Blocking pancreatic cancer stem cells

John Cashman

Cancer stem cells are one of the main reasons why cancers are able to survive surgery, chemotherapy and radiation. They are able to hide from those therapies and, at a future date, emerge and spread the cancer in the body once again.

Jionglia Cheng, PhD.

Jionglia Cheng, PhD., the lead author of a new CIRM-funded study, says that’s one of the reasons why pancreatic cancer has proved so difficult to treat.

“Pancreatic cancer remains a major health problem in the United States and soon will be the second most common cause of mortality due to cancer. A majority of pancreatic cancer patients are often resistant to clinical therapies. Thus, it remains a challenge to develop an efficacious clinically useful pancreatic cancer therapy.”

Dr. Cheng, a researcher with ChemRegen Inc., teamed up with John Cashman at the Human BioMolecular Research Institute and identified a compound, that seems to be effective in blocking the cancer stem cells.

In earlier studies the compound, called PAWI-2, demonstrated effectiveness in blocking breast, prostate and colon cancer. When tested in the laboratory PAWI-2 showed it was able to kill pancreatic cancer stem cells, and also was effective in targeting drug-resistant pancreatic cancer stem cells.

In addition, when PAWI-2 was used with a drug called erlotinib (brand name Tarceva) which is commonly prescribed for pancreatic cancer, the combination proved more effective against the cancer stem cells than erlotinib alone.

In a news release Dr. Cheng said: “In the future, this molecule could be used alone or with other chemotherapy albeit at lower doses, as a new therapeutic drug to combat pancreatic cancer. This may lead to much less toxicity to the patient,”

The study is published in the journal Scientific Reports.

Rave reviews for new Killer-T Cell study

Anytime you read a news headline that claims a new discovery “may treat all cancer” it’s time to put your skeptic’s hat on. After all, there have been so many over-hyped “discoveries” over the years that later flopped, that it would be natural to question the headline writer. And yet, this time, maybe, this one has some substance behind it.

Andrew Sewell with research fellow Garry Dolton. (Photo Credit: Cardiff University)

Researchers at the University of Cardiff in Wales have discovered a new kind of immune cell, a so-called “killer T-cell”, that appears to be able to target and kill many human cancer cells, such as those found in breast, prostate and lung cancer. At least in the lab.

The immune system is our body’s defense against all sorts of threats, from colds and flu to cancer. But many cancers are able to trick the immune system and evade detection as they spread throughout the body. The researchers found one T-cell receptor (TCR) that appears to be able to identify cancer cells and target them, but leave healthy tissues alone.

In an interview with the BBC, Prof. Andrew Sewell, the lead researcher on the study said: “There’s a chance here to treat every patient. Previously nobody believed this could be possible. It raises the prospect of a ‘one-size-fits-all’ cancer treatment, a single type of T-cell that could be capable of destroying many different types of cancers across the population.”

The study, published in the journal Nature Immunology, suggests the TCR works by using a molecule called MR1 to identify cancerous cells. MR1 is found on every cell in our body but in cancerous cells it appears to give off a different signal, which enables the TCR to identify it as a threat.

When the researchers injected this TCR into mice that had cancer it was able to clear away many of the cells. The researchers admit there is still a long way to go before they know if this approach will work in people, but Sewell says they are encouraged by their early results.

“There are plenty of hurdles to overcome. However, if this testing is successful, then I would hope this new treatment could be in use in patients in a few years’ time.”

CIRM is funding a number of clinical trials that use a similar approach to targeting cancers, taking the patient’s own immune T-cells and, in the lab, “re-educating” to be able to recognize the cancerous cells. Those cells are then returned to the patient where it’s hoped they’ll identify and destroy the cancer. You can read about those here , here, here, here, and here.

USC study shows how tumor cells in the bloodstream can target distant organs

Various types of cancer can become particularly aggressive and difficult to treat once they spread from their initial point of origin to other parts of the body. This unfortunate phenomenon, known as metastasis, can make treatment very challenging, decreasing the chance of survival for the patient.

In order to better understand this process, a CIRM supported study at USC looked at breast cancer cells circulating in the blood that eventually invade the brain. The findings, which appear in Cancer Discovery, shed light on how tumor cells in the blood are able to target a particular organ, which may enable the development of treatments than can prevent metastasis from occurring.

Dr. Min Yu

Dr. Min Yu and her lab at USC were able to isolate breast cancer cells from the blood of breast cancer patients whose cancer had already metastasized. The team then expanded the number of cancer cells through a process known as cell culture. These expanded human tumor cells were then injected into the bloodstream of animal models. It was found that these cells migrated to the brain as was predicted.

Upon further analysis, Dr. Yu and her lab discovered a protein on the surface of the tumor cells in the bloodstream that enable them to breach the blood brain barrier, a protective layer around the brain that blocks the passage of certain substances, and enter the brain. Additionally, Dr. Yu and her team discovered another protein inside the tumor cells that shield them from the brain’s immune response, enabling these cells to grow inside the brain.

In a news release in Science Magazine, Dr. Yu talks about how these findings could be used to improve treatment and prevention options for those with aggressive cancers:

“We can imagine someday using the information carried by circulating tumor cells to improve the detection, monitoring and treatment of the spreading cancers. A future therapeutic goal is to develop drugs that get rid of circulating tumor cells or target those molecular signatures to prevent the spread of cancer.”

CIRM has also funded a separate clinical trial related to the treatment of breast cancer related brain metastases.

Predicting the Impact of Stem Cell Cures on Healthcare Burden in California

A new independent report says developing stem cell treatments and cures for some of the most common and deadly diseases could produce multi-billion dollar benefits for California in reduced healthcare costs and improved quality and quantity of life.

The report, by researchers at the University of Southern California’s Leonard D. Schaeffer Center for Health Policy & Economics, looked at the value of hypothetical future interventions to reduce or cure cancer, diabetes, stroke and blindness.

Predicting the future is always complicated and uncertain and many groups are looking at the best models to determine the value and economic impact of cell and gene therapy as the first products are just entering the market. This study provides some insights into the potential financial benefits of developing effective stem cell treatments for some of the most intractable diseases affecting California today.

The impact could affect millions of people. In 2018 for Californians over the age of 50:

  • Nearly half were predicted to develop diabetes in their lifetime
  • More than one third will experience a stroke
  • Between 5 and 8 percent will develop either breast, colorectal, lung, or prostate cancer

The report says that a therapy that decreased the incidence of diabetes by 50 percent in Californians over the age of 51 would translate into a gain for the state of $322 billion in social value between now and 2050. Even just reducing diabetes 10% would lead to a gain of $60 billion in social value over the same period.

  • For stroke a 50 percent reduction would generate an estimated $229 billion in social value. A 10 percent reduction would generate $47 billion
  • For breast cancer a 50 percent reduction would generate $56 billion in social value; for colorectal cancer it would be $72 billion; for lung cancer $151 billion; and prostate cancer $53 billion. 

The impact of a cure for any one of those diseases would be enormous. For example, a 51-year-old woman cured of lung cancer could expect to gain a lifetime social value of almost half a million dollars ($467,275). That’s a measure of years of healthy life gained, of years spent enjoying time with family and friends and not wasting away or lying in a hospital bed.

The researchers say: “Though advances in scientific research defy easy predictions, investing in biomedical research is important if we want to reduce the burden of common and costly diseases for individuals, their families, and society. These findings show the value and impact breakthrough treatments could have for California.”

“Put in this context, the CIRM investment would be worthwhile if it increased our chances of success even modestly. Against the billions of dollars in disease burden facing California, the relatively small initial investment is already paying dividends as researchers work to bring new therapies to patients.”

The researchers determined the “social value” using a measure called a quality adjusted life-year (QALY). This is a way of estimating the cost effectiveness and consequences of treating or not treating a disease. For example, one QALY is equivalent to one year of perfect health for an individual. In this study the value of that year was estimated at $150,000. If someone is sick with, say, diabetes, their health would be estimated to be 0.5 QALY or $75,000. So, the better health a person enjoys and the longer they enjoy it the higher QALY score they accumulate. In the case of a disease affecting millions of people in that state or country that can obviously lead to very large QALY scores representing potentially billions of dollars.

Newly discovered “don’t eat me” signal shows potential for ovarian and triple-negative breast cancer treatment

Stanford researchers have found that cancer cells have a protein called CD24 on their surface that enables them to protect themselves against the body’s immune cells.
Courtesy of Shutterstock

Getting a breast cancer diagnosis is devastating news in and of itself. Currently, there are treatment options that target three different types of receptors, which are named hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR), commonly found in breast cancer cells, . Unfortunately, in triple-negative breast cancer, which occurs in 10-20% of breast cancer cases, all three receptors are absent, making this form of breast cancer very aggressive and difficult to treat.

In recent years, researchers have discovered that proteins on the cell surface can tell macrophages, an immune cell designed to detect and engulf foreign or abnormal cells, not to eat and destroy them. This can be useful to help normal cells keep the immune system from attacking them, but cancer cells can also use these “don’t eat me” signals to hide from the immune system. 

An illustration of a macrophage, a vital part of the immune system, engulfing and destroying a cancer cell. Antibody 5F9 blocks a “don’t eat me” signal emitted from cancer cells. Courtesy of Forty Seven, Inc.

In fact, because of this concept, a CIRM-funded clinical trial is being conducted that uses an antibody called 5F9 to block a “don’t eat me” signal known as CD47 that is found in cancer cells. The results of this trial, which have been announced in a previous blog post, are very promising.

Further building on this concept, a CIRM-funded study has now discovered a potential new target for triple-negative breast cancer as well as ovarian cancer. Dr. Irv Weissman and a team of researchers at Stanford University have discovered an additional “don’t eat me” signal called CD24 that cancers seem to use to evade detection and destruction by the immune system.

In a press release, Dr. Weissman talks about his work with CD47 and states that,

“Finding that not all patients responded to anti-CD47 antibodies helped fuel our research at Stanford to test whether non-responder cells and patients might have alternative ‘don’t eat me’ signals.” 

The scientists began by looking for signals that were produced more highly in cancers than in the tissues from which the cancers arose. It is here that they discovered CD24 and then proceeded to implant human breast cancer cells in mice for testing. When the CD24 signaling was blocked, the mice’s immune system attacked the cancer cells.

An important discovery was that ovarian and triple-negative breast cancer were highly affected by blocking of CD24 signaling. The other interesting discovery was that the effectiveness of CD24 blockage seems to be complementary to CD47 blockage. In other words, some cancers, like blood cancers, seem to be highly susceptible to blocking CD47, but not to CD24 blockage. For other cancers, like ovarian cancer, the opposite is true. This could suggest that most cancers will be susceptible to the immune system by blocking the CD24 or CD47 signal, and that cancers may be even more vulnerable when more than one “don’t eat me” signal is blocked.

Dr. Weissman and his team are now hopeful that potential therapies to block CD24 signaling will follow in the footsteps of the clinical trials related to CD47.

The full results to the study were published in Nature.

CIRM Board Approves New Clinical Trial for Breast Cancer Related Brain Metastases

Dr. Saul Priceman

Yesterday the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $9.28 million to Dr. Saul Priceman at City of Hope to conduct a clinical trial for the treatment of breast cancer related brain metastases, which are tumors in the brain that have spread from the original site of the breast cancer.

This award brings the total number of CIRM-funded clinical trials to 56. 

Breast cancer is the second-most common cancer in women, both in the United States (US) and worldwide.  It is estimated that over 260,000 women in the US will be diagnosed with breast cancer in 2019 and 1 out of 8 women in the US will get breast cancer at some point during her lifetime. Some types of breast cancer have a high likelihood of metastasizing to the brain.  When that happens, there are few treatment options, leading to a poor prognosis and poor quality of life. 

Dr. Priceman’s clinical trial is testing a therapy to treat brain metastases that came from breast cancers expressing high levels of a protein called HER2.   The therapy consists of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells.  The T cells are modified with a protein called a chimeric antigen receptor (CAR) that recognizes the tumor protein HER2.  These modified T cells (CAR-T cells) are then infused into the patient’s brain where they are expected to detect and destroy the HER2-expressing tumors in the brain.

CIRM has also funded the earlier work related to this study, which was critical in preparing the therapy for Food and Drug Administration (FDA) approval for permission to start a clinical trial in people.

“When a patient is told that their cancer has metastasized to other areas of the body, it can be devastating news,” says Maria T. Millan, M.D., the President and CEO of CIRM.  “There are few options for patients with breast cancer brain metastases.  Standard of care treatments, which include brain irradiation and chemotherapy, have associated neurotoxicity and do little to improve survival, which is typically no more than a few months.  CAR-T cell therapy is an exciting and promising approach that now offers us a more targeted approach to address this condition.”

The CIRM Board also approved investing $19.7 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Dr. Mark Tuszynski at the University of California San Diego (UCSD) was awarded $6.23 million to develop a therapy for spinal cord injury (SCI). Dr. Tuszynski will use human embryonic stem cells (hESCs) to create neural stem cells (NSCs) which will then be grafted at the injury site.  In preclinical studies, the NSCs have been shown to help create a kind of relay at the injury site, restoring communication between the brain and spinal cord and re-establishing muscle control and movement.

Dr. Mark Humayun at the University of Southern California (USC) was awarded $3.73 million to develop a novel therapeutic product capable of slowing the progression of age-related macular degeneration (AMD), the leading cause of vision loss in the US.

The approach that Dr. Humayun is developing will use a biologic product produced by human embryonic stem cells (hESCs). This material will be injected into the eye of patients with early development of dry AMD, supporting the survival of photoreceptors in the affected retina, the kind of cells damaged by the disease.

The TRAN1 awards went to:

Stay tuned for our next blog which will dive into each of these awards in much more detail.

Developing a non-toxic approach to bone-crushing cancers

When cancer spreads to the bone the results can be devastating

Battling cancer is always a balancing act. The methods we use – surgery, chemotherapy and radiation – can help remove the tumors but they often come at a price to the patient. In cases where the cancer has spread to the bone the treatments have a limited impact on the disease, but their toxicity can cause devastating problems for the patient. Now, in a CIRM-supported study, researchers at UC Irvine (UCI) have developed a method they say may be able to change that.

Bone metastasis – where cancer starts in one part of the body, say the breast, but spreads to the bones – is one of the most common complications of cancer. It can often result in severe pain, increased risk of fractures and compression of the spine. Tackling them is difficult because some cancer cells can alter the environment around bone, accelerating the destruction of healthy bone cells, and that in turn creates growth factors that stimulate the growth of the cancer. It is a vicious cycle where one problem fuels the other.

Now researchers at UCI have developed a method where they combine engineered mesenchymal stem cells (taken from the bone marrow) with targeting agents. These act like a drug delivery device, offloading different agents that simultaneously attack the cancer but protect the bone.

Weian Zhao; photo courtesy UC Irvine

In a news release Weian Zhao, lead author of the study, said:

“What’s powerful about this strategy is that we deliver a combination of both anti-tumor and anti-bone resorption agents so we can effectively block the vicious circle between cancers and their bone niche. This is a safe and almost nontoxic treatment compared to chemotherapy, which often leaves patients with lifelong issues.”

The research, published in the journal EBioMedicine, has already been shown to be effective in mice. Next, they hope to be able to do the safety tests to enable them to apply to the Food and Drug Administration for permission to test it in people.

The team say if this approach proves effective it might also be used to help treat other bone-related diseases such as osteoporosis and multiple myeloma.

A cancer therapy developed at a CIRM Alpha Stem Cell Clinic tests its legs against breast cancer

Breast cancer cells

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.”

Stem Cell Roundup: Protein shows promise in treating deadliest form of breast cancer: mosquito spit primes our body for disease

Triple negative breast cancerTriple negative breast cancer is more aggressive and difficult to treat than other forms of the disease and, as a result, is more likely to spread throughout the body and to recur after treatment. Now a team at the University of Southern California have identified a protein that could help change that.

The research, published in the journal Nature Communications, showed that a protein called TAK1 allows cancer cells from the tumor to migrate to the lungs and then form new tumors which can spread throughout the body. There is already an FDA-approved drug called OXO that has been shown to block TAK1, but this does not survive in the blood so it’s hard to deliver to the lungs.

The USC team found a way of using nanoparticles, essentially a tiny delivery system, to take OXO and carry it to the lungs to attack the cancer cells and stop them spreading.

triple_negative_breast_cancer_particle_graphic-768x651In a news release Min Yu, the principal investigator on the team, said that although this has only been tested in mice the results are encouraging:

“For patients with triple-negative breast cancer, systemic chemotherapies are largely ineffective and highly toxic. So, nanoparticles are a promising approach for delivering more targeted treatments, such as OXO, to stop the deadly process of metastasis.”

Mosquito spit and your immune system

Mosquito

Mosquito bite: Photo courtesy National Academy of Sciences

Anyone who has ever been bitten by a mosquito knows that it can be itchy and irritable for hours afterwards. But now scientists say the impact of that bite can last for much longer, days in fact, and even help prime your body for disease.

The scientists say that every time a mosquito bites you they inject saliva into the bite to keep the blood flowing freely. But that saliva also has an impact on your immune system, leaving it more vulnerable to diseases like malaria.

OK, so that’s fascinating, and really quite disgusting, but what does it have to do with stem cells? Well, researchers at the National Institute of Health’s (NIH) Malaria and Vector Research Laboratory in Phnom Penh, Cambodia engrafted human stem cells into mice to study the problem.

They found that mice with the human stem cells developed more severe symptoms of dengue fever if they were bitten by a mosquito than if they were just injected with dengue fever.

In an article in Popular Science Jessica Manning, an infectious disease expert at the NIH, said previously we had no idea that mosquito spit had such a big impact on us:

“The virus present in that mosquito’s saliva, it’s like a Trojan horse. Your body is distracted by the saliva [and] having an allergic reaction when really it should be having an antiviral reaction and fighting against the virus. Your body is unwittingly helping the virus establish infection because your immune system is sending in new waves of cells that this virus is able to infect.”

The good news is that if we can develop a vaccine against the saliva we may be able to protect people against malaria, dengue fever, Zika and other mosquito-borne diseases.

Stem cell study holds out promise for kidney disease

Kidney failure

Image via youtube.com

Kidney failure is the Rodney Dangerfield of diseases, it really doesn’t get the respect it deserves. An estimated 660,000 Americans suffer from kidney failure and around 47,000 people die from it every year. That’s more than die from breast or prostate cancer. But now a new study has identified a promising stem cell candidate that could help in finding a way to help repair damaged kidneys.

Kidneys are the body’s waste disposal system, filtering our blood and cleaning out all the waste products. Our kidneys have a limited ability to help repair themselves but if someone suffers from chronic kidney disease then their kidneys are slowly overwhelmed and that leads to end stage renal disease. At that point the patient’s options are limited to dialysis or an organ transplant.

Survivors hold out hope

Italian researchers had identified some cells in the kidneys that showed a regenerative ability. These cells, which were characterized by the expression of a molecule called CD133, were able to survive injury and create different types of kidney cells.

Researchers at the University of Torino in Italy decided to take these findings further and explore precisely how CD133 worked and if they could take advantage of that and use it to help repair damaged kidneys.

In their findings, published in the journal Stem Cells Translational Medicine, the researchers began by working with a chemotherapy drug called cisplatin, which is used against a broad range of cancers but is also known to cause damage to kidneys in around one third of all patients. The team found that CD133 was an important factor in helping those damaged kidneys recover. They also found that CD133 prevents aging of kidney progenitor cells, the kind of cell needed to help create new cells to repair the kidneys in future.

Hope for further research

The finding opens up a number of possible lines of research, including exploring whether infusions of CD133 could help patients whose kidneys are no longer able to produce enough of the molecule to help repair damage.

In an interview in DD News, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine – praised the research:

“This is an interesting and novel finding. Because the work identifies mechanisms potentially involved in the repair of tissue after injury, it suggests the possibility of new therapies for tissue repair and regeneration.”

CIRM is funding several projects targeting kidney disease including four clinical trials for kidney failure. These are all late-stage kidney failure problems so if the CD133 research lives up to its promise it might be able to help people at an earlier stage of disease.