Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors. Cancer Res; 70(4); 1544-54. ©2010 AACR.

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BackgroundFamily caregivers of cancer patients often experience an impaired quality of life (QOL) and emotional distress as a result of their caregiving duties, which may potentially influence the quality of care of their care recipients. The COPE (Caregivers of cancer Outpatients’ Psycho-Education support group therapy) intervention was developed as a response to the lack of work done among family caregivers of ambulatory cancer patients in Asia. This group intervention comprised four weekly sessions simultaneously targeting psychoeducation, skills training, and supportive therapy. The present study sought to evaluate the pilot COPE intervention using both quantitative and qualitative measures. The Hospital Anxiety and Depression Scale (HADS) was used to measure both depression and anxiety, while the Caregiver QOL – Cancer (CQOLC) measured caregiver QOL. These instruments were measured at baseline pre-intervention, and immediately post-intervention. A waitlist control group design was adopted. A subset of caregivers from the intervention group were invited for a semi-structured interview post-intervention.FindingsQuantitative analyses suggest that while QOL remained stable in control group participants, intervention group participants experienced QOL improvements – both in overall QOL and in the specific domain of burden. There were no significant differences in the trajectories of depression and anxiety in both groups. Qualitative analyses suggest that this might have been a result of the intervention not only equipping participants with the relevant coping skills, but also providing a platform for emotional expression and situational reappraisal.ConclusionsThe COPE intervention has shown some efficacy in helping family caregivers of cancer patients, but more work is required before this can be implemented.Trial registrationCurrent Controlled Trials NCT02120183. Registered 17 April 2014. Retrospectively registered.

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Cross-cultural differences, which require further investigations, appear to underlie the utility and understanding of the CQOLC. More research is needed to better understand the needs of Singapore caregivers.