Pamela Pollock, PhD

Translational Genomics Research Institute, Phoenix, Arizona
“Investigation of FGFR2 as a Novel Oncogene in Melanoma”

Research Summary:

For a normal cell to divide and make two cells (proliferate), it detects growth factors from outside the cell through growth factor receptors on the cell surface. When these growth factors bind to their specialized receptor, the receptor has a change in conformation (shape), which turns the receptor “on”, this then results, through a complex cascade of phosphorylation events (chemical signals), to the transmission of a signal into the cells nucleus to tell the cell to divide. In cancer, one of the many events that result in uncontrolled tumor growth, is that these growth factor receptors can acquire mutations (changes in the DNA sequence) which alter the receptors conformation so that it is now stuck in a permanently “on” position and signals as if there are growth factors outside the cell telling it to divide, when in fact there are not.

My lab has found mutations in one of these receptors, the fibroblast growth factor receptor 2 (FGFR2) in 12% of melanoma samples. We have also found alternative spliceforms, differences in which exons (segments) of DNA are combined to produce the finished receptor, in ~40% of melanoma cell lines. My lab is now studying how these mutations and alternative spliceforms change the receptor so it is stuck in the “on” position. We are also testing a new drug that has been shown to bind to several of these growth factor receptors, including FGFR2, in a panel of melanoma cell lines. We want to work out whether this drug can stop these melanoma cell lines growing and/or kill them and we want to know if it works better in cell lines carrying mutations in FGFR2. As these growth factor receptors are expressed in many normal tissues and not just melanomas, we are also investigating in detail the different downstream signaling pathways that FGFR2 uses to specifically signal melanoma cells to proliferate. We hope this will help us identify better targets for which we can design inhibitors (drugs), in the event that broad inhibition of multiple FGFR receptors proves to be either ineffective or have unwanted side effects in future clinical trials on melanoma patients.

Dr. Antiono Ribas
Research Statement
Year 1 Progress Report

Dr. Ribas and his colleagues are conducting studies aimed at understanding how the immune system can be effectively used to treat cancer. The work is focused on the ability to activate immune killer cells specifically targeted to the cancer. One line of research is the use of dendritic cell vaccines that are genetically modified to increase their ability to activate immune killer cells. This approach has been taken from studies in mice to human gene therapy phase I clinical trials in patients with malignant melanoma and liver carcinoma. Another line of research is the genetic engineering of blood stem cells or immune killer cells to become specific for a melanoma tumor antigen. In addition, these immune killer cells redirected to target melanoma antigens are also being engineered to express genes that allow to imaging them in living mice without having to sacrifice the animal. Therefore, their circulation in the recipient mice and their ability to adequately target to the melanoma tumors can be studied in a living animal. Another line of research is the clinical development of approaches based on CTLA4 blocking monoclonal antibodies. When given to patients with melanoma, a small subset of patients has complete regression of their cancer. Research is focused in understanding the factors that guide the sensitivity and resistance of tumors to the administration of CTLA4 blocking antibodies, and means to increase the response rates. Finally, a line of research is aimed at increasing the contribution of natural killer cells to immune responses against cancer.