IGF-IR targeted cancer gene therapy

Since the declaration of "War on cancer" in 1971, and with the insight provided by recent advances in human genetics and in molecular technology, the field of cancer biology has been expanded rapidly providing hope that a cure for this lethal disease will be found. One of the major contributions of the field of cell biology to the understanding of malignant diseases has been the identification of growth factors and their receptors as major promoters of transformation and malignant progression. In particular, the appreciation of the central role that receptor tyrosine kinases (RTK) play in different cancers has led to development of effective therapeutic reagents. One of the RTK implicated in malignant progression is the receptor for the type 1 insulin like growth factor (IGF-IR) that has been identified as a target for anti-cancer treatments.;In the present work, I have introduced two different strategies to inhibit liver metastases formation using established human and murine cancer cell lines. The first strategy is based on targeting the IGF-IR in tumor cells using an antisense technology (chapter 2). This strategy was also shown to be applicable in cancer gene therapy of glioblastoma growing in the brain (chapter 3). Very interestingly and for the first time, we showed that reduction of IGF-IR expression levels in glioma cells can induce a state of dormancy, providing a unique model to study this clinically important phenomenon.;As the second strategy, I designed a novel soluble IGF-IR molecule. I showed that expression of this molecule in tumor cells caused an inhibition of tumor growth and metastasis by interfering with tumor cell access to paracrine IGF-I.;The present work provides proof of principal pre-clinical data that these strategies are viable and may be of clinical potential. It is hoped that they will eventually be the basis for clinical safety and efficacy trials, for eventual application in the treatment of cancer.;Cancer gene therapy is a rapidly developing modality for cancer therapy. Many gene therapy strategies have been developed generally targeting the genes and proteins involved in cancer initiation and progression. To design a successful gene therapy strategy requires an understanding of the molecular basis of cancer progression and knowledge of human and animal genetics and physiology.