Despite the widespread use of current antiangiogenic cancer therapies, many tumors escape this blockade, which is designed to shut down growth of new blood vessels that feed tumors and spread cancer cells. Now, a study reported at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics suggests that targeting a novel antiangiogenic receptor may help patients whose cancer does not respond to existing agents.
The experimental agent, PF-03446962, targets activin receptor-like kinase 1 (ALK-1), which is part of the transforming growth factor ß (TGFß) superfamily of receptors that potentially regulate cell growth and differentiation. Known as a tumor suppressor, TGFß can conversely promote invasion and metastasis during the later stages of cancer progression, said Filippo de Braud, M.D., who was director of new drugs at the European Institute of Oncology when the study was conducted and is now chief of the Medical Oncology Department at the National Tumor Institute in Milan, Italy.
Tumor cells frequently lose the growth inhibitory response to TGFß, which makes it a prime target for cancer treatment, he said. PF-03446962, a fully humanized monoclonal antibody, specifically inhibits the activity of ALK-1, which the researchers said is in part regulated by vascular endothelial growth factor (VEGF), the protein that activates angiogenesis and other proangiogenic factors. Shutting down ALK-1 inhibits the VEGF pathway in a manner different from other antiangiogenic treatments now on the market, de Braud said.
Researchers tested PF-03446962 in a phase 1 clinical trial, which demonstrated that the agent exerted anticancer activity in tumors already resistant to VEGF treatment.
De Braud and his colleagues tested eight different doses of PF-03446962 in 44 patients with solid tumors. Results showed a partial response in three patients and stable disease lasting at least four months in seven patients. Most of the patients who benefitted had previously been treated with prior antiangiogenic therapy for lung, renal or liver cancer. Some of these patients did not achieve remission with previous antiangiogenic therapy, "suggesting that ALK-1 can operate as an escape mechanism to VEGF," de Braud said.
The two patients with the longest response (stable disease for about a year) had been diagnosed with adrenocortical cancer and mesothelioma.
The researchers noted that three patients developed telangiectasia, which is dilation of blood vessels near the skin. This disorder is known to be caused by a mutation in the ALK-1 gene, and development of this mild side effect in these patients demonstrates PF-03446962 is affecting ALK-1 function.
"Based on this clinical activity, anti-ALK-1 may be a promising novel strategy to help patients who have failed previous VEGF therapy," de Braud said. The agent might be used on its own or in combination with current antiangiogenic therapy to strengthen inhibition of the VEGF pathway.
Toxicities seen in the phase 1 trial were manageable, a finding that demonstrates that the agent is safe to use, he said.
Saturday, 26 November 2011
Thursday, 21 April 2011
Following A Path To A Potential Therapy For NF2, A Rare Tumor Disorder
The proteins that provide cells with a sense of personal space could lead to a therapeutic target for Neurofibromatosis Type 2 (NF2), an inherited cancer disorder, according to researchers at The Wistar Institute. Their findings, which appear in the April 12 issue of the journal Cancer Cell, could have profound implications for NF2 and related cancers, such as Mesothelioma.
The researchers describe, for the first time, that Merlin, the protein encoded within the NF2 gene interacts with a protein called angiomotin. This connection between Merlin and angiomotin also brings together two important information networks in cells, both of which have been implicated in numerous forms of cancer. It is a connection, the researchers say, between the sensors that detect interactions between cells and the signaling networks that drive cell division.
"Angiomotin is required for movement of cells that form new blood vessels, so it is fascinating to see it so closely linked to merlin, the product of the NF2 gene, loss of which leads to tumor formation," said Joseph Kissil, Ph.D., senior author of the study and associate professor in the Molecular and Cellular Oncogenesis Program of The Wistar Institute Cancer Center. "The discovery opens up a potential new method to treat NF2 by attacking the tumor cells directly and by starvation, a strategy already employed in certain cancer therapies."
"Drugs like Avastin, for example, target the growing blood vessels," Kissil said, "but what makes angiomotin a tempting target is that it is used by both blood vessels and the growing tumor cells that need the nutrients these blood vessels provide."
NF2 is a genetic disorder caused by a mutation in both copies of a person's NF2 gene. It occurs in about one in every 30,000 people, and it is mostly hereditary. NF2 generally appears as benign tumors in the nervous system of young adults, often causing deafness as tumors affect the auditory nerves. While the tumors are mostly benign, more malignant tumors may eventually arise. Moreover, even the benign tumors often cause debilitating pain as they spread throughout the nervous system. There is currently no treatment for NF2 other than surgery to remove tumors as they appear.
Mutations in the NF2 gene disrupt the function of the gene's protein product, Merlin, which is part of an elaborate molecular signaling pathway that regulates how cells grow and divide. These pathways are akin to information channels, and disrupting one protein can alter the function of other proteins both upstream and downstream along the channel. Merlin is particularly interesting to cancer biologists, as the mutations have been found in about half of all cases of the deadly lung cancer mesothelioma, and in some instances of thyroid, bladder and other cancers.
According to Kissil, Merlin normally stops cells from growing once they come into contact with adjacent cells. That is, Merlin binds to the angiomotin at "junctions," areas where cells come into contact with each other. When bound together, the interacting proteins relate a signal to the cell that, essentially, orders it to cease further growth and movement. It is a way for cells to coordinate their growth within a tissue. Cancerous cells, for example, often lack that sense of inhibition, and they will continue growing unchecked.
The Kissil laboratory plans to continue their exploration of angiomotin as a potential therapeutic target for treating NF2, as well as look into the role of angiomotin in other cancers known to be affected by NF2 mutations.
Notes:
Funding for this study was provided in part through a grant to Kissil from the National Cancer Institute of the National Institutes of Health. The study was also supported by a Young Investigator Award from the Children's Tumor Foundation to Chunling Yi, Ph.D., a postdoctoral fellow in the Kissil laboratory.
Wistar collaborators also include research assistants Scott Troutman and Neepa Christian; graduate students Daniela Fera and Jacqueline L. Avila; and Wistar professors David W. Speicher, Ph.D. and Ronen Marmorstein, Ph.D. Co-authors also include Akihiko Shimono, Ph.D., of the Cancer Science Institute of Singapore at the National University of Singapore; Lars Holmgren, Ph.D., and Nathalie L. Persson of the Karolinska Institute in Stockholm, Sweden; and Anat Stemmer-Rachamimov, M.D., of Massachusetts General Hospital in Boston.
Source:
Greg Lester
The Wistar Institute
The researchers describe, for the first time, that Merlin, the protein encoded within the NF2 gene interacts with a protein called angiomotin. This connection between Merlin and angiomotin also brings together two important information networks in cells, both of which have been implicated in numerous forms of cancer. It is a connection, the researchers say, between the sensors that detect interactions between cells and the signaling networks that drive cell division.
"Angiomotin is required for movement of cells that form new blood vessels, so it is fascinating to see it so closely linked to merlin, the product of the NF2 gene, loss of which leads to tumor formation," said Joseph Kissil, Ph.D., senior author of the study and associate professor in the Molecular and Cellular Oncogenesis Program of The Wistar Institute Cancer Center. "The discovery opens up a potential new method to treat NF2 by attacking the tumor cells directly and by starvation, a strategy already employed in certain cancer therapies."
"Drugs like Avastin, for example, target the growing blood vessels," Kissil said, "but what makes angiomotin a tempting target is that it is used by both blood vessels and the growing tumor cells that need the nutrients these blood vessels provide."
NF2 is a genetic disorder caused by a mutation in both copies of a person's NF2 gene. It occurs in about one in every 30,000 people, and it is mostly hereditary. NF2 generally appears as benign tumors in the nervous system of young adults, often causing deafness as tumors affect the auditory nerves. While the tumors are mostly benign, more malignant tumors may eventually arise. Moreover, even the benign tumors often cause debilitating pain as they spread throughout the nervous system. There is currently no treatment for NF2 other than surgery to remove tumors as they appear.
Mutations in the NF2 gene disrupt the function of the gene's protein product, Merlin, which is part of an elaborate molecular signaling pathway that regulates how cells grow and divide. These pathways are akin to information channels, and disrupting one protein can alter the function of other proteins both upstream and downstream along the channel. Merlin is particularly interesting to cancer biologists, as the mutations have been found in about half of all cases of the deadly lung cancer mesothelioma, and in some instances of thyroid, bladder and other cancers.
According to Kissil, Merlin normally stops cells from growing once they come into contact with adjacent cells. That is, Merlin binds to the angiomotin at "junctions," areas where cells come into contact with each other. When bound together, the interacting proteins relate a signal to the cell that, essentially, orders it to cease further growth and movement. It is a way for cells to coordinate their growth within a tissue. Cancerous cells, for example, often lack that sense of inhibition, and they will continue growing unchecked.
The Kissil laboratory plans to continue their exploration of angiomotin as a potential therapeutic target for treating NF2, as well as look into the role of angiomotin in other cancers known to be affected by NF2 mutations.
Notes:
Funding for this study was provided in part through a grant to Kissil from the National Cancer Institute of the National Institutes of Health. The study was also supported by a Young Investigator Award from the Children's Tumor Foundation to Chunling Yi, Ph.D., a postdoctoral fellow in the Kissil laboratory.
Wistar collaborators also include research assistants Scott Troutman and Neepa Christian; graduate students Daniela Fera and Jacqueline L. Avila; and Wistar professors David W. Speicher, Ph.D. and Ronen Marmorstein, Ph.D. Co-authors also include Akihiko Shimono, Ph.D., of the Cancer Science Institute of Singapore at the National University of Singapore; Lars Holmgren, Ph.D., and Nathalie L. Persson of the Karolinska Institute in Stockholm, Sweden; and Anat Stemmer-Rachamimov, M.D., of Massachusetts General Hospital in Boston.
Source:
Greg Lester
The Wistar Institute
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