In fact, one of the drugs -- ZD6474 -- significantly slowed the growth of three different types of brain tumors, a remarkable finding given that brain tumors are very distinct in their biologic makeup, said Jeremy Rich, M.D., an assistant professor of medicine in the Brain Tumor Center at Duke.
"Despite our best efforts in the laboratory and the clinic, the survival rate for glioblastoma -- the most common and lethal brain tumor -- hasn't changed in 10 years, said Rich. "This new class of drugs has shown great promise in treating human tumors that were grown in mice, and we feel these results are indicative of how the drugs may act in humans."
Rich will present results of the three studies -- funded by the Pediatric Brain Tumor Foundation and ABC2 -- at the Molecular Targets and Cancer Therapeutics Meeting in Boston Nov. 17-21, 2003.
Each of the new drugs is designed to aim for a specific target within brain cancer cells, as opposed to the current strategy in which the body is indiscriminately bombarded with chemotherapy --the so called "sledgehammer" approach, said Rich. Tumors are often resistant to chemotherapy, and patients can suffer unpleasant side effects due to its toxicity.
The new drugs selectively target particular molecules within brain tumors, so they should be more effective inhibitors of tumor growth and carry far fewer side effects for the patient, said Rich.
Moreover, the selective nature of the new drugs means they will target different types of tumors, each of which exhibits its own unique characteristics. Thus, doctors will be able to customize therapy based on each individual's tumor type.
"Brain tumors are very diverse in their molecular makeup, so no single therapy will combat all of them," said Rich. "Our best defense is to devise an arsenal of drugs and select the best ones for each particular tumor type."
Three of the new drugs are in a class called small molecule inhibitors, designed to prevent growth factors from activating themselves inside cancer cells. Cancer cells over-produce growth factors that cause cells to rapidly reproduce, to unnaturally prolong their lives, to grow blood vessels to support their growth, and to invade surrounding tissue -- all of which are hallmarks of cancer, said Rich.
The new drugs work by plugging up small "pockets" inside the cells where a molecule called ATP would normally dock and enable growth factors to activate. When ATP cannot activate these pockets (called binding sites) on the cell's internal receptor, the growth factor receptors cannot initiate the chain of events that ultimately leads the cell to become cancerous.
The four drugs work as follows:
ZD6474
ZD6474 inhibited the growth of three primary central nervous system tumors in mice: glioblastoma, medulloblastoma, and ependymoma. Mice that received ZD6474 showed a 10- to 25-day delay in growth in all of the tumors compared to control mice. A comparable delay in humans would be difficult to assess, said Rich, because the lifecycle of mice is quite short and because the drug was only administered for 10 days.
Nonetheless, Rich said this two- to three-week delay represented a "significant effect," given that most mouse tumors grow in a few weeks whereas most patients with glioblastoma live for approximately one year from the time of diagnosis.
The drug worked by blocking angiogenesis, the process by which tumor cells grow new blood vessels. Specifically, ZD6474 blocked activation of the receptor for vascular endothelial growth factor (VEGF), the protein that malignant cells secrete in order to grow and maintain their blood vessels. When VEGF receptor cannot activate itself, the tumor's blood supply is diminished and the tumor shrinks and slows its spread.
Secondarily, ZD6474 prevented activation of the EGF (epidermal growth factor) receptor, another protein that cells use to grow new blood vessels, to resist dying, and to invade other cells. Blocking the activation of two growth factors has a more profound effect on cell growth than just blocking one, said Rich.
Finally, ZD6474 showed promise in treating tumors that had genetically manipulated themselves to resist the effects of toxic chemotherapy, the study showed.
SB431542
Another new compound, SB431542, was tested in human malignant glioma cell lines in the laboratory but not in animals. The drug successfully inactivated the receptor for a protein called transforming growth factor-beta (TGF-beta). In normal cells, TGF-beta suppresses cancer by decreasing proliferation of cells, but in cancer cells, its tumor-suppressor role is lost. Thus, TGF-beta promotes invasion, blood vessel growth and the tumor's ability to evade the immune system.
By blocking the activity of the TGF-beta receptor, SB431542 also inhibited the expression of another critical protein in the cell called PAI-1. This protein, which normally communicates with TGF-beta in cancer cells, is a predictor of poor prognosis in patients. Thus, reducing its expression can theoretically improve prognosis for patients, said Rich.
AEE788 in Combination with RAD001
The compound AEE788 inhibited the growth of glioblastomas when it was combined with another compound called RAD001. AEE788 primarily targets epidermal growth factor receptor (EGFR) and secondarily targets the VEGF receptor.
RAD001 targets a different protein in cancer cells called mTOR. This protein is essential for regulating a cell's metabolism. Without it, cells cannot produce adequate levels of protein to carry out cellular functions, and thus the cells do not grow properly.
The combination of these two drugs inhibited tumor growth more significantly than either drug alone, said Rich, suggesting that a dual drug approach may be more effective than using a single drug.
Moreover, Rich said the drugs that target EGFR could actually be more effective in humans because epidermal growth factor is more highly expressed in human tumors than it is in human tumors transplanted into mice.
The combination of AEE788 and RAD001 will begin testing in patients within the next year, said Rich.