Anti-BCL2L1 monoclonal antibody

Background To investigate the potential predictors of response to regorafenib, in chemorefractory metastatic colorectal cancer (mCRC) patients with long-term efficacy from regorafenib treatment. Methods Retrospective, single institution analysis of patients with chemorefractory mCRC treated with regorafenib, in clinical practice setting. 123 patients were treated and stratified into two groups according to number of cycles received (< 7 and >= 7). Overall survival (OS), progression-free survival (PFS) and safety were evaluated. 20 tumour samples (10 poor and 10 long responders) were analysed with the OncoMine Comprehensive Assay for 143 genes. Results A good Eastern Cooperative Oncology Group performance status, a lung limited metastatic disease and a long history of metastatic disease were significantly associated with better OS and PFS from treatment with regorafenib. Mutations were mostly found in TP53, KRAS and PIK3CA as well as in NRAS, ERBB2, SMAD4 and PTEN genes. BCL2L1, ERBB2, KRAS, MYC, GAS6 gene amplifications were detected as well as ALK rearrangement. No significant correlation between molecular alterations and response to regorafenib was observed. However, HER2 gene alterations were found in three poor responder patients, suggesting a potential role in regorafenib resistance. Conversely, GAS6 amplification and SMAD4 mutation, detected in two long responder patients, might suggest a role of epithelialmesenchymal transition phenotype in regorafenib response. Conclusion A subgroup of long responder patients to regorafenib treatment was identified and a comprehensive molecular characterisation was performed; however, further research efforts are essential to confirm our data.

STUDY QUESTION: Is the phosphoinositol 1,3-kinase/protein kinase B (PI3K/AKT) pathway expression profile in cumulus cells (CCs) a potential marker of oocyte competence and predictive of pregnancy outcome? SUMMARY ANSWER: Eleven genes (AKT1, ARHGEF7, BCL2L1, CCND1, E2F1, HRAS, KCNH2, PIK3C2A, SHC1, SOS1 and SPP1) in the PI3K/AKT pathway were significantly down-regulated in CCs from oocytes that went on to produce a pregnancy compared to CCs associated with a negative outcome. WHAT IS KNOWN ALREADY: The PI3K/AKT pathway plays a pivotal role in the interdependence and continuous feedback between the oocyte and CCs. STUDY DESIGN SIZE, DURATION: The expression analysis of 92 transcripts in the PI3K/AKT pathway in CCs from patients with negative or positive pregnancy outcome, after single embryo transfer, was performed. Mouse CCs target gene expression was conducted to associate the expression profile of PI3K/AKT pathway to oocyte developmental profile. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fifty-five good prognosis IVF patients who had been referred to IVF or intracytoplasmic sperm injection treatment for male-factor infertility or tubal disease were enroled. CCs from single cumulus-oocyte complexes (COCs) from 16 patients who underwent a single embryo transfer were analyzed. Twenty-five CD-1 mice were used to assess gene expression in CCs associated with oocytes with different competence in relation to hCG priming. A total 220 human COCs were collected. The RNA extracted from CCs of 16 selected patients was used to analyze PI3K/AKT pathway gene expression employing a 96-well custom TaqMan Array. Expression data of CCs associated to positive IVF outcome were compared to data from negative outcome samples. Mice were sacrificed after 9, 12, 15, 21 and 24 h post-hCG administration to obtain CCs from MII oocytes with different developmental competence. Akt1, Bcl2l2 and Shc1 expression were tested in the collected mouse CCs. In addition, the expression of upstream regulator ESR1, the gene encoding for the oestrogen receptor ER beta, and the downstream effectors of the pathway FOXO1, FOXO3 and FOXO4 was evaluated in human and mouse samples. MAIN RESULTS AND THE ROLE OF CHANCE: Transcripts involved in the PI3K Signaling Pathway were selectively modulated according to the IVF/ICSI outcome of the oocyte. Eleven transcripts in this pathway were significantly down-regulated in all samples of CCs from oocytes with positive when compared those with a negative outcome. These outcomes were confirmed in mouse CCs associated with oocytes at different maturation stages. Expression data revealed that the down-regulation of ESR1 could be related to oocyte competence and is likely to be the driver of expression changes highlighted in the PI3K/AKT pathway. LIMITATIONS REASONS FOR CAUTION: Small sample size and retrospective design. WIDER IMPLICATIONS OF THE FINDINGS: The CCs expression profile of PI3K/AKT signaling genes, disclosed a specific CCs gene signature related to oocyte competence. It could be speculated that CCs associated with competent oocytes have completed their role in sustaining oocyte development and are influencing their fate in response to metabolic and hormonal changes by de-activating anti-apoptotic signals.