The tumor suppressor gene p53 can induce the tidy destruction of cells via the cellular suicide program called apoptosis. In more than half of all tumors, p53 is mutated or deleted. Malfunctions in ARF and MDM2, critical regulators of p53 function, occur in another 30% of tumors. With one notable exception, most of these mutations are sporadic (patients with LiFraumeni syndrome have an inherited p53 mutation). "p53 is the holy grail for cancer therapy," said Howard Hughes Medical Institute investigator Steve Dowdy, Ph.D.
Cancer treatments based on targeting specific protein abnormalities such as p53 mutations have come up against some serious obstacles. But in the February issue of PLoS Biology, Dowdy and his University of California at San Diego colleagues "have raised the bar in treating late-stage tumors that have metastasized," said Wafik El-Deiry, M.D., Ph.D., of the University of Pennsylvania.
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The group used a unique strategy to try to restore p53 function in mouse models of advanced-stage peritoneal carcinomatosis and disseminated peritoneal lymphomas, which are resistant to chemotherapy treatment. They used a small peptide corresponding to the HIV TAT protein, exploiting the fact that TAT can pass through cell membranes in a receptorless fashion and so is not specific to any particular cell type. They also used a peptide derived from the C terminus of p53, which, by an unknown mechanism, can activate mutant p53 proteins so that they behave more like the wild-type protein. A fusion of TAT to the activator peptide of p53, then, has the capacity to enter, or "transduce" into, all cells it contacts.
They injected the p53TAT fusion protein into the peritonea of the mice and, in the models of peritoneal carcinomatosis, untreated mice died within 11 days. Mice that were given 12 daily injections of the fusion protein lived on average more than 70 days after tumor inoculation. In the disseminated peritoneal lymphoma model using the fusion protein, half of the mice were alive after more than 200 days. Untreated mice lived only 35 days. The exciting aspect of this, El-Deiry said, is that the peptide can restore function to the so-called "hot-spot" mutants of p53, which account for p53 mutations in a great number of tumors.
In addition to lifespan extension, treatment with the fusion protein reduced the number of cells in the tumorseven tumors distant from the injection site.
Other Attempts
There have been many other attempts to design a treatment that targets p53. Adenoviruses such as ONYX-015 designed to specifically kill cells with mutant p53 have been tested in phase III trials. Another strategy is to inhibit p53s interaction with key players of the p53 pathway, such as MDM2. Because MDM2 is responsible for degrading p53, disrupting the p53MDM2 interaction can stabilize p53. Small molecules such as the Nutlins have provided such protection in mouse models of subcutaneous human cancer xenografts. Other small moleculesCP-31398 and PRIMA-1were also successful in xenograft models and seem to act by binding and stabilizing p53 directly.
Conversely, clinical trials of p53 gene replacement have had limited success. Dowdys strategy focused instead on restoring the activity of mutant p53 proteins in the cancer cells. In addition, the mice that they used were modeled after ovarian cancers, and, Dowdy said, they are a great mimic for the real thing.
The traditional xenograft model is limited by the fact that the cells that are transplanted under the skin are often from different species, said Tyler Jacks, Ph.D., a Howard Hughes investigator and cancer geneticist at the Massachusetts Institute of Technology.
"These tumors were chosen because they are growing in a defined compartment that you can access through injection into that same compartment," Jacks speculated.
A widespread delivery mechanism is a huge challenge with all cancer therapy strategies. At the crux of the gene therapy and ONYX-015 strategies are both targeting issues and an issue with neutralizing antibodies. Dowdys strategy is based on activation of mutant p53 and so should be specific to cancer cells. When the TATp53 fusion enters normal cells, it presumably has no effect. Regardless, this strategy "may well have similar issues to address in terms of distribution and targeting, as well as neutralizing antibodies," said Frank McCormick, Ph.D., of the University of California at San Francisco.
Further Work
Before it can be considered for clinical trials, Dowdy and his colleagues hope to improve the technology with respect to the delivery method, targeting, and potency. In the meantime, Jacks suggests that protein transduction using p53 activators may be clinically useful even now, in cases where delivery is not so crucial. For instance, a fair number of women with ovarian cancer have p53 mutations. Because the metastases from ovarian cancer tend to be local and confined to the peritoneum, refinements to make the TATp53 spread to very distant sites would be unnecessary. This attack on p53 could also be used following tumor removal surgery to eliminate residual tumor cells.
"The approach with a completely different mechanism and basis is welcomed in this field," said McCormick.
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