Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer.

Preclinical studies demonstrate that epidermal growth factor receptor (EGFR) signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with metastatic colorectal cancer was analyzed for safety and antitumor activity. Forty-one patients with heavily pretreated metastatic colorectal cancer received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (68%), hypomagnesemia (37%), and fatigue (15%). Thirty of 34 patients (88%) treated at the full FDA-approved doses of all three drugs tolerated treatment without drug-related dose-limiting effects. Eleven patients (27%) achieved stable disease (SD) ≥6 months and three (7%) achieved a partial response (PR) (total SD>6 months/PR= 14 (34%)). Of the 14 patients with SD≥6 months/PR, eight (57%) had received prior sequential bevacizumab and cetuximab, two (5%) had received bevacizumab and cetuximab concurrently, and four (29%) had received prior bevacizumab but not cetuximab or erlotinib (though three had received prior panitumumab). The combination of bevacizumab, cetuximab, and erlotinib was well tolerated and demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer

Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

Repeated social stress and the maturation of sexual behavior in juvenile male golden hamsters

textIn certain species, puberty is thought to be a period of susceptibility to various stressors, resulting in pathological behavioral and physiological changes subsequent to exposure during this period. However, juvenile male golden hamsters appear to be fairly resilient to pubertal stress, as compared to adult hamsters and many other species. In these experiments, repeatedly stressed juvenile male hamsters were found to be avoidant of aggressive adult male social stimuli, but did not display anxious behavior outside of a social context. In addition, several long-term changes in neural activity were associated with social stress during early puberty. The medial preoptic area and medial preoptic nucleus, and ventral tegmental area showed decreased neural activity in subjugated juveniles than in naïve individuals. Since these brain areas are involved in the expression of motivated behaviors, specifically sexual behavior, and reward pathways, we next investigated sexual behavior in virgin juveniles. When placed in a confined space with receptive females, consummatory behavior in subjugated juveniles was similar to those observed in naive juveniles. Appetitive aspects of sexual behavior were also tested in a Y-maze to allow subjects to choose whether to approach a social stimulus. When given a choice between a sexually receptive and non-receptive female social stimulus, socially stressed individuals showed anxiety related behaviors and did not show a preference. However, naïve hamsters preferred the non-receptive female. Interestingly, this effect was less significant in naïve animals tested during late puberty and early adulthood, and a preference for sexually receptive females was not observed. In addition, stressed hamsters tested with harnessed females at mid-puberty were slower to approach females, indicating altered motivation to approach adult conspecifics. This research is unique in that it is the first to suggest the disconnect between the development of consummatory and appetitive aspects of sexual behavior. Together, these data examine the effects of stress on the development of pubertal social behaviors.Neuroscienc