The Per1 gene is a core clock factor that plays an essential role in generating circadian rhythms. Recent data reveal that major biological pathways, including those critical to cell division, are under circadian control. We report here that Per1 provides an important link between the circadian system and the cell cycle system. Overexpression of Per1 sensitized human cancer cells to DNA damage-induced apoptosis; in contrast, inhibition of Per1 in similarly treated cells blunted apoptosis. The apoptotic phenotype was associated with altered expression of key cell cycle regulators. In addition, Per1 interacted with the checkpoint proteins ATM and Chk2. Ectopic expression of Per1 in human cancer cell lines led to significant growth reduction. Finally, Per1 levels were reduced in human cancer patient samples. Our results highlight the importance of circadian regulation to fundamental cellular functions and support the hypothesis that disruption of core clock genes may lead to cancer development.
Epidermal growth factor receptor (EGFR) mutations are commonly observed in Glioblastoma (GBM) and have long posed as a target for new therapies. Trials involving erlotinib have shown mixed results, likely owing to a mechanism of the mutation that may instead favor other EGFR inhibitors, such as lapatinib. We aimed to determine whether or not pulse high-dose lapatinib was a safe and tolerable regimen in addition to standard therapy. We recruited adult patients with newly-diagnosed GBM who had Karnofsky Performance Status ≥60, normal baseline hematological, hepatic, and renal function tests, and no prior history of radiation or treatment with EGFR inhibitor. Lapatinib was administered at 2500 mg twice daily for two consecutive days per week on a weekly basis throughout concomitant and adjuvant standard therapy. The primary endpoints were tolerability and safety. 12 patients were enrolled in this study over 2 years. Of the non-hematological adverse events, there were 2 grade 3 events, fatigue and post-radiation cystic brain necrosis. The most common adverse events in general were fatigue, rashes, and diarrhea. Of the hematological adverse events, there were 13 grade 3 events, all of which were due to lymphopenia and affected 6 of 12 patients. Pulse high-dose lapatinib in addition to standard therapy for newly-diagnosed GBM is a tolerable and safe regimen, but higher rates of lymphopenia should be noted. However, further investigations will be required to evaluate the efficacy of this combination for the treatments of GBM.
Trial registration
ClinicalTrials.gov Identifier: NCT01591577.
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