Nav: Home

Protein-protein interaction activates and fuels leukemia cell growth

December 21, 2015

Building upon previous research, scientists at University of California, San Diego School of Medicine and UC San Diego Moores Cancer report that a protein called Wnt5a acts on a pair of tumor-surface proteins, called ROR1 and ROR2, to accelerate the proliferation and spread of chronic lymphocytic leukemia (CLL) cells, the most common form of blood cancer in adults.

They note, however, that these effects of Wnt5a were blocked by a humanized monoclonal antibody specific for ROR1, called cirmtuzumab (or UC-961), which inhibited the growth and spread of CLL cells in both cell lines and mouse models of leukemia. The findings are published in the Dec. 21, 2015 issue of The Journal of Clinical Investigation.

Although the findings are made with leukemia cells, researchers said the study has implications for patients with other cancers, including solid-tissue tumors. 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 over-expressed in patients with CLL and can act as a survival/growth factor for leukemia cells. By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells," said senior author Thomas J. Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research and deputy director for research at Moores Cancer Center.

"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 I clinical trial for patients with CLL."

The JCI paper follows a series of fundamental findings published by Kipps and colleagues in recent years:
  • In 2008, they reported that patients vaccinated with their own leukemia cells could make antibodies against ROR1, some of which had the ability to reduce the survival of leukemia cells. They found ROR1 on leukemia cells but not on all normal adult tissues examined.
  • In 2012, they 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 anti-cancer drug research.
  • In June 2013, they 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, they reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
  • In September 2014, they launched a phase 1 human clinical trial of a new monoclonal antibody for patients with CLL. The drug, called cirmtuzumab, targets ROR1 in cancer cells in general and cancer stem cells in particular. The safety trial is on-going.
  • In November 2014, they described cellular experiments indicating cirmtuzumab might also 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 critical roles of ROR1 and ROR2 in cancer development. Both are evolutionarily conserved proteins, found in many species, and 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. Researchers found that in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of cancer cells. Such migration contributes to the spread of cancer to cause metastasis, which is responsible for 90 percent of cancer-related deaths.

But treating mice with cirmtuzumab disrupted the process, inhibiting engraftment of leukemia cells and slowing or stopping the disease from spreading.
-end-
Co-authors include Jian Yu, Liguang Chen, Bing Cui, George F. Widhopf II, Zhouxin Shen, Rongrong Wu, Ling Zhang and Suping Zhang, all at UC San Diego Moores Cancer Center; and Steven P. Briggs, UC San Diego.

Funding for this research came, in part, from the California Institute for Regenerative Medicine (grant DR3-06924), the UC San Diego Foundation Blood Cancer Research Fund, the Leukemia and Lymphoma Society (SPORE grant 7005-14) and the National Institutes of Health (5P01CA081534-14 to the CLL Research Consortium).

University of California - San Diego

Related Cancer Articles:

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
More Cancer News and Cancer Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab