Cancer stem cells are the dark cousins of the normal stem cells that promulgate life and offer such therapeutic promise. They, too possess the key characteristics of self-renewal and the ability to give rise to all of the cell types found in a particular cancer. It is the persistent presence of treatment-resistant cancer stem cells that allows tumors to recur and spread.
An antibody therapy already in clinical trials to treat chronic lymphocytic leukemia (CLL) may also prove effective against ovarian cancer – and likely other cancers as well, report researchers at the University of California, San Diego School of Medicine in a study published in the Nov. 17 online early edition of the Proceedings of the National Academy of Sciences (PNAS).
The findings extend the anti-cancer potential of an experimental monoclonal antibody called cirmtuzumab, developed at UC San Diego Moores Cancer Center by Thomas Kipps, MD, PhD, and colleagues. Cirmtuzumab is currently in a first-in-human phase 1 clinical trial to assess its safety and efficacy in treating CLL.
Cirmtuzumab targets ROR1, a protein used by embryonic cells during early development and exploited by cancer cells to promote tumor growth and metastasis, the latter being responsible for 90 percent of all cancer-related deaths.
Because normal adult cells do not express ROR1, scientists suspect ROR1 is a specific biomarker of cancer cells in general and cancer stem cells in particular. Because it appears to drive tumor growth and disease spread, they believe it also presents an excellent target for anti-cancer therapies. Earlier research by Kipps and colleagues has shown a link between ROR1 and both breast cancer and CLL.
In their latest PNAS paper, Kipps and colleagues investigated whether cirmtuzumab also might be effective against ovarian cancer, which has rebuffed efforts to find a cure or long-term remedy. Most ovarian cancer patients initially respond well to standard chemotherapy, sometimes appearing to become disease-free, but 85 percent relapse within two years after systemic treatment, often with a more aggressive and disseminated form of the disease.
More than 21,000 women are diagnosed with ovarian cancer annually; more than 14,000 die from the disease each year. The 5-year survival rate after diagnosis is 44.6 percent.
The Moores Cancer Center team found that ovarian cancer stem cells, which are thought to be responsible for cancer recurrence and metastasis and are largely resistant to standard chemotherapies, singularly express ROR1. Patients whose tumors had high levels of ROR1 experienced more aggressive forms of ovarian cancer. They had higher rates of relapse and shorter median survival times than patients with lower levels of ROR1.
“ROR1 is used by embryo cells to migrate and to develop new organs,” said Kipps. “Cancer stem cells subsequently use ROR1 for their own growth and dissemination throughout the body. They are essentially the seeds of the cancer. The more seeds a tumor has, the greater its ability to recur after therapy or metastasize.”
The researchers tested their theory in transgenic mice lacking an immune system, which allowed them to graft human ovarian cancer tumors into the animals. “The tumors grow just like they would in a human patient. They maintain the same genomic complexity and microenvironment,” Kipps said.
Some of the tumor-engrafted mice were then infused with low doses of cirmtuzumab, which appears to induce senescence in cancer stem cells, degrading their ability to grow and metastasize. “It seems like ROR1 may be required to keep cancer stem cells healthy,” Kipps said.
The scientists found that mice with tumors treated with cirmtuzumab did not form new tumors – the disease did not metastasize – and residual tumors appeared to be depleted of cancer stem cells. When these latter tumors were engrafted into new mice, they did not flourish or spread.
“The phenotype of cancer stem cells has been well defined for cancers from several organs, but reliable biomarkers for cancer stem cells in ovarian cancer have remained elusive. ROR1 promises to provide such a biomarker,” said Robert C. Bast, Jr., MD, professor and vice president for translational research at the University of Texas MD Anderson Cancer Center. “And the anti-ROR1 antibody is a promising candidate for targeted therapy, either alone or conjugated with toxic peptides or small molecule.” Bast was not part of the study team.
Kipps said the results reaffirm the idea that at least some forms of cancer – perhaps many – are the result of cancer cells replaying embryonic programs with disastrous effect. “If we can get a handle on that, keep cancer stem cells from replaying that growth program by targeting ROR1, then we may be able to stop cancer, and prevent its recurrence. You have to go after the seeds of the cancer and kill them before they geminate into recurrent or metastatic disease.”
Pictured: Ovarian cancer cells forming small tumor. Image courtesy of University of Gothenburg.
He was tired of running. He morphed back into human form and sat down, hugging his knees to his chest. Stupid m!a stupid anon. He closed his eyes and tried to block out the world. Stupid zelda for using him. He should have know. But how could h have? He had a powerful love spell mucking up his brain. Now he was heartbroken. And it hurt.
Scientists have been able to put a virtually incurable disease into complete remission by altering patients’ blood cells inside the body to fight the stubborn cancer.
The process allows the patient’s own immune system to fight chronic lymphocytic leukemia (CLL). Three of 14 patients in a four-year study are in complete remission–and four others showed partial remission.
Summary: Phil has been out for ages and he couldn’t be happier. But dresses still call his name, even after he’s transitioned. He hates the thought of Dan laughing at him for it, but he can’t help trying them on now and them. Warnings: Sexual content Word Count: 2551 Author’s Notes: i haven’t touched any phanfics since december, but it’s spring and things are super nice for me right now, so i’m going to be working on more fics! between working in my shop and making art and school, i might not be able to post often, but i’m going to write as much as i can!
Researchers at the University of California, San Diego School of Medicine have launched a phase 1 human clinical trial to assess the safety and efficacy of a new monoclonal antibody for patients with chronic lymphocytic leukemia (CLL), the most common form of blood cancer in adults.
The new antibody targets ROR1, a protein used by embryonic cells during early development and exploited by cancer cells to promote tumor growth and metastasis, the latter responsible for 90 percent of all cancer-related deaths.
Because ROR1 is not expressed by normal adult cells, scientists believe it is a biomarker of cancer cells in general and cancer stem cells in particular. Because it appears to drive tumor growth and disease spread, they believe it also presents an excellent target for anti-cancer therapy.
Developed at UC San Diego Moores Cancer Center by Thomas Kipps, MD, PhD, who holds the Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues, the antibody is called cirmtuzumab (also known as UC-961). In previous animal studies, Kipps’ team reported that ROR1 is singularly expressed on CLL and also on a variety of different cancers, including cancers of the breast, pancreas, colon, lung and ovary. In mouse models of CLL, ROR1 acts as an accelerant when combined with another oncogene to produce a faster-growing, more aggressive cancer.
Cirmtuzumab was developed under the auspices of the California Institute for Regenerative Medicine’s HALT leukemia grant awarded to Dennis Carson, MD, principal investigator, and Catriona Jamieson, MD, PhD, co-principal investigator to develop six distinct therapies against cancer stem cells. Kipps led one of the six projects and generated antibodies against ROR1, leading to the cirmtuzumab trial in patients with CLL.
“The primary goal of this phase I clinical trial is to evaluate whether cirmtuzumab is a safe and well-tolerated cancer stem cell-targeted agent in patients with CLL,” said Jamieson, chief of the Division of Regenerative Medicine, associate professor of medicine, director of stem cell research at UC San Diego Moores Cancer Center, deputy director of the Sanford Stem Cell Clinical Center and a principal investigator of the cirmtuzumab clinical trial.
Michael Choi, MD, assistant clinical professor of medicine and co-principal investigator of the clinical trial said, “The trial will involve patients with relapsed or refractory CLL, who will receive an intravenous infusion every 14 days at Moores, followed by regular monitoring and clinic visits to assess efficacy and identify and manage any adverse effects. Initial treatment is planned for two months.”
To learn more about eligibility for this clinical trial, call Reilly L. Kidwell at 858-534-4801 or Samuel Zhang at 858-534-8127.
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 December 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 ìorphan receptors,î 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.
Al regresar del callejón de los amantes mi cabello estaba blanco como la nieve. Alegría, incomprensión, dolor habían pasado por mi vida como las estaciones. De cómo llegué a casa medio muerto y helado, tal vez lo sepas.
Ocultas una sonrisa y citas un texto: Los deseos insatisfechos persisten de una vida a la siguiente. Hace tiempo nos apartamos de los hogares que nos acogieron, hace tiempo eran marcas sobre un plano de “orgullo abrasador”.
Tiempo sin cordura, el brillo de la burbuja sobre el nivel carbonizado anuncia la vuelta de abril. Un fulgor repentino… Sigue hablando mientras me convierto en el diseño de un arroyo bordeado por juncos blancos sobre azul.
JAMES MERRILL Versión de Jeannette L. Clariond (CLL)
When I returned from lovers` lane My hair was white as snow. Joy, incomprehension, pain I`d seen like seasons come and go. How I got home again Frozen half dead, perhaps you know.
You hide a smile and quote a text: Desires ungratified Persist from one life to the next. Hearths we strip ourselves beside Long, long ago were x`d On blueprints of “consuming pride”.
Times out of mind, the bubble-gleam To our charred level drew April back. A sudden beam… -Keep talking while I change into The pattern of a stream Bordered with rushes white on blue.
So, in ENglish class, the teacher made us do a mock interview where she asked questions and everyone in the class recorded themselves to answer. And she was like “Oh yeah but you know, the internet is kinda wonky in this place, how will you call your family and friends ?” and I straight up said “I have no friends.”
Except that my friend heard me and started laughing and I couldn’t answer half the questions because I could hear her laugh
Anyway, I’m gonna go listen to her interview and see how she did with her “russian polar bears”