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    Research Grants Awarded

    Gene Profiling and in vivo Imaging in Characterizing the Metastatic Phenotype Regulated by the Type I IGF Receptor in Breast Cancer

    Study Section:
    Tumor Cell Biology IV

    Scientific Abstract:
    Background: Metastatic breast cancer is incurable. New targets that inhibit metastases offers hope to patients. The type I insulin-like growth factor receptor (IGF1R) stimulates growth and proliferation of breast cancers. Its role in regulating metastasis is not clearly delineated. We have discovered that in some metastatic breast cancer cells IGF1R does not affect tumor growth but regulates the development of pulmonary metastases in athymic mice. Several reagents against IGF1R are in phase I clinical trials for breast cancer. Objective/Hypothesis: The hypothesis is that IGF1R regulates metastases independent of tumor growth. Thus, response to anti-IGF1R therapy will need to be measured by methods other than shrinkage in tumor size. Our objective is to determine if the expression patterns of a set of genes can predict response to reagents targeting IGF1R in the metastatic setting. Specific Aims: 1) To determine if a genetic profile distinguishes tumors where IGF1R regulates the metastatic phenotype independent of tumor growth and if response to anti-IGF1R therapy can be predicted by changes in the expression of a set of genes, 2) To validate the metastatic signature against other metastatic breast cancer cell lines where IGF1R regulates motility, and 3) Identify the mechanisms by which IGF1R enhances metastasis. Study Design: MDA435/LCC6 cells, a metastatic variant of ER- MDA-MB-435 breast cancer cells cells, MDA-MB-231BO, and T47D-YA cells will be used. We have shown that in these cells IGF1R does not regulate growth but stimulates motility in vitro. IGF1R does not affect tumor growth in a xenograft model when the cells are injected into the mammary fat pad. However, IGF1R regulates pulmonary metastases in the same xenograft model. Two approaches to inhibit signaling via IGF1R in LCC6 cells will be used. Cells with the truncated receptor (LCC6-DN) grow as xenograft tumors in athymic mice similar to cells with wild-type receptor (LCC6-WT), but unlike LCC6-WT cells, LCC6-DN do not colonize the lungs in the metastasis model. We will determine the expression profile of selected genes in LCC6-WT cells compared to LCC6-DN cells. The identification of these genes will then be validated against LCC6-WT cells treated with an antibody against IGF1R, EM164, which inhibits metastases in our model, and against two other metastatic breast cancer cells, in order to identify selected genes whose expression profile could serve as a signature of response to anti-IGF1R therapy in the metastatic setting. Potential outcomes: This is highly relevant to breast cancer metastasis in particular for patients with primary tumors that may not respond to anti-IGF1R drugs but who may still have inhibition of their metastases. However, since response to therapy is generally monitored by tumor size in clinical trials, such patients who could benefit from this targeted therapy will be excluded. Our work will test an important concept in the development of new therapies.

    Lay Abstract:
    Women whose breast cancers are diagnosed earlier in the course of disease progression before the cancer cells have spread or metastasized to other organs have relatively good prognosis. Most of the deaths due to breast cancer are caused by metastasis of the cancer at sites removed from the breast such as the lungs, liver or bone. Thus, identification of new targets that cause breast cancer metastasis is needed so that drugs targeting them can be developed to inhibit metastasis. Several proteins on the surface of the cells are responsible for the growth and metastasis of cancer. One such protein is HER2 and an antibody against it called Herceptin is used to successfully treat some metastatic breast cancer patients. Thus, a reagent that targets a protein on the surface of cells is useful in treating metastatic disease. Another protein on the surface of cells is called the type I IGF receptor (IGF1R). Factors secreted by our cells called insulin-like growth factors bind to IGF1R and transmit signals that make breast cancer cells grow and move. The importance of IGF1R in causing cancers to grow is clear and IGF1R has become a new target for developing therapies to inhibit tumor growth. The effect of IGF1R on cancer metastasis is not well understood. There are several reagents targeting IGF1R that have been developed in the past two years for potential use in cancer therapy. One of them is currently in a Phase I clinical trial for multiple myeloma. Others are finishing preclinical testing and will be entering clinical trials in the next year. Like other drugs developed, these drugs are being tested based only on their ability to cause tumor shrinkage in animal models. However, we have recently discovered that IGF1R can cause metastasis of breast cancer cells independent of regulating growth of the primary tumor in a mouse model of cancer. When cells with a functional IGF1R were used, the cells grew as tumors and spread to the lungs of mice where they formed metastatic nodules. When we made a modified IGF1R which was no longer functional, these cells still grew as tumors but did not metastasize to the lungs. Similarly, when we utilized a therapeutic approach using an antibody against IGF1R which inhibits the signals transmitted by IGF1R, we found that in these cells, this antibody did not inhibit the growth of the tumor, but it completely blocked or prevented the formation of metastases in the lungs of mice. These data suggest that IGF1R can cause metastases to form but not affect the growth of the primary tumor. This also suggests that a drug that targets IGF1R can prevent or inhibit metastasis. Our hypothesis is that IGF1R can affect breast cancer metastasis without affecting tumor growth. However, since clinical trials do not measure tumor metastasis, it is extremely important to develop methods that can detect metastases. Our goal is to develop other techniques to measure this important characteristic of cancer that is regulated by IGF1R.