In vivo functional characterization of kinases that contribute to resistance to endocrine therapy
Resistance to endocrine therapy in estrogen receptor (ER) positive breast cancers is a major clinical challenge. Studies show that resistant tumors may develop the ability to grow independently of estrogen and these will therefore not respond to the ER-targeting drugs. One feature of hormone resistance is activation of other signalling pathways via receptor tyrosine kinases (RTKs) such as Human epidermal growth factor receptor (HER), Fibroblast growth factor receptor (FGFR) or other kinases such as cyclin dependent kinases (CDKs). Studies show that there are ER-independent pathways controlling tumour growth in breast tumours via the transcription factor FOXA1. FOXA1 may induce growth independently of ER, which confers resistance to the anti ER therapies.
The aim of this project is to investigate how activation of signaling pathways mediated by RTKs influences the growth of hormone responsive tumors as well as resistant tumors. Additionally, how these tumors respond to commonly used breast cancer therapy, especially therapies targeting ER, HERs, FGFRs and CDKs.
Increased knowledge concerning tumour development and resistance to therapy is of importance to improve treatment of cancer patients, identify novel treatment strategies and enable development of new cancer drugs. Breast cancer is the most frequent cancer type in women however up to 30% develop resistance to endocrine therapy. Thus, understanding the molecular mechanisms involved in this resistance may contribute to the development of new therapeutic strategies.
The effect of kinase inhibitors combined with growth factors will be assessed using tumor growth as a measure and this cannot be done without using animals. We have developed a protocol for testing drugs ex vivo from cells derived from the PDX mice in order to reduce the number of animals. Additionally, all drugs and growth factors are tested in cell lines prior to in vivo experiments.
The PDX models that is included in this project are well established in our lab and we have long experience working with with these models. All experimental procedures are internationally accepted and performed by trained personnel to minimise the stress applied on the mice. The tumours developing in the mammary gland are not to hinder for the natural behaviour of the mice. We will use approximately 1500 NOD/SCID +/- EGFP mice over a 4 year period of time.
Furthermore, we follow relevant literature, participate in meetings and discussions aiming at refining our experimental procedures and reducing the number of animals required to obtain valid experimental data.
This project is a continuation of the preceding project FOTS nr 7755.
The aim of this project is to investigate how activation of signaling pathways mediated by RTKs influences the growth of hormone responsive tumors as well as resistant tumors. Additionally, how these tumors respond to commonly used breast cancer therapy, especially therapies targeting ER, HERs, FGFRs and CDKs.
Increased knowledge concerning tumour development and resistance to therapy is of importance to improve treatment of cancer patients, identify novel treatment strategies and enable development of new cancer drugs. Breast cancer is the most frequent cancer type in women however up to 30% develop resistance to endocrine therapy. Thus, understanding the molecular mechanisms involved in this resistance may contribute to the development of new therapeutic strategies.
The effect of kinase inhibitors combined with growth factors will be assessed using tumor growth as a measure and this cannot be done without using animals. We have developed a protocol for testing drugs ex vivo from cells derived from the PDX mice in order to reduce the number of animals. Additionally, all drugs and growth factors are tested in cell lines prior to in vivo experiments.
The PDX models that is included in this project are well established in our lab and we have long experience working with with these models. All experimental procedures are internationally accepted and performed by trained personnel to minimise the stress applied on the mice. The tumours developing in the mammary gland are not to hinder for the natural behaviour of the mice. We will use approximately 1500 NOD/SCID +/- EGFP mice over a 4 year period of time.
Furthermore, we follow relevant literature, participate in meetings and discussions aiming at refining our experimental procedures and reducing the number of animals required to obtain valid experimental data.
This project is a continuation of the preceding project FOTS nr 7755.