Studies of p53 Point to New Therapies for Soft Tissue Sarcoma

BUFFALO, NY—There are too many questions and not enough new answers about soft tissue sarcomas, Raphael E. Pollock, MD, PhD, said at the Surgical Oncology Symposium, hosted by Roswell Park Cancer Institute.

“There have been essentially no new therapies introduced for soft tissue sarcomas since the 1970s, and the 5-year survival is stagnant at only 50%,” said Dr. Pollock, professor and head, Division of Surgery, M.D. Anderson Cancer Center. “We need more information about the cancer cells that cause this disease and the genetic derangement driving this malignancy.”

Although the most common mutation found in sarcoma cells is in the p53 gene, he said, “each patient may be a molecular universe unto themselves. The critical need in the future will be to identify pertinent cellular changes and target therapies to the unique needs of each patient.”

In soft tissue sarcoma, a defective p53 gene is more often detected in high-grade rather than low-grade tumors and in metastatic rather than primary tumors. A malfunctioning p53 gene is also linked to an increase in overall mortality in sarcoma patients.

Research at M.D. Anderson is currently focused on changes in p53 at the DNA, RNA, and protein product levels. “The mutation in the p53 gene offers a clue as to how sarcoma cells become metastatic. The loss of a functional p53 gene leads to the loss of G1 cell cycle arrest, and thus cells continue to divide. This observation has pointed the way to two potential therapeutic approaches,” Dr. Pollock said.

Gene Therapy Approach

The first approach is gene therapy. Dr. Pollock’s team transfected a wild type p53 gene into leiomyosarcoma tumors bearing mutated p53 genes that were already growing in SCID mice. Tumors that were not transfected with wild type p53 served as controls and grew unchecked, whereas with wild type p53 transfection, tumors grew but did not progress beyond 0.5 cm in diameter.

The second potential therapy is based on angiogenesis. In the first study, the researchers noticed that the sarcomas were “rich with blood vessels,” Dr. Pollock said. However, microvessel density was 50% less in the wild type p53 tumors, compared with the mutated p53 tumors. Further studies identified increased levels of vascular endothelial growth factor (VEGF) in the mutated p53 tumors.

Thus, Dr. Pollock said, “we have an opportunity to study both p53 and VEGF in this system to understand the mechanisms by which p53 modulates angiogenesis.” Future research will examine the best way to incorporate gene therapy into treatment modalities, he said, including modifying isolated limb perfusion as a gene delivery system.