Purpose: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors. Experimental Design: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks. Results: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mgonce daily. A plateauin steady-state exposure was observedat doses of z800 mg once daily.The mean elimination half-life at this dose was 31.1hours. A mean target trough concentration (C 24 ) z15 Ag/mL (34 Amol/L) was achieved at 800 mg once daily.Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of z6 months was observedin 14 patients; clinical benefit was generally observed in patients who received doses of z800 mg once daily or 300 mg twice daily. Conclusion: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.

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Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer.

Research has indicated that childhood cancer may lead to posttraumatic growth (PTG), given cancer's association with posttraumatic stress. PTG may be associated with family/home and health care dynamics, as well as parental resilience, distress, and coping. This cross-sectional study investigated the associations of psychosocial factors of the patient, family, and health care team with PTG and illness-related burden (IRB) in childhood cancer survivors. The sample comprised 61 children and adolescents (7-18 years of age), their parents, and their nurses. Respondents completed their assessment an average of 1.73 years after the end of treatment for the child's disease, which was either leukemia, a solid tumor, or lymphoma. Regression analyses showed that PTG was positively associated with the patients' posttraumatic stress symptoms. It was also positively associated with the parents' religious coping, and with measures of stronger family and oncologist relationships (R = .32). IRB was positively associated with patient-reported posttraumatic stress symptoms, negatively associated with the nurse's trust in the family, and positively associated with parent-reported mental distress, lower family socioeconomic status, and female gender (R = .53). There was no significant association with parenting style or parent-reported posttraumatic stress symptoms in the child. The findings suggested that the young cancer patient's psychosocial and resource milieu (e.g., financial) may be instrumental in PTG and IRB. Psychosocial interventions with high-risk families and their health care teams could increase growth and reduce burden.

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