Conclusions DCE MRI assessments of iAUC60 and Ktrans responses provide evidence that the multi angiokinase inhibitor nintedanib can modulate tumour blood flow and perme ability in patients with advanced, refractory CRC, while maintaining an acceptable, manageable safety profile. A RECIST response of stable disease or better was also ob served in 80% of this population Vismodegib FDA of heavily pretreated patients. encouraging results that support further clinical investigation of nintedanib in this salvage setting. Study design Define the role of ER and E2F1 in the resistance of ER negative breast cancer cells to 4 hydroxy tamoxifen and develop new therapies to promote E2F1 mediated apoptosis in this type of breast cancer cell. Background Human breast cancer is a heterogeneous disease with respect to molecular alterations, incidence, survival, and response to therapy.

Tamoxifen has been used for the systemic treatment of patients with breast cancer for nearly four decades, and the success of this treatment is primarily dependent on the presence of oestrogen receptor in the breast carcinoma. Approxi mately half of patients with advanced ER positive disease immediately fail to respond to tamoxifen, and the disease ultimately progresses to a resistant pheno type in the responding patients. The possible causes for intrinsic and acquired resistance have been attributed to the pharmacology of tamoxifen, alterations in the struc ture and function of the ER, interactions with the tumour environment, and genetic alterations within the tumour cells.

Therefore, understanding the role of ER in the development and progression of hormone unresponsive and receptor dependent breast cancer is an important step in the development of future therapeutics. Tamoxifen and newer selective ER modifiers compete with estradiol to bind the ER in multiprotein complexes that involve several co repressor proteins. In contrast to estradiol bound ER, the tamoxifen ER complex is typic ally unable to promote tumour growth due to altered gene transcription and nongenomic activities of the ER. In vitro studies have shown that anti oestrogen treatment of breast cancer cells can induce growth arrest via the induction of the cyclin dependent kinase inhibitors p21 and p27 and cell death by mecha nisms that are still being defined.

The growth inhibitory effects of anti oestrogens in ER positive breast cancer cells are profound, and this allowed early demonstration of a G1 phase site of action for anti oestrogens. Studies using Carfilzomib synchronized cells dem onstrated that cells were more sensitive to oestrogens and anti oestrogens in the early G1 phase, immediately following mitosis, compatible with a model whereby oestrogens and anti oestrogens acting via the ER regulate the rate of progression through the early G1 phase of the cell cycle.