The Department of Radiation Oncology is in the new Perelman Center. Occupying approximately 80,000 square feet on the Concourse Level, the new treatment facilities includes the most advanced proton and conventional radiation treatment modalities available as well as public spaces designed for the highest levels of patient comfort.
Janice Lau, B.A. (Masters Student)
1) Regulation of VEGF/HIF-1a by the PI3K/Akt pathway
Vascular endothelial growth factor (VEGF) is an important regulator of blood vessel growth in cancer, and targeting it may be a means of inhibiting tumor growth. We have focused on a specific pathway that is often deregulated in human cancers, the PI3 kinase/Akt pathway. We have found that activation of this pathway leads to increased VEGF expression and have made significant progress in the last year in understanding the mechanism underlying this. Our data indicate that Akt activation is associated with phosphorylation of a transcription factor Sp1, resulting in increased binding to the VEGF promoter and activation of VEGF mRNA transcription. This pathway is operative under normal oxygen conditions; however, the PI3K/Akt pathway also appears to contribute to increased VEGF expression under hypoxia by increasing expression of a different transcription factor, hypoxia-inducible factor (HIF)-1alpha. Mechanistically this occurs through increased translation of the protein. Therefore, we have identified two separate mechanisms by which Akt can increase VEGF expression and continue to try to understand the details of these pathways.
The studies mentioned above provide insight into how oncogenic changes lead to deregulated tumor growth; however, we have also been conducting studies that may have great relevance to clinical radiotherapy. A number of EGFR inhibitors are currently being tested in the clinic, sometimes in combination with radiotherapy. These inhibitors can also decrease the expression of VEGF, and our studies show that the PI3K/Akt pathway is involved through both the Sp1 and HIF-1a transcription factors described above. Furthermore, we have found that one of these inhibitors, gefitinib, appears to increase tumor oxygenation in vivo. In theory increased tumor oxygenation should improve the efficacy of radiotherapy since optimal DNA damage and cell killing by radiation requires the presence of oxygen. It is possible that this effect on increasing tumor oxygenation results from decreased VEGF expression. This finding could be of great practical importance in terms of combining EGFR inhibitors with radiation, and we are vigorously pursuing this particular avenue of investigation.
2) Modulation of radiosensitivity by agents that alter signal transduction
There is evidence that activation of the PI3K/Akt pathway leads to increased resistance to radiation therapy. We have been conducting experiments with Dr. Anjali Gupta, another PI in the department, with nelfinavir, an HIV protease inhibitor that sensitizes tumors to radiation, perhaps by inhibiting the PI3K/Akt pathway. We have found that the drug can increase tumor oxygenation, which has important implications in the use of the drug with radiotherapy since increased oxygenation of hypoxic tumors should make them more sensitive to radiation. We are very interested in determining how nelfinavir works to radiosensitize tumors in vivo. We are also investigating other PI3K inhibitors that are currently undergoing clinical testing to determine their effects on radiosensitivity.
3) Clinical detection of hypoxia in patients with cancer
Many human cancers contain regions of hypoxia. Hypoxia is associated with resistance to radiation and perhaps to certain chemotherapeutic agents as well. Drs. Cameron Koch and Sydney Evans in our department have developed an agent (EF5) that can be used to detect these hypoxic regions. However, this agent is difficult to use in that the patient must be injected with EF5, then the tumor must be removed within 24-48 hours and stained for EF5. A less invasive means is be to inject [F-18] EF5 into a patient and then use PET scanning to detect EF5 binding. We have been involved in the development of protocols that use [F-18] EF5 PET scanning in patients. A protocol is currently open for patients with brain tumors, and we are developing one that will be used in patients with lung cancer. Ultimately we plan to incorporate this [F-18] EF5 PET scanning to determine whether tumor oxygenation is altered by various biological modifiers and radiation.