BUFFALO, NYThere 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.
Gene Therapy Approach
The first approach is gene therapy. Dr. Pollocks 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