A Trial of Irinotecan and BKM120 in Previously Treated Advanced Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2102944 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Aberrant activation of PI3K pathway is frequently observed in triple negative breast cancer (TNBC). However single agent PI3K inhibitors have shown modest anti-tumor activity. To investigate biomarkers of response, we tested 17 TNBC PDX models with diverse genetic and proteomic background, with varying PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor BKM120 as well as baseline and treatment induced proteomic changes as assessed by reverse phase protein array (RPPA). We demonstrated that PI3K inhibition induces varying degrees of tumor growth inhibition (TGI), with 5 models demonstrating over 80% TGI. BKM120 consistently reduced PI3K pathway activity as demonstrated by reduced pAKT following therapy. Several biomarkers showed significant association with resistance, including baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment induced increase in the levels of phosphorylated forms of Aurora kinases. Sensitivity was associated with higher baseline levels of proapoptotic markers (Bak and Caspase 3) and higher number of markers being changed following BKM120 therapy. Interestingly, markers indicating PI3K pathway signaling activation at baseline were not significantly correlated to %TGI. These results provide important insights in biomarker development for PI3K inhibitors in TNBC.
2020-12-31 | GSE148949 | GEO
Project description:The objective of this study was to analyze gene expression changes with BKM120 treatment across PDX models.
2018-05-29 | GSE98824 | GEO
Project description:BKM120 Treated WHIMs_17 Model Cohort
| PRJNA626611 | ENA
Project description:In people whos cancers have a PIK3CA mutation, this trial will be evaluating the drug BKM120 as a possible treatment. BKM120 works by blocking the phosphatidylinositol-3-kinase (PI3K)pathway, thereby inhibiting tumor growth and survival.
The purpose of this study is to learn if the study drug BKM120 can shrink or slow the growth of your tumor. The safety of BKM120 will also be studied. Your physical state, symptoms, change in the size of your tumor, and laboratory findings obtained while you are on study will help the research team decide if BKM120 is safe and effective in patients with advanced cancers.
| 2117958 | ecrin-mdr-crc
Project description:The primary objective of this study was to determine the effectiveness of bortezomib alone or in combination with irinotecan in patients with advanced gastric and gastroesphageal cancer. A secondary objecitve was to determine whether treatment was associated with changes in gene expression in the tumor and normal adjascent tissue. Tumor biopsies and biopsies of normal adjascent tissue were obtained before therapy and 24 hours after therapy. Differences in gene expression were evaluated between tumor and normal tissue (N=8 patients), and between post-treatment and pretreatment specimens for bortezomib alone (N=2 patients) and bortezomib plus irinotecan (N=10 patients).
2013-11-07 | E-GEOD-52138 | biostudies-arrayexpress
Project description:The purpose of this study is to establish the safety and tolerability of BKM120 when combined with mFOLFOX6 and to define the maximum tolerated dose of BKM120 in this combination in advanced solid tumors including metastatic pancreatic cancer.
| 2123256 | ecrin-mdr-crc
Project description:Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumor efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p=0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven percent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted.
2024-08-26 | GSE275628 | GEO
Project description:Advanced colorectal cancer (CRC) is an unresolved clinical problem. Epigenetic drugs belonging to the group of histone deacetylase inhibitors (HDACi) may combat CRC in rationally designed treatment schedules. Unfortunately, there is sparse evidence on molecular mechanisms and markers that determine cellular sensitivity to HDACi. Irinotecan is widely used to treat CRC and causes replication stress (RS) and DNA damage as topoisomerase-I inhibitor. We applied irinotecan and the class I HDACi entinostat (MS-275) to isogenic p53-positive and -negative CRC cells. Combinations of irinotecan and MS-275 evoke mitochondrial damage, caspase-mediated apoptosis, and RS-associated DNA damage synergistically and p53-dependently. Targeted mass spectrometry and immunoblot show that irinotecan induces phosphorylation, acetylation, and accumulation of p53 and its target genes. Addition of MS-275 augments the irinotecan-induced acetylation of C-terminal lysine residues of p53 but decreases its phosphorylation and p53 target gene induction. Furthermore, MS-275 increases the amount of acetylated p53 at mitochondria and dysregulates the expression of pro- and anti-apoptotic BCL2 proteins in irinotecan-treated cells. Regarding DNA repair, we see that MS-275 represses the homologous recombination (HR) filament protein RAD51, which limits DNA damage and pro-apoptotic effects of irinotecan. These data suggest that key class I HDAC-dependent functions of p53 in cells with RS are linked to mitochondrial damage and a breakdown of HR. Most importantly, combinations of irinotecan plus MS-275 also kill short-term primary CRC cell cultures and organoids from CRC patients but spare organoids of adjacent matched normal tissue. Thus, irinotecan/HDACi treatment is a promising new approach for the therapy of p53-proficient tumors with clinically tractable inhibitors.
2022-02-15 | PXD019999 | Pride
Project description:A phase II study of guadecitabien combined with irinotecan vs regorafenib or TAS-102 in previously treated metastatic colorectal cancer patients
2023-03-31 | GSE226221 | GEO
Project description:For the first phase of this study (phase I), the purpose will be to find the dose of a new drug, BKM120, that can safely be given in combination with standard dose panitumumab.
For the second phase of this study (phase II), the purpose is to find out what effects the combination of BKM120 and panitumumab, in doses found to be safe in the first part of the study, has on patients and their colorectal cancer.
| 2124804 | ecrin-mdr-crc