Eradicate cancer stem cells, eradicate drug-resistant leukema

Markus Müschen/UCSF

CIRM grantees at the University of California San Francisco have found the protein certain leukemia cells use to evade chemotherapy. A press release from UCSF says:

Doctors who treat children with the most common form of childhood cancer – acute lymphoblastic leukemia – are often baffled at how bulk cancer cells die from chemotherapy whereas the rare stem cells in cancer survive their best efforts and the most powerful modern cancer drugs. Months after a seemingly successful treatment, the cancer stem cells re-initiate the disease, which is then more resistant to treatment than before.

It turns out the resistant cancer stem cells make a protein called BCL6, which protects them from the effects of chemotherapy. In a Nature paper published today, the team tested an experimental drug called RI-BPI, which attacks cells that make BCL6. Combined with the drug Gleevac, which is very effective at destroying the non-BCL6 cells, the experimental drug could effectively cure mice with drug resistant leukemia. In the release, CIRM grantee and senior author Markus Müschen said:

“We believe this discovery is of immediate relevance to patient care.”

In the work reported in this paper, the team used a molecule to block BCL6 that, though effective for small scale use, would be difficult to mass produce. Müschen has a CIRM Early Translational II Award to develop a drug that is similarly effective at destroying drug-resistant leukemia cells but that would be easier to mass produce for widespread use.

We have more information about cancer stem cells on our website:

• Leukemia information
• Cancer stem cell video

Nature, May 18, 2011
CIRM Funding: Markus Müschen (TR2-01816)

Celebrating National Cancer Research Month with a cancer stem cell round-up

In celebration of National Cancer Research Month, our colleagues at Sanford-Burnham Medical Research Institute have posted a series of blog entries about cancer research at their institute. The latest installment includes CIRM grantee Robert Wechsler-Reya, who moved to California from Duke University on a CIRM Research Leadership Award.

According to their blog:

Dr. Robert Wechsler-Reya, who directs the Tumor Development Program in Sanford-Burnham’s Cancer Center, has spent many years studying how “good” processes can also cause disease. He is particularly interested in how mechanisms that are normal in embryonic development can cause cancer when turned on in children and adults.

“We work on the relationship between development and cancer, particularly in the brain,” says Dr. Wechsler-Reya. “We’re interested in how normal stem cells and progenitor cells make decisions like when to divide, when to differentiate and what to differentiate into. We’re interested in how those decisions go wrong in cancer.”

To-date, CIRM has awarded more than $130 million to cancer research, including grantees working to understand the role of cancer stem cells in the disease and other teams working to develop therapies. Among our Disease Team projects, which have the goal of reaching clinical trials by 2014, CIRM funded two teams working on therapies for glioma (City of Hope and UCSF), two working on therapies for leukemia (Stanford and UCSD), and one working on solid tumors (UCLA).

Here are a few resources CIRM offers for people trying to get information about stem cells and cancer.

• Information about stem cells and glioma
• Information about stem cells and leukemia
• Information about stem cells and solid tumors

We also produced this video with CIRM grantee Catriona Jamieson at Moore's UCSD Cancer Center at the University of California, San Diego. Jamieson has a therapy in clinical trial for a pre-cancerous blood condition. The work that led to that trial was funded in part by a CIRM SEED grant.



A.A.

Blood-forming stem cells for Japanese nuclear workers?

According to a story in The Guardian, Japanese officials are considering blood-forming stem cell transplants in workers exposed to high radiation levels. They write:

The proposal has been drawn up as a precautionary measure that could potentially save the lives of workers if they receive high doses of radiation while battling to bring the damaged nuclear reactors under control.

If those transplants take place and are effective, the brave men and women will be part of a story that began with the bombing of Hiroshima and Nagasaki during World War II. People exposed to radiation from those bombs frequently developed leukemias. Investigating those cancers led scientists in Canada to discover cells in the bone marrow that constantly form new blood and immune cells. The leukemias arose when bone marrow stem cells suffered mutations and turned some cells cancerous.

Eventually, scientists used these discoveries to develop bone marrow transplants, in which a person's bone marrow is eliminated by radiation then replaced with donor bone marrow. Blood-forming stem cells within that bone marrow then form a new blood and immune system — presumably one that's cancer-free. CIRM grantee Irv Weissman at Stanford University identified the blood-forming stem cells amidst the many cell types in the bone marrow.

Now, the technique that started with radiation-exposed people in Japan could help the brave men and women who have been exposed while trying to save the nuclear plants damaged during the country's earthquake and tsunami. The idea is that Japanese scientists would freeze blood-forming stem cells from workers, which could then be used to treat those workers if they are exposed.

Although the stored cells could treat blood cancers, some warn that workers might consider the cells a safety net and take unnecessary risks. Stored blood cells wouldn't be able to treat damage to other tissues. The Guardian quotes Robert Peter Gale, a US medical researcher advising the Japanese government:

"These cells can reconstitute bone marrow function; that is not the only target of high dose radiation, they would have damage elsewhere, to their lungs, gastrointenstinal tract and their skin."

He also warns about the logistics of extracting blood-forming stem cells from the roughly 800 workers.

- A.A.

Knocking out leukemia stem cells

A good report about bone marrow transplantation in progress comes from the National Hockey League, of all places. Mandi Schwartz, a Yale women’s hockey player, was diagnosed with acute myeloid leukemia and is being treated at the Seattle Cancer Care Alliance.

In the name of full disclosure, that’s the center that cured my mother’s lymphoma, so let’s just say I’m a fan.

NHL.com wrote a nice description of how bone marrow transplantation knocks out leukemia stem cells. Acute myeloid leukemia is a cancer that begins in the bone marrow stem cells — the cells that continuously produce new blood and immune cells throughout a person’s life. A bone marrow transplant essentially replaces the cancerous leukemia stem cells with new ones from a donor, like an organ transplant but with bone marrow. The NHL writes:

Engraftment, which was the next phase in her recovery, is needed in order for the transplanted stem cells to begin to grow in her bone marrow and manufacture new blood cells and immune cells... Complete recovery of a new immune system can take a year or longer depending on any complications as a result of the transplant.

Bone marrow transplants like this one are effective, but dangerous. The process of eliminating a person’s diseased bone marrow leaves the person extremely weak and prone to infections. This danger is why several CIRM grantees are working on a less toxic way of killing off the diseased bone marrow stem cells (here's a list of our awards targeting blood cancers). Irving Weissman at Stanford University has found molecules on the surface of the stem cells underlying acute myelogenous leukemia. He has a CIRM disease team award to develop a chemotherapy that could destroy those cells in a way that’s far less toxic than bone marrow transplant.

If that research is successful, future people like Schwartz may recover from acute myelogenous leukemia with fewer side effects. As someone who has seen a family member battle cancer, fewer side effects for an effective therapy is a winning combination.

A.A.

Hope for CIRM leukemia disease team

The clock is ticking on the 14 CIRM Disease Team projects issued last October, which are working under a four-year deadline to hit the clinic. The $20 million acute myeloid leukemia project headed up by Irv Weissman of Stanford University just reported some promising progress.

Weissman and his team are developing a chemotherapy drug that binds to a protein found on leukemia stem cells, killing the cells. The protein, called CD47, is also found on other cancer stem cells.

The work, which was published in the Sept. 3 issue of Cell, was focused on non-Hodgkins lymphoma. The group gave mice with non-hodgkins lymphoma the molecule that blocks CD47 in addition to another antibody, and cured the disease in 60 percent of cases.

According to a Stanford press release:

The researchers point out that, although the CIRM grant focuses on investigating anti-CD47 therapies for acute myeloid leukemia, the drug development process will result in an antibody that could also be used for other cancers. They focused their preliminary investigations on non-Hodgkin’s lymphoma because they were curious as to how the anti-CD47 antibody would work with rituximab, which also binds to human lymphoma cells.

The release goes on to say that the researchers hope to try the therapy in other cancers:

The researchers are moving forward to conduct tests on other CD47-expressing cancer cells, which include acute leukemia, bladder and several other cancer stem cells. They speculate that they might see a similar synergistic effect between anti-CD47 and other cancer-specific monoclonal antibodies currently in clinical use. They are also moving ahead as quickly as possible to bring the anti-CD47 antibody treatment to trials in human patients.

Recently, CIRM disease teams targeting brain tumors (blogged about here) and HIV/AIDS (blogged about here) have also had some preliminary success.

You can learn more about the CIRM disease team program in our October press release.

If you aren’t familiar with cancer stem cells, here’s a video with Catriona Jameison, a cancer stem cell scientist at University of California, San Diego, talking about their role in cancer.



A.A.