Imatinib, known commercially as Gleevec, worked best when combined with the chemotherapy paclitaxel to slash the incidence of bone metastases and the size of tumors in mice injected with a multiple-drug resistant form of prostate cancer. Tumors were found in only 4 of 18 mice treated with the combination, median tumor weight was one tenth of a gram, and the cancer spread to the lymph nodes in three cases. Tumors grew in all 19 control mice, their median tumor weight was 1.3 grams, and all metastasized to the lymph nodes.
This extremely drug-resistant form of the cancer, designed by the research team to emulate the grim clinical reality of prostate cancer that has spread into the bone, successfully warded off the combined medications in lab experiments, said Isaiah J. Fidler, D.V.M., Ph.D., chair of the Department of Cancer Biology and director of the Cancer Metastasis Research Center at M. D. Anderson.
"Why, then, did it work so well in the animal? Because we didn't attack the tumor, we attacked the blood vessels. We target and destroy the vasculature that provides oxygen and nutrients to tumor cells," said Fidler, the paper's senior author.
Fidler and colleagues show in the JNCI paper that imatinib killed tumor-related blood vessel (endothelial) cells by inactivating the platelet-derived growth factor receptors (PDGF-R) on the cell surface. This prevents the receptor's activation either by PDGF binding to it externally or by a signal generated internally by the cell.
Activation of PDGF-R stimulates the birth of new blood vessels, promotes cell division and migration, and inhibits a protective form of cell suicide known as apoptosis, all harmful effects in the service of a cancer cell.
With imatinib preventing activation of PDGF-R, Fidler said, the endothelial cells died by apoptosis first, with tumor cells following suit one to two weeks later.
Fidler said the findings are a vibrant example of the "seed and soil" hypothesis in metastasis - the deadly spreading of a cancer from its organ of origin to other organs, a process that kills 90 percent of all patients who die from their disease.
In landmark findings, Fidler and colleagues demonstrated that the vast majority of cancer cells that depart a tumor die swiftly once in circulation and that metastases originate from less than 1 percent of a cancer's cells and even can arise from a single cell.
When these metastatic "seeds" enter circulation, they still need to find the exact microenvironment that permits them to grow. For prostate cancer, the second-leading cause of cancer death among men, that microenvironment is the bone.
Earlier research by Fidler and colleagues showed PDGF-R activation in metastatic prostate tumors adjacent to the bone but not in tumor cells next to muscle. PDGF-R also was activated in tumor-associated endothelial cells in the bone, but not in those blood vessel cells in neighboring muscle.
A JNCI paper by Fidler and colleagues in 2003 showed that blocking PDGF-R signaling in the mouse model of metastatic prostate cancer cut the incidence of cancer, reduced the size of tumors and incidence of metastasis.
The question was whether the combination of imatinib and paclitaxel achieved this by attacking the tumor itself or the tumor-related blood vessels. This week's JNCI paper answers that question: it kills the blood vessels first. "Here, we attack the soil. The seeds can be resistant. Kill the endothelial cell, you kill the soil," Fidler said.
Imatinib had an effect by itself, but the best result came from the pairing with paclitaxel, known commercially as Taxol, which induces apoptosis in non-resistant cancer cells. Taxol, developed by the Bristol-Myers Squibb Co., is frontline therapy for prostate cancer but eventually loses its effect as resistant tumor cells proliferate.
Gleevec, developed by Novartis Pharmaceuticals Corporation, is used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors.
Cancer cells are biologically diverse and genetically unstable, Fidler says, so it is highly unlikely that a single therapy will prevail, necessitating a multi-modal attack on the disease.
Paul Mathew, M.D., assistant professor, and Christopher Logothetis, M.D., professor and chair of the Department of Genitourinary Medical Oncology at M. D. Anderson, are leading a phase II clinical trial employing imatinib and docetaxel against androgen-independent prostate cancer. Docetaxel is in the same family of medication as paclitaxel.
This research project was funded by a Cancer Center Support Core grant and a Specialized Programs in Research Excellence (SPORE) grant, both from the National Cancer Institute of the National Institutes of Health. Fidler, Mathew and Logothetis have research projects that are sponsored by Novartis Pharmaceuticals.
Co-authors of the JNCI paper, all from M. D. Anderson, are: first author Sun-Jin Kim, M.D., Ph.D.; Hisanori Uehara, M.D., Ph.D.; Sertac Yazici, M.D.; Joseph Erik Busby, M.D.; Toru Nakamura, M.D., Ph.D.; Junqin He, M.D.; Marva Maya; Christopher Logothetis, M.D.; Paul Mathew, M.D.; Xuemei Wang; Kim-Anh Do, Ph.D.; and Dominic Fan, Ph.D.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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