Improving Radiation Efficacy: The Advent of New Sensitizers
Gillies McKenna, MD, PhD
In this session, some of the newest and most exciting anticancer agents being used as radiation sensitizers were discussed. The panelists each reviewed their work with farnesyl transferase inhibitors, nucleoside analogs, and anti-EGFR antibodies. The panelists detailed the translational research that is currently ongoing with each agent.
Discussion #1: Farnesyl Transferase inhibitors
Presenter: W. Gillies McKenna, MD, PhD
Mutant ras alleles are expressed in high frequency in pancreatic, ovarian, lung, sarcoma, cervix, colon, and head and neck cancers. H-ras expression leads to increased G2 delay after radiation and correlates with radiation resistance. Ras appears to suppress the apoptotic (programmed cell death) response in tumor cells.
Ras must be inserted into the cell membrane to be active in cell signaling. The essential step in this process is the farnesylation of ras which activates the ras. Farnesyl transferase inhibitors (FTI) block this pathway of activation. FTI has been shown to work in vitro utilizing T24 human bladder cell lines.
It turns out K-ras is the most frequent mutation in human tumors and not H-ras. Much higher doses of the drug are required to inhibit K-ras. In H-ras, FTI blocks the only pathway available for farnesylation and is very effective. K-ras activation can utilize a second pathway with geranylgeranly transferase (GTI). It has been found that the combination of a low concentration of FTI and GTI can effectively inhibit K-ras.
It is believed that tumor radiosensitizers may ultimately affect the outcome in a variety of cancers. Oncogenic ras does affect radiosensitivity. Inhibition of prenylation can sensitize cells having oncogenic ras but not normal cells. A phase I study is currently underway at the University of Pennsylvania to evaluate FTI.
Discussion #2: Radiosensitization by Flouropyrimidines
Panelist: Theodore S. Lawrence, MD, Ph.D.
Nucleoside analogs cause dysregulation of the S-phase of the cell cycle. S-phase progression after radiation therapy on damaged DNA templates may be the mechanism of action. Flourouracil can both damage RNA or inhibit thymidylate synthases. Sensitization is not due to cell cycle redistribution.
A model hypothesis was proposed to explain the differential sensitization of tumor versus normal cells. Sensitization occurs in cells that progress into S-phase and is different from the classic p-53 checkpoint. It is felt increased levels of cyclin E cause tumor cells to move into S-phase and ultimately results in increased radiosensitivity with incorporation of flouropyrimidines. Increased cyclin E levels may not cause the normal cells to move into S-phase thus causing differential sensitization.
If entry into S-phase is prevented in vitro, radiosensitization does not occur. P-53 status does not effect sensitization. MRI spectroscopy data suggests that radiation may affect the clearance of 5-FU in vivo.
There are a number of clinical implications of this data. Continuous infusion of FU may be superior to bolus FU. Drugs that accelerate S-phase are promising to use in conjunction with flouropyrimidines. Convenient "continuous infusion" with new oral agents such as capecitabine, UFT, and ethenyluracil should be evaluated in the future.
Discussion #3: Epidermal Growth Factor Receptor as a Therapeutic Target
Panelist: Jim Bonner, MD
Virtually all head and neck cancers express epidermal growth factor receptor (EGFR) and many overexpress the receptor. The EGFR is a complicated receptor that when activated can facilitate a proliferation response depending on the surrounding conditions. A significant increase in EGFR has been found in head and neck tumors compared to normal tissues. It has been shown that there is a worse relapse free survival and overall survival with increased EGFR expression.
It was hypothesized that blocking EGFR may improve outcome. In vitro studies showed utilization of an EGFR antibody (C225) showed a decrement in cellular proliferation. This decrement was much larger when C225 was used in combination with radiation when compared to radiation alone or C225 alone. There is a marked decrease in tyrosine kinase activity once a threshold dose of 1 microgram/ml is obtained. It was then concluded that C225 in combination with radiation caused increased apoptosis over either treatment alone.
A phase I study was then initiated at the University of Alabama to evaluate C225 with radiation therapy in patients with unresectable head and neck cancer. Patients were treated with radiation therapy to 70 Gy qD or 74.4 BID over 7 weeks. The patients received C225 concurrently. This was a dose escalation study with 16 patients enrolled in the study. Toxicity was comparable to an aggressive head and neck treatment regimen with radiation therapy alone. A mild follicular rash was observed in the radiation portals that resolved 1-2 months after treatment. There were 13/16 complete responses in this group of patients with advanced head and neck cancer.
It was concluded that acceptable toxicity was obtained with the current regimen of combined C225 and radiation therapy. A rash does occur that is very manageable. The dramatic response of these patients warrants further study. A multi-institutional trial has recently been initiated.