:16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 27 samples (12 primary + 15 metastatic) from the 16 unique patients were assayed on Agilent 60K expression microarrays, and association between expression and response data were evaluated to identify potential biomarker of MK2206 response We conducted a phase 1b study of MK-2206 in combination with weekly paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed.
Project description:We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients.
Project description:In order to characterize the dynamics of proteins between different cellular compartments in response to selinexor (XPO1 inhibitor), MK-2206 (Akt inhibitor) an the combination i AML cells, we treated MV4-11 and PL-21 cells for 6 hours with DMSO, 1 uM selinexor, 1 uM MK-2206 or the combination. Each condition was performed in 4 biological bio-reps.
Project description:To investigate initial changes to chromatin accessibility associated with resistance to lapatinib, we performed ATAC-seq on ESO26 cells treated with 500 nM lapatinib plus 1000 nM MK-2206 (an AKT inhibitor) for 24 hours and vehicle control (DMSO) for 24 hours.
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded tissues from 53 patients with primary HER2-positive (HER2+) tumors. The series consists in 23 relapsed and 30 non-relapsed cases with similar clinical-pathological characteristics (size, pathological lymph node involvement and estrogen receptor positivity) (3-year median follow up).
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab.
Project description:Gene expression was assessed with Nanostring in the surgical specimens obtained from a Window of Opportunity trial with MK-2206 in early stage breast cancer. Tumor biopsies and surgical specimens were compared for patients who received MK-2206 along with a prospective untreated control group of patients. Greater expression of interferon related genes was seen in surgical specimens following MK-2206 and compared to untreated controls.
Project description:Gene expression was assessed with Nanostring in the surgical specimens obtained from a Window of Opportunity trial with MK-2206 in early stage breast cancer. Tumor biopsies and surgical specimens were compared for patients who received MK-2206 along with a prospective untreated control group of patients. Greater expression of interferon related genes was seen in surgical specimens following MK-2206 and compared to untreated controls.
Project description:To identify the regulatory mechanisms and signalling pathways involved in colorectal cancer (CRC) development, we compared the transcriptome of patient-derived tumor-initiating cells (TICs) with their normal stem cell counterparts of the same patient. This study demonstrates the relevance of AKT-signalling in colonic TIC proliferation and survival. Functional testing uncovered the selective AKT-inhibitor MK-2206 as a potential therapeutic for TIC-directed therapy in CRC. Gene expression profiling of tumor and normal tissues from 5 patients.
Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
