Tyrosine Kinase Inhibitors Curb Bone Metastases in Animals

SAN FRANCISCO—Use of tyrosine kinase inhibitors, including PKI166 (investigational, Novartis) and imatinib mesylate (STI571, Gleevec) can significantly reduce the size of metastatic bone tumors, decrease angiogenesis, and preserve bone structures, according to animal studies presented at the 93rd Annual Meeting of the American Association for Cancer Research.

In the studies, the tyrosine kinase inhibitors PKI166 and imatinib mesylate were tested against human prostate and kidney cell lines implanted in mice. Both agents reduced bone lesions significantly and significantly reduced angiogenesis by specifically targeting endothelial cells associated with bone metastasis.

"We hope this treatment modality can increase the specificity of cancer treatment and reduce side effects by blocking the growth factors EGFR [epithelial growth factor receptor] and PDGFR [platelet derived growth factor receptor]," said Sun Jin Kim, MD, PhD, instructor, Cancer Biology Department at The University of Texas M. D. Anderson Cancer Center.

In the study (abstract 4234), conducted in the laboratory of Dr. Isaiah J. Fidler, the tibias of male mice were injected with tumor cells from a patient with end-stage prostate cancer. Groups of 10 mice received one of seven treatments or saline. The treatments consisted of paclitaxel (Taxol), PKI166, or imatinib mesylate alone; paclitaxel plus PKI166 or imatinib mesylate; PKI166 plus imatinib mesylate; or a combination of all three drugs.

Results showed that mice treated with saline or paclitaxel alone retained significantly large tumors in the tibia with bone lysis. In mice treated with paclitaxel plus PKI166 or paclitaxel plus imatinib mesylate, the bone tumors were smaller and the bone structure was preserved. The incidence of lymph node metastasis was also significantly lower in mice treated with PKI166 or imatinib mesylate.

Combination therapy with PKI166, imatinib mesylate, and paclitaxel produced the most significant therapeutic effects, with decreased tumorigenicity, tumor size, lymph node metastasis, and preservation of bone structure.

Analysis showed that the drugs blocked the phosphorylation of EGFR and PDGFR. Treatment also induced apoptosis of endothelial cells in tumor-related blood vessels, but not in endothelial cells of normal leg vessels.

Dr. Fidler’s group has seen similar outcomes in mouse models with human kidney, pancreatic, and colon tumors. "The tyrosine kinase inhibitors of EGFR (PKI166) and PDGFR (imatinib mesylate) produce significant inhibition of tumor growth and angiogenesis by specific targeting of bone metastasis-associated endothelial cells," Dr. Kim said.

Kidney Cancer

In another study presented at the AACR meeting (abstract 1561), treatment with PKI166 alone or in combination with paclitaxel reduced bony tumor lesions in the leg by 40% to 60% in mice with metastatic kidney cancer.

"Our experiments revealed that PKI166 blocks the EGFR signaling pathway and inhibits tumor growth," said Kristy Weber, MD, assistant professor of surgical oncology and of cancer biology at The University of Texas M. D. Anderson Cancer Center.

Groups of 25 mice, injected with a cell line derived from bone metastasis of human kidney cancer, received one of three treatments: PKI166 alone, paclitaxel alone, or PKI166 plus paclitaxel.

As well as decreasing the number of bone lesions, both PKI166 regimens produced a significant drop in tumor weight. The addition of paclitaxel did not improve on the effect of PKI166 alone but did appear to decrease angiogenesis. "PKI166 does seem to have long-term effectiveness. We’re not sure if it would be effective alone in humans, but it has promise in being used in combination with more aggressive drugs for renal cancer," Dr. Weber said.

When treated with PKI166, the cancer cells showed an 87% decrease in tyrosine autophosphorylation of the EGFR. Analysis indicated a significant reduction in activated EGFR in the mice treated with PKI166 with or without paclitaxel.

The researchers also found that PKI166 blocks TGF [transforming growth factor]-alpha, another potent stimulus of cell growth, from binding to receptors and signaling cells to multiply. PKI166 also seems to decrease angiogenesis, suggesting that the drug may affect endothelial cells in blood vessels. After treatment, there was an increase in apoptotic endothelial cells in the groups given PKI166.

In separate research, Dr. Weber’s group has found that treatment with PKI166 is a deterrent to tumor growth in mice with primary kidney cancer. "In the future, we may see an even more dramatic effect on primary tumors in the kidney," she said.

The next step will be to test PKI166 in combination with bone-preserving drugs. "This drug is very promising in the mouse model. It is effective not just against one but against several targets. And it can be given orally, which makes it attractive for clinical use," she said.