PurposeThe primary objective of this phase I dose-escalation study was to identify the maximum tolerated dose (MTD) of sunitinib plus pemetrexed in patients with advanced cancer.MethodsUsing a 3 + 3 dose-escalation design, patients received oral sunitinib qd by continuous daily dosing (CDD schedule; 37.5 or 50 mg) or 2 weeks on/1 week off treatment schedule (Schedule 2/1; 50 mg). Pemetrexed (300–500 mg/m2 IV) was administered q3w. At the proposed recommended phase 2 dose (RP2D), additional patients with non-small cell lung cancer (NSCLC) were enrolled.ResultsThirty-five patients were enrolled on the CDD schedule and seven on Schedule 2/1. MTDs were sunitinib 37.5 mg/day (CDD/RP2D) or 50 mg/day (Schedule 2/1) with pemetrexed 500 mg/m2. Dose-limiting toxicities included grade (G) 5 cerebral hemorrhage, G3 febrile neutropenia, and G3 anorexia. Common G3/4 drug-related non-hematologic adverse events (AEs) at the CDD MTD included fatigue, anorexia, and hand–foot syndrome. G3/4 hematologic AEs included lymphopenia, neutropenia, and thrombocytopenia. No significant drug–drug interactions were identified. Five (24%) NSCLC patients had partial responses.ConclusionsIn patients with advanced solid malignancies, the MTD of sunitinib plus 500 mg/m2 pemetrexed was 37.5 mg/day (CDD schedule) or 50 mg/day (Schedule 2/1). The CDD schedule MTD was tolerable and demonstrated promising clinical benefit in NSCLC.
For a small group o f important developmental genes, there is preferential silencing o f either the maternal or paternal allele. This process o f preferential expression is called 'genomic imprinting'. Imprinted genes often cluster in imprinted domains. Interestingly, many imprinting domains are associated with a non-coding RNA (ncRNA) that may regulate imprinted gene expression across the entire domain. Disruptions in imprinting can have severe consequences for growth and development. To understand the complex regulation o f genomic imprinting, studies are required to determine how early embryos set up a hierarchy o f events that will establish imprinting across large chromosomal domains. The goal o f this project is to characterize the mouse K cn q lo tl ncRNA and its role in imprinted gene regulation. My findings indicate that the K cn q lo tl ncRNA terminates at 463 kb from the transcriptional start site, and that this length is conserved in various tissues and developmental stages. This extends the boundary between the K cn q lo tl and H I9 domains, downstream o f Th, between 464 and 617 kb. shRNA and siRNA depletion o f the K cn q lo tl transcript at 43 kb and 460 kb, respectively, indicates that K cn q lotl is one continuous transcript as opposed to having multiple start sites along the length. In addition, the K cn q lo tl transcript originates from the imprinting control region (ICR), as deletion o f the paternal ICR, which contains the K cn q lo tl promoter, results in loss o f amplification along the entire length o f the transcript. To determine whether the K cn q lo tl ncRNA regulates domain-wide imprinting during early embryogenesis, RNA interference was employed to deplete K cnqlotl in embryonic and extraembryonic stem cells. Loss o f >90% o f the K cnqlotl transcript had no effect on imprinted expression in the domain, nor on imprinted méthylation at the K cn q lo tl ICR, suggesting that transcription itself may play a more important role than the transcript per se. Results from this study will lead to a better understanding o f the role that long ncRNAs play in establishing and/or maintaining imprinted gene regulation across imprinting domains, as well as their role in human imprinted disorders.
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