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Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading. 
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.