When you read about a new drug or therapy being approved to help patients it always seems so simple. Researchers come up with a brilliant idea, test it to make sure it is safe and works, and then get approval from the US Food and Drug Administration (FDA) to sell it to people who need it.
But it’s not always that simple, or straight forward. Sometimes it can take years, with several detours along the way, before the therapy finds its way to patients.
That’s the case with a blood cancer drug called fedratinib (we blogged about it here) and the relentless efforts by U.C. San Diego researcher Dr. Catriona Jamieson to help make it available to patients. CIRM funded the critical early stage research to help show this approach could help save lives. But it took many more years, and several setbacks, before Dr. Jamieson finally succeeded in getting approval from the FDA.
The story behind that therapy, and Dr. Jamieson’s fight, is told in the San Diego Union Tribune. Reporter Brad Fikes has been following the therapy for years and in the story he explains why he found it so fascinating, and why this was a therapy that almost didn’t make it.
Chronic myelogenous leukemia (CML) is a cancer of the white blood cells. It causes them to increase in number, crowd out other blood cells, leading to anemia, infection or heavy bleeding. Up until the early 2000’s the main weapon against CML was chemotherapy, but the introduction of drugs called tyrosine kinase inhibitors changed that, dramatically improving long term survival rates.
However, these medications are not a
cure and do not completely eradicate the leukemia stem cells that can fuel the
growth of the cancer, so if people stop taking the medication the cancer can
But now Dr. John Chute and a team of researchers at UCLA, in a CIRM-supported study, have found a way to target those leukemia stem cells and possibly eliminate them altogether.
The team knew that mice that had the genetic mutation
responsible for around 95 percent of CML cases normally developed the disease
and died with a few months. However, mice that had the CML gene but lacked
another gene, one that produced a protein called pleiotrophin, had normal white
blood cells and lived almost twice as long. Clearly there was something about
pleiotrophin that played a key role in the growth of CML.
They tested this by transplanting blood stem cells from mice
with the CML gene into healthy mice. The previously healthy mice developed
leukemia and died. But when they did the same thing from mice that had the CML
gene but lacked the pleiotrophin gene, the mice remained healthy.
So, Chute and his team wanted to know if the same thing
happens in human cells. Studying human CML stem cells they found these had not
just 100 times more pleiotrophin than ordinary cells, they were also producing
their own pleiotrophin.
In a news release Chute, said this was unexpected:
“This provides an example of cancer stem cells
that are perpetuating their own disease growth by hijacking a protein that
normally supports the growth of the healthy blood system.”
Next Chute and the team developed an antibody that blocked
the action of pleiotrophin and when they tested it in human cells the CML stem
Then they combined this antibody with a drug called imatinib
(better known by its brand name, Gleevec) which targets the genetic abnormality
that causes most forms of CML. They tested this in mice who had been
transplanted with human CML stem cells and the cells died.
“Our results suggest that it may be possible to eradicate
CML stem cells by combining this new targeted therapy with a tyrosine kinase
inhibitor,” said Chute. “This could lead to a day down the road when people
with CML may not need to take a tyrosine kinase inhibitor for the rest of their
The next step is for the researchers to modify the antibody so that it is better suited for humans and not mice and to see if it is effective not just in cells in the laboratory, but in people.
Glioblastoma is an aggressive form of cancer that invades brain tissue, making it extremely difficult to treat. Current therapies involving radiation and chemotherapy are effective in destroying the bulk of brain cancer cells, but they are not able to reach the brain cancer stem cells, which have the ability to grow and multiply indefinitely. These cancer stem cells enable the glioblastoma to continuously grow even after treatment, which leads to recurring tumor formation.
Dr. Jeremy Rich and his team at UC San Diego examined glioblastomas further by obtaining glioblastoma tumor samples donated by patients that underwent surgery and implanting these into mice. Dr. Rich and his team tested a combinational treatment that included a targeted cancer therapy alongside a drug named teriflunomide, which is used to treatment patients with multiple sclerosis. The research team found that this approach successfully halted the growth of glioblastoma stem cells, shrank the tumor size, and improved survival in the mice.
In order to continue replicating, glioblastoma stem cells make pyrimidine, one of the compounds that make up DNA. Dr. Rich and his team noticed that higher rates of pyrimidine were associated with poor survival rates in glioblastoma patients. Teriflunomide works by blocking an enzyme that is necessary to make pyrmidine, therefore inhibiting glioblastoma stem cell replication.
In a press release, Dr. Rich talks about the potential these findings hold by stating that,
“We’re excited about these results, especially because we’re talking about a drug that’s already known to be safe in humans.”
However, he comments on the need to evaluate this approach further by saying that,
“This laboratory model isn’t perfect — yes it uses human patient samples, yet it still lacks the context a glioblastoma would have in the human body, such as interaction with the immune system, which we know plays an important role in determining tumor growth and survival. Before this drug could become available to patients with glioblastoma, human clinical trials would be necessary to support its safety and efficacy.”
The full results to this study were published in Science Translational Medicine.
CIRM-funded research at Sanford Burnham Prebys Medical Discovery Institute in San Diego is identifying compounds that could be used to help children battling a deadly brain cancer.
The cancer is choroid plexus carcinoma (CPC), a rare
brain tumor that occurs mainly in children. As it grows the tumor can affect
nearby parts of the brain resulting in nausea, vomiting and headaches.
Treatment involves surgery to remove the tumor followed
by chemotherapy and radiation. However, many of the children are too young to
undergo radiation and only around 40 percent are still alive five years after
being diagnosed. Even those who do survive often experience life-long
consequences such as developmental disabilities.
One obstacle to developing better therapies has been the
lack of a good animal model to enhance our understanding of the disease. That’s
where this later research, published in the journal Cancer Research, comes in.
The team at Sanford Burnham developed a new mouse model,
by knocking out p53, a gene known to suppress tumor formation, and activating a
gene called Myc, which is known to cause cancer.
In a news release, Robert Wechsler-Reya, the senior author of the paper, says this new model mirrors the way CPC grows and develops in humans.
“This model is a
valuable tool that will increase our understanding of the biology of the cancer
and allow us to identify and test novel approaches to therapy. This advance
brings us one step closer to a future where every child survives—and thrives—after
diagnosis with CPC.”
As proof of that
the team tested nearly 8,000 compounds against the mouse tumor cells, to see if
they could help stop or slow the progression of the disease. They identified
three that showed potential of not just stopping the cancer, but of also not
harming healthy surrounding cells.
“These compounds are promising, much-needed leads in the
quest for an effective CPC treatment,” says Wechsler-Reya. “Our laboratory
plans to evaluate these and additional compounds that can effectively treat
Every three minutes, one person in the United States is diagnosed with a blood cancer, which amounts to over 175,000 people every year. Every nine minutes, one person in the United States dies from a blood cancer, which is over 58,000 people every year. These eye opening statistics from the Leukemia & Lymphoma Society demonstrate why almost one in ten cancer deaths in 2018 were blood cancer related.
For those unfamiliar with the term, a blood cancer is any type of cancer that begins in blood forming tissue, such as those found in the bone marrow. One example of a blood cancer is leukemia, which results in the production of abnormal blood cells. Chemotherapy and radiation are used to wipe out these cells, but the blood cancer can sometimes return, something known as a relapse.
What enables the return of a blood cancer such as leukemia ? The answer lies in the properties of cancer stem cells, which have the ability to multiply and proliferate and can resist the effects of certain types of chemotherapy and radiation. Researchers at Tel Aviv University are looking to decrease the rate of relapse in blood cancer by targeting a specific type of cancer stem cell known as a leukemic stem cell, which are often found to be the most malignant.
Dr. Michael Milyavsky and his team at Tel Aviv University have developed a biosensor that is able to isolate, label, and target specific genes found in luekemic stem cells. Their findings were published on January 31, 2019 in Leukemia.
“The major reason for the dismal survival rate in blood cancers is the inherent resistance of leukemic stem cells to therapy, but only a minor fraction of leukemic cells have high regenerative potential, and it is this regeneration that results in disease relapse. A lack of tools to specifically isolate leukemic stem cells has precluded the comprehensive study and specific targeting of these stem cells until now.”
In addition to isolating and labeling leukemic stem cells, Dr. Milyavsky and his team were able to demonstrate that the leukemic stem cells labeled by their biosensor were sensitive to an inexpensive cancer drug, highlighting the potential this technology has in creating more patient-specific treatment options.
In the article, Dr. Milyavsky said:
” Using this sensor, we can perform personalized medicine oriented to drug screens by barcoding a patient’s own leukemia cells to find the best combination of drugs that will be able to target both leukemia in bulk as well as leukemia stem cells inside it.”
The researchers are now investigating genes that are active in leukemic stem cells in the hope finding other druggable targets.
CIRM has funded two clinical trials that also use a more targeted approach for cancer treatment. One of these trials uses an antibody to treat chronic lymphocytic leukemia (CLL) and the other trial uses a different antibody to treat acute myeloid leukemia (AML).
Can cell therapy beat the most difficult diseases?
the question posed in a headline in National
Geographic. The answer; maybe, but it is going to take time and
article focuses on the use of iPS cells, the man-made equivalent of embryonic
stem cells that can be turned into any kind of cell or tissue in the body. The
reporter interviews Kemal
Malik, the member of the Board of Management for pharmaceutical giant Bayer who
is responsible for innovation. When it comes to iPS cells, it’s clear Malik is
a true believer in their potential.
“Because every cell
in our bodies can be produced from a stem cell, the applicability of cell
therapy is vast. iPSC technology has the potential to tackle some of the most
challenging diseases on the planet.”
he also acknowledges that the field faces some daunting challenges, including:
How to manufacture
the cells on a large scale without sacrificing quality and purity
How do you create
products that have a stable shelf life and can be stored until needed?
How do you handle
immune reactions if you are giving these cells to patients?
Malik remains confident we can overcome those challenges and realize the full
potential of these cells.
“I believe human
beings are on the cusp of the next big wave of pharmaceutical innovation. The
use of living cells to make people better.”
if to prove Malik right there was also news this week that researchers at
Japan’s Keio University have been given permission to start a clinical trial
using iPS cells to treat people with spinal cord injuries. This would be the
first of its kind anywhere in the world.
Japan launches iPSC clinical trial for spinal cord injury
article in Biospace
says that the researchers plan to treat four patients who have suffered varying
degrees of paralysis due to a spinal cord injury. They will take cells from the patients and,
using the iPS method, turn them into the kind of nerve cells found in the
spinal cord, and then transplant two million of them back into the patient. The
hope is that this will create new connections that restore movement and feeling
in the individuals.
trial is expected to start sometime this summer.
has already funded a first-of-its-kind clinical trial for spinal cord injury
Biotherapeutics. That clinical trial used embryonic stem cells
turned into oligodendrocyte progenitor cells – which develop into cells that support
and protect nerve cells in the central nervous system. We blogged about the
encouraging results from that trial here.
High fat diet drives
Finally today, researchers at Salk have uncovered a possible cause to the rise in colorectal cancer deaths among people under the age of 55; eating too much high fat food.
digestive system works hard to break down the foods we eat and one way it does
that is by using bile acids. Those acids don’t just break down the food,
however, they also break down the lining of our intestines. Fortunately, our
gut has a steady supply of stem cells that can repair and replace that lining.
Unfortunately, at least according to the team from Salk, mutations in these
stem cells can lead to colorectal cancer.
study, published in the journal Cell,
shows that bile acids affect a protein called FXR that is responsible for
ensuring that gut stem cells produce a steady supply of new lining for the gut
wall. When someone eats a high fat diet it upsets the balance of bile acids,
starting a cascade of events that help cancer develop and grow.
release Annette Atkins, a co-author of the study, says there is a
strong connection between bile acid and cancer growth:
“We knew that
high-fat diets and bile acids were both risk factors for cancer, but we weren’t
expecting to find they were both affecting FXR in intestinal stem cells.”
next time you are thinking about having that double bacon cheese burger for
lunch, you might go for the salad instead. Your gut will thank you. And it
might just save your life.
No one sets out to be a Patient Advocate. It’s something that you become because of something that happens to you. Usually it’s because you, or a loved one or a friend, becomes ill and you want to help find a treatment. Whatever the reason, it is the start of a journey that often throws you into a world that you know nothing about: a world of research studies and scientific terminology, of talking to and trying to understand medical professionals, and of watching someone you love struggle.
a tough, demanding, sometimes heart-breaking role. But it’s also one of the
most important roles you can ever take on. Patient Advocates not only care for
people afflicted with a particular disease or disorder, they help them navigate
a new and scary world, they help raise money for research, and push researchers
to work harder to find new treatments, maybe even cures. And they remind all of
us that in the midst of pain and suffering the human touch, a simple kindness
is the most important gift of all.
But what makes a great Patient Advocate, what skills do you need and how can you get them? At CIRM we are blessed to have some of the most amazing Patient Advocates you will ever meet. So we asked three of them to join us for a special Facebook Live “Ask the Stem Cell Team” event to share their knowledge, experience and expertise with you.
The Facebook Live “Ask the Stem Cell Team About Patient Advocacy” event will be on Thursday, March 14th from noon till 1pm PST.
three experts are:
Gigi McMillan became a Patient Advocate when her 5-year-old son was diagnosed with a brain tumor. That has led her to helping develop support systems for families going through the same ordeal, to help researchers develop appropriate consent processes and to campaign for the rights of children and their families in research.
Adrienne Shapiro comes from a family with a long history of Sickle Cell Disease (SCD) and has fought to help people with SCD have access to compassionate care. She is the co-founder of Axis Advocacy, an organization dedicated to raising awareness about SCD and support for those with it. In addition she is now on the FDA’s Patient Engagement Collaborative, a new group helping the FDA ensure the voice of the patient is heard at the highest levels.
David Higgins is a CIRM Board member and a Patient Advocate for Parkinson’s Disease. David has a family history of the disease and in 2011 was diagnosed with Parkinson’s. As a scientist and advocate he has championed research into the disease and strived to raise greater awareness about the needs of people with Parkinson’s.
Please join us for our Facebook Live event on Patient Advocates on Thursday, March 14 from noon till 1pm and feel free to share information about the event with anyone you think would be interested.
You never know when you write something if people are going to read it. Sometimes you wonder if anyone is going to read it. So, it’s always fun, and educational, to look back at the end of the year and see which pieces got the most eyeballs.
It isn’t always the ones you think will draw the biggest audiences. Sometimes it is diseases that are considered “rare” (those affecting fewer than 200,000 people) that get the most attention.
Maybe it’s because those diseases have such a powerful online community which shares news, any news, about their condition of interest with everyone they know. Whatever the reason, we are always delighted to share encouraging news about research we are funding or encouraging research that someone else is funding.
That was certainly the case with the top two stories this year. Both were related to ALS or Lou Gehrig’s disease. It’s a particularly nasty condition. People diagnosed with ALS have a life expectancy of just 2 to 5 years. So it’s probably not a big surprise that stories suggesting stem cells could expand that life span got a big reception.
Whatever the reason, we’re just happy to share hopeful news with everyone who comes to our blog.
And so, without further ado, here is the list of the most popular Stem Cellar Blog Posts for 2018.
All of us in the Communications team at CIRM consider it an honor and privilege to be able to work here and to meet many of the people behind these stories; the researchers and the patients and patient advocates. They are an extraordinary group of individuals who help remind us why we do this work and why it is important. We love our work and we hope you enjoy it too. We plan to be every bit as active and engaged in 2019.
Three-dimensional culture of human breast cancer cells, with DNA stained blue and a protein on the cell surface membrane stained green. Image courtesy The National Institutes of Health
A Phase 1 clinical trial co-sponsored by CIRM and Oncternal Therapeutics, has started treating patients at UC San Diego (UCSD). The goal of the trial is to test the safety and anti-tumor activity of the Oncternal-developed drug, cirmtuzumab, in treating breast cancer.
Breast cancer is the second most common cancer to occur in women, regardless of race or ethnicity. More than 260,000 new cases are expected to be diagnosed this year in the United States alone. Typically, breast cancer cases are treated by a combination of surgery to remove the tumor locally, followed by some kind of systemic treatment, like chemotherapy, which can eliminate cancer cells in other parts of the body. In certain cases, however, surgery might not be a feasible option. Cirmtuzumab may be a viable option for these patients.
The drug acts by binding to a protein called ROR1, which is highly abundant on the surface of cancer cells. By blocking the protein Cirmtuzumab is able to promote cell death, stopping the cancer from spreading around the body.
Because ROR1 is also found on the surface of healthy cells there were concerns using cirmtuzumab could lead to damage to healthy tissue. However, a previous study revealed that using this kind of approach, at least in a healthy non-human primate model did not lead to any adverse clinical symptoms. Therefore, this protein is a viable target for cancer treatment and is particularly promising because it is a marker of many different types of cancers including leukemia, lung cancer and breast cancer.
Phase 1 clinical trials generally enroll a small number of patients who have do not have other treatment options. The primary goals are to determine if this approach is safe, if it causes any serious side-effects, what is the best dosage of the drug and how the drug works in the body. This clinical trial will enroll up to 15 patients who will receive cirmtuzumab in combination with paclitaxel (Taxol), a vetted chemotherapy drug, for six months.
Earlier this year, a similar clinical trial at UCSD began to test the effectiveness a of cirmtuzumab-based combination therapy to treat patients with B-cell cancers such as chronic lymphocytic leukemia. This trial was also partially funded by CIRM.
In a press release, Dr. Barbara Parker, the co-lead on this study states:
“Our primary objective, of course, is to determine whether the drug combination is safe and tolerable and to measure its anti-tumor activity. If it proves safe and shows effectiveness against breast cancer, we can progress to subsequent trials to determine how best to use the drug combination.”
The context was the recent initial public offering (IPO) of Forty Seven Inc.. a company co-founded by Dr. Weissman. That IPO followed news that two Phase 2 clinical trials being run by Forty Seven Inc. were demonstrating promising results against hard-to-treat cancers.
Dr. Weissman says the therapies used a combination of two monoclonal antibodies, 5F9 from Forty Seven Inc. and Rituximab (an already FDA-approved treatment for cancer and rheumatoid arthritis) which:
“Led to about a 50% overall remission rate when used on patients who had relapsed, multi-site disease refractory to rituximab-plus-chemotherapy. Most of those patients have shown a complete remission, although it’s too early to tell if this is complete for life.”
5F9 attacks a molecule called CD47 that appears on the surface of cancer cells. Dr. Weissman calls CD47 a “don’t eat me signal” that protects the cancer against the body’s own immune system. By blocking the action of CD47, 5F9 strips away that “don’t eat me signal” leaving the cancer vulnerable to the patient’s immune system. We have blogged about this work here and here.
The news from these trials is encouraging. But what was gratifying about Dr. Weissman’s statement is his generosity in sharing credit for the work with CIRM.
Here is what he wrote:
“What is unusual about Forty Seven is that not only the discovery, but its entire preclinical development and testing of toxicity, etc. as well as filing two Investigational New Drug [IND] applications to the Food and Drug Administration (FDA) in the US and to the MHRA in the UK, as well as much of the Phase 1 trials were carried out by a Stanford team led by two of the discoverers, Ravi Majeti and Irving Weissman at Stanford, and not at a company.
The major support came from the California Institute of Regenerative Medicine [CIRM], funded by Proposition 71, as well as the Ludwig Cancer Research Foundation at the Ludwig Center for Cancer Stem Cell Research at Stanford. CIRM will share in downstream royalties coming to Stanford as part of the agreement for funding this development.
This part of the state initiative, Proposition 71, is highly innovative and allows the discoverers of a field to guide its early phases rather than licensing it to a biotech or a pharmaceutical company before the value and safety of the discovery are sufficiently mature to be known. Most therapies at early-stage biotechs are lost in what is called the ‘valley of death’, wherein funding is very difficult to raise; many times the failure can be attributed to losing the expertise of the discoverers of the field.”
Dr. Weissman also had praise for CIRM’s funding model which requires companies that produce successful, profitable therapies – thanks to CIRM support – to return a portion of those profits to California. Most other funding agencies don’t have those requirements.
“US federal funds, from agencies such as the National Institutes of Health (NIH) similarly support discovery but cannot fund more than a few projects to, and through, early phase clinical trials. And, under the Bayh-Dole Act, the universities keep all of the equity and royalties derived from licensing discoveries. In that model no money flows back to the agency (or the public), and nearly a decade of level or less than level funding (at the national level) has severely reduced academic research. So this experiment of funding (the NIH or the CIRM model) is now entering into the phase that the public will find out which model is best for bringing new discoveries and new companies to the US and its research and clinical trials community.”
We have been funding Dr. Weissman’s work since 2006. In fact, he was one of the first recipients of CIRM funding. It’s starting to look like a very good investment indeed.