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.

CIRM invests in stem cell clinical trial targeting lung cancer and promising research into osteoporosis and incontinence

Lung cancer

Lung cancer: Photo courtesy Verywell

The five-year survival rate for people diagnosed with the most advanced stage of non-small cell lung cancer (NSCLC) is pretty grim, only between one and 10 percent. To address this devastating condition, the Board of the California Institute for Regenerative Medicine (CIRM) today voted to invest almost $12 million in a team from UCLA that is pioneering a combination therapy for NSCLC.

The team is using the patient’s own immune system where their dendritic cells – key cells in our immune system – are genetically modified to boost their ability to stimulate their native T cells – a type of white blood cell – to destroy cancer cells.  The investigators will combine this cell therapy with the FDA-approved therapy pembrolizumab (better known as Keytruda) a therapeutic that renders cancer cells more susceptible to clearance by the immune system.

“Lung cancer is a leading cause of cancer death for men and women, leading to 150,000 deaths each year and there is clearly a need for new and more effective treatments,” says Maria T. Millan, M.D., the President and CEO of CIRM. “We are pleased to support this program that is exploring a combination immunotherapy with gene modified cell and antibody for one of the most extreme forms of lung cancer.”

Translation Awards

The CIRM Board also approved investing $14.15 million in four projects under its Translation Research Program. The goal of these awards is to support promising stem cell research and help it move out of the laboratory and into clinical trials in people.

Researchers at Stanford were awarded almost $6 million to help develop a treatment for urinary incontinence (UI). Despite being one of the most common indications for surgery in women, one third of elderly women continue to suffer from debilitating urinary incontinence because they are not candidates for surgery or because surgery fails to address their condition.

The Stanford team is developing an approach using the patient’s own cells to create smooth muscle cells that can replace those lost in UI. If this approach is successful, it provides a proof of concept for replacement of smooth muscle cells that could potentially address other conditions in the urinary tract and in the digestive tract.

Max BioPharma Inc. was awarded almost $1.7 million to test a therapy that targets stem cells in the skeleton, creating new bone forming cells and blocking the destruction of bone cells caused by osteoporosis.

In its application the company stressed the benefit this could have for California’s diverse population stating: “Our program has the potential to have a significant positive impact on the lives of patients with osteoporosis, especially in California where its unique demographics make it particularly vulnerable. Latinos are 31% more likely to have osteoporosis than Caucasians, and California has the largest Latino population in the US, accounting for 39% of its population.”

Application Title Institution CIRM funding
TRAN1-10958 Autologous iPSC-derived smooth muscle cell therapy for treatment of urinary incontinence

 

 

Stanford University

 

$5,977,155

 

TRAN2-10990 Development of a noninvasive prenatal test for beta-hemoglobinopathies for earlier stem cell therapeutic interventions

 

 

Children’s Hospital Oakland Research Institute

 

$1,721,606

 

TRAN1-10937 Therapeutic development of an oxysterol with bone anabolic and anti-resorptive properties for intervention in osteoporosis  

MAX BioPharma Inc.

 

$1,689,855

 

TRAN1-10995 Morphological and functional integration of stem cell derived retina organoid sheets into degenerating retina models

 

 

UC Irvine

 

$4,769,039

 

Latest space launch sends mice to test bone-building drug

Illustration of mice adapting to their custom-designed space habitat on board the International Space Station. Image courtesy of the Center for the Advancement of Science in Space

Astronauts on the International Space Station (ISS) received some furry guests this weekend with the launch of SpaceX’s Dragon supply capsule. On Saturday June 3rd, 40 mice were sent to the ISS along with other research experiments and medical equipment. Scientists will be treating the mice with a bone-building drug in search of a new therapy to combat osteoporosis, a disease that weakens bones and affects over 200 million people globally.

The bone-building therapy comes out of CIRM-funded research by UCLA scientists Dr. Chia Soo, Dr. Kang Ting and Dr. Ben Wu. Back in 2015, the UCLA team published that a protein called NELL-1 stimulates bone-forming stem cells, known as mesenchymal stem cells, to generate new bone tissue more efficiently in mice. They also found that NELL-1 blocked the function of osteoclasts – cellular recycling machines that break down and absorb bone – thus increasing bone density in mice.

Encouraged by their pre-clinical studies, the team decided to take their experiments into space. In collaboration with NASA and a grant from the Center for the Advancement of Science in Space (CASIS), they made plans to test NELL-1’s effects on bone density in an environment where bone loss is rapidly accelerated due to microgravity conditions.

Bone loss is a major concern for astronauts living in space for extended periods of time. The earth’s gravity puts pressure on our bones, stimulating bone-forming cells called osteoblasts to create new bone. Without gravity, osteoblasts stop functioning while the rate of bone resorption increases by approximately 1.5% per month. This translates to almost a 10% loss in bone density for every 6 months in space.

In a UCLA news release, Dr. Wu explained how they modified the NELL-1 treatment to stand up to the tests of space:

“To prepare for the space project and eventual clinical use, we chemically modified NELL-1 to stay active longer. We also engineered the NELL-1 protein with a special molecule that binds to bone, so the molecule directs NELL-1 to its correct target, similar to how a homing device directs a missile.”

The 40 mice will receive NELL-1 injections for four weeks on the ISS, at which point, half of the mice will be sent back to earth to receive another four weeks of NELL-1 treatment. The other half will stay in space and receive the same treatment so the scientists can compare the effects of NELL-1 in space and on land.

The Rodent Research Hardware System includes three modules: Habitat, Transporter, and Animal Access Unit.
Credits: NASA/Dominic Hart

The UCLA researchers hope that NELL-1 will prevent bone loss in the space mice and could lead to a new treatment for bone loss or bone injury in humans. Dr. Soo explained in an interview with SpaceFlight Now,

“We are hoping this study will give us some insights on how NELL-1 can work under these extreme conditions and if it can work for treating microgravity-related bone loss, which is a very accelerated, severe form of bone loss, then perhaps it can (be used) for patients one day on Earth who have bone loss due to trauma or due to aging or disease.”

If you want to learn more about this study, watch this short video below provided by UCLA. 

License to heal: UC Davis deal looks to advance stem cell treatment for bone loss and arthritis

Nancy Lane

Wei Yao and Nancy Lane of UC Davis: Photo courtesy UC Davis

There are many challenges in taking even the most promising stem cell treatment and turning it into a commercial product approved by the Food and Drug Administration (FDA). One of the biggest is expertise. The scientists who develop the therapy may be brilliant in the lab but have little experience or expertise in successfully getting their work through a clinical trial and ultimately to market.

That’s why a team at U.C. Davis has just signed a deal with a startup company to help them move a promising stem cell treatment for arthritis, osteoporosis and fractures out of the lab and into people.

The licensing agreement combines the business acumen of Regenerative Arthritis and Bone Medicine (RABOME) with the scientific chops of the UC Davis team, led by Nancy Lane and Wei Yao.

They plan to test a hybrid molecule called RAB-001 which has shown promise in helping direct mesenchymal stem cells (MSCs) – these are cells typically found in the bone marrow and fat tissue – to help stimulate bone growth and increase existing bone mass and strength. This can help heal people suffering from conditions like osteoporosis or hard to heal fractures. RAB-001 has also shown promise in reducing inflammation and so could prove helpful in treating people with inflammatory arthritis.

Overcoming problems

In a news article on the UC Davis website, Wei Yao, said RAB-001 seems to solve a problem that has long puzzled researchers:

“There are many stem cells, even in elderly people, but they do not readily migrate to bone.  Finding a molecule that attaches to stem cells and guides them to the targets we need provides a real breakthrough.”

The UC Davis team already has approval to begin a Phase 1 clinical trial to test this approach on people with osteonecrosis, a disease caused by reduced blood flow to bones. CIRM is funding this work.

The RABOME team also hopes to test RAB-001 in clinical trials for healing broken bones, osteoporosis and inflammatory arthritis.

CIRM solution

To help other researchers overcome these same regulatory hurdles in developing stem cell therapies CIRM created the Stem Cell Center with QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider that has deep experience and therapeutic expertise. The Stem Cell Center will help researchers overcome the challenges of manufacturing and testing treatments to meet FDA standards, and then running a clinical trial to test that therapy in people.

Pregnant women’s stem cells could help battle brittle bone diseases like osteoporosis

pregnant

Sometimes I wonder how a scientist ever came up with an idea for a potential treatment. Case in point is a study in the journal Scientific Reports, where researchers use stem cells from the amniotic fluid of a pregnant woman to cure osteoporosis in mice! What researcher, seeing a pregnant woman, thought to her or himself “I wonder if…..”

Regardless of how they came up with the idea, we might be glad they did because this study showed that those stem cells could reduce the number of fractures in mice with brittle bone disease by 78 percent. And that’s raising hopes they might one day be able to do the same for people.

Researchers at University College London took mesenchymal stem cells (MSCs) that had been shed by babies into the amniotic fluid of their mother, and injected them into mice with brittle bone disease. Previous studies had suggested that MSCs, taken at such an early age, might be more potent than similar cells taken from adults. That certainly seems to have been the case here where the treated mice had far fewer fractures than untreated mice.

Pascale Guillot, the lead researcher of the study, told the Guardian newspaper:

“The stem cells we’ve used are excellent at protecting bones. The bones become much stronger and the way the bone is organised internally is of much higher quality.”

 

What was also interesting was not just what they did but how they did it. You might think that the injected stem cells helped reduce fractures by forming new bones. You might think that, but you’d be wrong. Instead, the stem cells seem to have worked by releasing growth factors that stimulated the mouse’s own bone cells to kick into a higher gear, and help build stronger bones.

In the study the researchers say using MSCs from amniotic fluid has a number of distinct advantages over using MSCs from adults:

  • They are easier to expand into large numbers needed for therapies
  • They don’t create tumors
  • The body’s immune system won’t attack them
  • They are smaller and so can move around with greater ease
  • They are easier to reprogram into different kinds of cells

Next Guillot and his team want to explore if this approach could be used to treat children and adults with brittle bone disease, and to help adults with osteoporosis, a problem that affects around 44 million people in the US.

 “The discovery could have a profound effect on the lives of patients who have fragile bones and could stop a large number of their painful fractures.”

Stem cell stories that caught our eye: Designer bags from human skin, large-scale stem cell production, new look at fat stem cells

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Designer bags from human skin? I had to share a bizarre story I read this week about a UK fashion designer who is making a collection of luxury handbags from lab-grown human skin called Pure Human. What’s even weirder is that the human skin used was engineered to contain the genetic material or DNA of the famous fashion designer Alexander McQueen who passed away in 2010.

A prototype bag, made with pig skin, from Tina Gorjanc’s Pure Human collection (Credit: Tina Gorjanc)

A prototype bag, made with pig skin, from Tina Gorjanc’s Pure Human collection (Credit: Tina Gorjanc & Signals blog for caption)

I had to admit I cringed when I first read about it in CCRM’s Signals Blog, but now I am fascinated that someone is actually doing this and intrigued about the ethical conversations that this story will undoubtedly stir up.

While it isn’t possible to patent a person’s DNA, it is possible to patent a technology that uses human DNA and products made from that technology. According to Signals, “the aim of the collection is to highlight existing legal loopholes around ownership of a person’s DNA and to open the doors for tissue bioengineering into the world of fashion.”

The collection’s designer, Tina Gorjanc, explained her motivation behind Pure Human:

Tina

Tina Gorjanc

“My main goal was to show that it is possible to patent a process using human genetic information in a domain other than medicine. Biotechnology is happening at a really rapid pace and legislation has not kept up with it.”

 

She also sees her bags as an untapped resource in the global luxury goods market which is now apparently worth $1 trillion dollars.

“When it comes to bioengineering, people tend to skip the luxury goods market because they think it’s too shallow and not important, but if you look at it, it’s one of the biggest markets that we have – and one that is open to new technology.”

Imagine having the option to bypass animal leather products for engineered human skin-based products? But on the flip side, the author of the Signals blog, Jovana Drinjakovic, makes a great point at the end of her piece by saying: just because we can do this, does it mean we should?

Drinjakovic finishes her piece with a reality-check quote from Dr. Marc Jeschke, the leader of a burn research and skin regeneration lab in Toronto:

“We are trying to find a way to make skin that is functional and won’t be rejected after a transplant. But just to grow skin for fashion – I don’t think that’s very useful.”

 

Large-Scale Stem Cell Production in Texas. A nonprofit company in San Antonio, Texas, called BioBridge, has big plans to produce large amounts of clinical-grade stem cells for regenerative medicine purposes. The company recently received $7.8 million in funding from the Medical Technology Enterprise Consortium to pursue this effort.

BioBridge will work with GenCure, a subsidiary company, to develop the technology to manufacture different types of stem cells at a large scale. These stem cells will be clinical-grade, meaning that they can be used for cell therapy applications in patients. BioBridge’s goal is to provide enough stem cells for both academic researchers and companies who need more than their current lab resources can generate.

The CEO of GenCure, Becky Cap, explained the need for this type of large-scale stem cell manufacturing technology in an interview with Xconomy:

“The capabilities in this sector right now are at a scale that’s appropriate for bench research and some clinical research, depending on the indication and volume of cells we need. We’re talking about moving from hundreds of millions of cells to billions of cells. You need billions of cells to do tissue regeneration and scaffold reengineering.”

Two other companies with expertise in cell manufacturing, StemBioSys from San Antonio and RoosterBio in Maryland, will be working with BioBridge and GenCure over the next three years on specific projects. StemBioSys plans to develop materials that will be used to promote stem cell growth. RoosterBio will take stem cell culturing from small-scale petri dishes to large-scale bioreactors that can produce billions of cells.

It will be interesting to see how the BioBridge collaboration works out. Xconomy concluded:

“This sort of large-scale manufacturing is still years out. The results that come from the work will be incorporated into a contract manufacturing operation that BioBridge is opening within GenCure.”

 

A new way to look at fat stem cells. (By Todd Dubnicoff)

Human fat stem cells, scientifically known as human adipose stem cells (hASC), are an attractive cell source for regenerative medicine. Their low tendency to cause tissue rejection and their ability to transform into bone cells make them particularly well-suited for developing cell-based treatments for osteoporosis, a disease that weakens bones and makes them susceptible to fractures. And thanks to the numerous liposuction procedures performed in the U.S. each year, hASCs are readily available to researchers.

Electron microscope image showing the eroded, inner structure of a back bone in an 89 year old woman with osteoposis. Image courtesy the Bone Research Society

Electron microscope image showing the eroded, inner structure of a back bone in an 89 year old woman with osteoposis. Image courtesy the Bone Research Society.

But a lingering problem with hASCs as a reliable cell source for future therapies is their extreme patient-to-patient variability. Studies have shown that all sorts of factors like gender, body mass index (BMI) and age can have profound effects on the ability of hASCs to multiply and to specialize into bone cells.

Now, University of Missouri researchers describe the novel use of a measuring device to make more quantitative comparisons of different sets of donor hASCs. The instrument, called an electrical cell-substrate impedance spectroscopy (ECIS) – try saying that three times fast! – sends a very weak, noninvasive current through the cells and can measure changes in the cells’ shape in real-time. Other studies had shown that ECIS can quantitatively detect differences between hASCs and human bone marrow-derived mesenchymal stem cells as they mature into their respective cell types.

In the current Stem Cells Translational Medicine study, picked up this week by Health Canal, hASCs were obtained from young (24–36 years old), middle-aged (48–55 years old), and elderly (60–81 years old) donors. The ECIS results showed that stem cells from older donors matured into bone cells much quicker (~ 1day) than the younger cell of cells (~10 day). You might have intuitively thought the youngest stem cells would mature the fastest. But the end result of the difference is that the young set of stem cells multiplied much more than the cells from older donor and they accumulated more calcium over time.

This noninvasive, quantitative tool for predicting a fat stem cell’s potential to specialize into bone has the promise to improve quality control for manufacturing cell therapies, and it also provides researchers a means to better observe the underlying biological basis for this patient-to-patient variability in human fat cells.

A Tale of Two Stem Cell Treatments for Growing New Bones

Got Milk?

GotmilkIf you grew up during the 90’s, you most certainly will remember the famous “Got Milk?” advertising campaign to boost milk consumption. The plug was that milk was an invaluable source of calcium, a mineral that’s essential for growing strong bones. Drinking three glasses of the white stuff a day, supposedly would help deter osteoporosis, or the weakening and loss of bone with old age.

Research has proven that calcium is essential for growing and maintaining healthy bones. But milk isn’t the only source of calcium in the human diet, and a diet rich in calcium alone won’t prevent everyone from experiencing some amount of bone loss as they grow older. It also won’t help patients who suffer from bone skeletal defects grow new bone.

So whatever are we to do about bone loss and bone abnormalities? Here, we tell the “Tale of two stem cell treatments” where scientists tackle these problems using stem cell-derived therapies.

Protein Combo Boosts Bone Growth

Osteoporosis. (Image source)

Osteoporosis. (Image source)

Our first story comes from a CIRM-funded team of UCLA scientists. This team is interested in developing a better therapy to treat bone defects and osteoporosis. The current treatment for bone loss is an FDA-approved bone regenerating therapy involving the protein BMP-2 (bone morphogenetic protein-2). The problem with BMP-2 is that it can cause serious side effects when given in high doses. Two of the major ones are abnormal bone growth and also making stem cells turn into fat cells as well as bone cells.

The UCLA group attempted to improve the BMP-2 treatment by adding a second protein called NELL-1 (which they knew was good at stimulating bone growth from previous studies).  The combination of BMP-2 and NELL-1 resulted in bone growth and also prevented stem cells from making fat cells.

Upon further exploration, they found that NELL-1 acts as a signaling switch that controls whether a stem cell becomes a bone cell or a fat cell. Thus, with NELL-1 present, BMP-2 can only turn stem cells into bone cells.

Kang Ting, a lead author on the study, explained the significance of their new strategy to improve bone regeneration in a UCLA press release:

Kang Ting, UCLA

Kang Ting, UCLA

“Before this study, large bone defects in patients were difficult to treat with BMP2 or other existing products available to surgeons. The combination of NELL-1 and BMP2 resulted in improved safety and efficacy of bone regeneration in animal models — and may, one day, offer patients significantly better bone healing.”

Chia Soo, another lead author on the study, emphasized the importance of using NELL-1 in combination with BMP-2:

“In contrast to BMP2, the novel ability of NELL-1 to stimulate bone growth and repress the formation of fat may highlight new treatment approaches for osteoporosis and other therapies for bone loss.”

Stem cells that could fix deformed skulls

Our second story comes from a group at the University of Rochester. Their goal is to repair bones in the face and skull of patients suffering from congenital deformities, or damage due to injury or cancer surgery.

In a report published in Nature Communications, the scientists identified a population of skeletal stem cells that orchestrate the formation of the skull and can promote craniofacial bone repair in mice.

They identified this special population of skeletal stem cells by their expression of a protein called Axin2. Genetic mutations in the Axin2 gene can cause a birth defect called craniosynostosis. This condition causes the bone plates of a baby’s skull to fuse too early, causing skull deformities and impaired brain development.

1651177064_WeiHsu-stem cell photo_4487_275x200

Axin2 stem cells shown in red and blue generated new bones cells after transplantation.

According to a news release from the University of Rochester, the group’s “latest evidence shows that stem cells central to skull formation are contained within Axin2 cell populations, comprising about 1 percent—and that the lab tests used to uncover the skeletal stem cells might also be useful to find bone diseases caused by stem cell abnormalities.”

Additionally, senior author on the study, Wei Hsu, “believes his findings contributee to an emerging field involving tissue engineering that uses stem cells and other materials to invent superior ways to replace damaged craniofacial bones in humans due to congenital disease, trauma, or cancer surgery.”

Two different studies, one common goal

Both studies have a common goal: to repair or regenerate bone to treat bone loss, damage, or deformities. I can’t help but wonder whether these different strategies could be combined in a way to that would bring more benefit to the patient than using either strategy alone.

Could we use BMP-2 and NELL-1 treatment along with Axin2 skeletal stem cells to treat craniosynostosis or repair damaged skulls? Or could we identify new stem cell populations in bone that would help patients suffering from osteoporosis?

I’m sure scientists will answer these questions sooner rather than later, and when they do, you’ll be sure to read about it on the Stem Cellar!


Related Links:

Protein Revs Up Bone Stem Cells; Points Toward Future Osteoporosis Drug

Take a moment to feel your arm and wrist bones. They’re a lot more like solid rock than the soft stretchy skin that covers them. But bone is very much a living tissue continually being broken down and built back up in a process called bone remodeling. In people with osteoporosis, this balance tips toward bone breakdown leading to more porous, fragile bones with increased risk of fractures. An estimated ten million people in the U.S. have osteoporosis accounting for 1.5 million fractures annually at a cost of $17 billion in medical care, not to mention the emotional toll of these often debilitating and even life threatening injuries.

Fluorescent imaging mouse spines. Treatment with NELL-1 (right) shows greater bone formation compared to untreated mice (left). Credit: Broad Stem Cell Research Center

Fluorescent imaging of mouse spines. Treatment with NELL-1 (right) shows greater bone formation compared to untreated mice (left). Credit: Broad Stem Cell Research Center

This week a CIRM-funded research team at UCLA reported in Nature Communications that injection of a human protein called NELL-1 into the blood of mice with osteoporosis-like symptoms tipped the balance back toward bone formation. In a large animal study, delivering NELL-1 directly into the spine also led to increased bone volume. In a university press release, co-senior author Kang Ting spoke of his hopes that these results open up a new therapeutic avenue for treating osteoporosis and other ailments:

“Our end goal is really to harness the bone forming properties of NELL-1 to better treat patients with diverse causes of bone loss, from trauma in military personnel to osteoporosis from age, disease or very weak gravity, which causes bone loss in astronauts.”

In petri dish experiments leading up to these animal results, the research team showed that NELL-1 acts by increasing the specialization of mesenchymal stem cells – a type of adult stem cell found in the bone marrow and fat – into osteoblasts, the cells responsible for building new bone. At the same time, NELL-1 reduced the generation of osteoclasts, the cells responsible for the breakdown, or resorption, of bone. This dual action of NELL-1 explains how it improved the osteoporosis-like symptoms in the animals. Check out this fascinating animation for a visual description of osteoblasts and osteoclasts:

Many of the other molecules that promote bone growth aren’t as efficient as NELL-1: while they increase osteoblast numbers they also increase osteoclasts to some extent. For example, Fosamax is a drug prescribed to women with osteoporosis to help build stronger bones but long-term use has been associated with even more brittle bones and fractures. So this finding with NELL-1 sets it apart and hints at fewer side effects as a therapeutic. Still, it’s known to play a role in brain, cartilage, and blood vessel development so careful studies of non-bone effects are needed as the team pursues a road to the clinic.

For more information about CIRM-funded projects related to osteoporosis, visit our online fact sheet.