Bye Bye BORIS: Gene Silencing Gives Cancer Stem Cells the Boot

A popular theory behind why cancer tumors recur post treatment is the existence of cancer stem cells (CSCs). These cells have stem cell-like qualities and are stubbornly resistant to common cancer cell killing techniques such as radiation and chemotherapy. CSCs are resilient and can reproduce themselves after all other cancer cells die off, creating new tumors and causing cancer relapse.

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Cancer stem cells are resistant to typical cancer therapies and can cause tumor relapse.

The origin of CSCs and whether they exist in all types of cancers are questions that are still up for debate. However, it seems that the cancer field has come to a consensus that CSCs do exist in many forms of cancer, and that they are a prime target for the development of new cancer therapies. Researchers hope to develop combination therapies that target regular cancer cells and CSCs. Because what’s the use of treating tumors with drugs if they will just grow back because of pesky CSCs?

There are many proposed strategies for killing cancer stem cells. Some of them center around overcoming life-extending features that CSCs have evolved including the ability to avoid normal cell death processes. One promising technology for targeting CSCs is gene silencing. This technique uses tools that turn off the expression of specific genes (hence the silencing) that are causing cancer cells to survive or divide.

Two independent groups recently announced positive results from studies that use gene silencing technology to kill breast and colon cancer stem cells. These two stories are a great example of how pre-clinical biology from academia can translate into clinical research in industry.

On the Academic Side

A group from Lausanne University Hospital in Switzerland reported in PloS One that silencing the expression of a gene called BORIS prevented the growth of breast and colon CSCs.

BORIS inhibits the function of an important tumor suppressor gene called CTCF. A tumor suppressor gene acts as a stop sign and prevents normal cells from turning into cancer cells. When tumor suppressors can’t do their normal job due to rogue jay-walkers like BORIS, normal cells lose an important line of defense and can turn into cancer cells. Typically, BORIS is only expressed in germ cells during development and not in adult cells in the body. However, scientists have found that BORIS is reactivated in some cancer cells, typically in CSCs.

The PLoS study confirmed that BORIS was reactivated in both breast and colon CSCs. One hallmark of CSCs is their ability to survive in 3D culture systems by forming sphere-like structures. They then asked whether silencing BORIS expression in breast and colon CSCs would prevent the formation of spheres in culture. They found that without BORIS, CSCs could no longer form spheres and survive in suspension. They went on to show that when BORIS is silenced, expression of stem cell and CSC genes was reduced in both the breast and colon CSCs. The authors concluded that BORIS is an important gene for CSC survival and “could be a potential new CSC biomarker that could be used as a therapeutic target for cancer therapy.”

BORIS is expressed in breast cancer stem cells (red) but not in breast cancer cells (blue).

BORIS is expressed in breast cancer stem cells (red) but not in breast cancer cells (blue). (Alberti et al. 2015)

On the Industry Side

Regen BioPharma reported on Monday that it successfully used gene silencing technology to kill colon CSCs by silencing BORIS expression. Their positive results have prompted the company to improve and advance its gene-silencing techniques so that it can file an IND (investigational new drug) application for the BORIS gene silencing technology. An IND with the Food and Drug Administration is the final step to beginning a clinical trial in humans.

Regen has published previously in this area and acknowledged the recent findings published in PLoS. In a press release, Thomas Ichim, CSO of Regen said:

From 2006-2008, together with a team of scientists from the Institute of Molecular Medicine and the National Institutes of Health, we published that vaccinating against BORIS results in immune response against and tumor regression in breast cancer, melanoma, and glioma.  Subsequently, we published that gene silencing of BORIS can be utilized to selectively kill breast cancer cells. As we saw in the recent publication, the role of BORIS as an “Achilles Heel” of cancer is becoming more and more apparent.  We are currently in the process of advancing our gene-silencing based approaches, in part by leveraging lessons we are learning during dCellVax development, in order to file an IND for BORIS gene silencing technology.

 

Big Picture

the boot

Silencing BORIS gives cancer stem cells the boot. (Image source: Glassdoor.com)

The issue with chemotherapies and other cancer treatments is that tumors become resistant to them over time. Gene silencing offers an advantage over these strategies by directly targeting CSCs, which are resistant to first-line cancer treatments. By silencing genes in CSCs that are required for cancer cell survival and metastasis, scientists can target tumors at their source. For patients with aggressive or recurring cancers, BORIS gene silencing technology could be what the doctor will order to prevent future relapse or metastasis. Time will tell, but hopefully gene silencing technologies against CSCs will enter clinical trials sooner than later.


Related links:

New Regenerative Liver Cells Identified

It’s common knowledge that your liver is a champion when it comes to regeneration. It’s actually one of the few internal organs in the human body that can robustly regenerate itself after injury. Other organs such as the heart and lungs do not have the same regenerative response and instead generate scar tissue to protect the injured area. Liver regeneration is very important to human health as the liver conducts many fundamental processes such as making proteins, breaking down toxic substances, and making new chemicals required to digest your food.

The human liver.

The human liver

Over the years, scientists have suggested multiple theories for why the liver has this amazing regenerative capacity. What’s known for sure is that mature hepatocytes (the main cell type in the liver) will respond to injury by dividing and proliferating to make more hepatocytes. In this way, the liver can regrow up to 70% of itself within a matter of a few weeks. Pretty amazing right?

So what is the source of these regenerative hepatocytes? It was originally thought that adult liver stem cells (called oval cells) were the source, but this theory has been disproved in the past few years. The answer to this million-dollar question, however, likely comes from a study published last week in the journal Cell.

Hybrid hepatocytes (shown in green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

Hybrid hepatocytes (green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

A group at UCSD led by Dr. Michael Karin reported a new population of liver cells called “hybrid hepatocytes”. These cells were discovered in an area of the healthy liver called the portal triad. Using mouse models, the CIRM-funded group found that hybrid hepatocytes respond to chemical-induced injury by massively dividing to replace damaged or lost liver tissue. When they took a closer look at these newly-identified cells, they found that hybrid hepatocytes were very similar to normal hepatocytes but differed slightly with respect to the types of liver genes that they expressed.

A common concern associated with regenerative tissue and cells is the development of cancer. Actively dividing cells in the liver can acquire genetic mutations that can cause hepatocellular carcinoma, a common form of liver cancer.

What makes this group’s discovery so exciting is that they found evidence that hybrid hepatocytes do not cause cancer in mice. They showed this by transplanting a population of hybrid hepatocytes into multiple mouse models of liver cancer. When they dissected the liver tumors from these mice, none of the transplanted hybrid cells were present. They concluded that hybrid hepatocytes are robust and efficient at regenerating the liver in response to injury, and that they are a safe and non-cancer causing source of regenerating liver cells.

Currently, liver transplantation is the only therapy for end-stage liver diseases (often caused by cirrhosis or hepatitis) and aggressive forms of liver cancer. Patients receiving liver transplants from donors have a good chance of survival, however donated livers are in short supply, and patients who actually get liver transplants have to take immunosuppressant drugs for the rest of their lives. Stem cell-derived liver tissue, either from embryonic or induced pluripotent stem cells (iPSC), has been proposed as an alternative source of transplantable liver tissue. However, safety of iPSC-derived tissue for clinical applications is still being addressed due to the potential risk of tumor formation caused by iPSCs that haven’t fully matured.

This study gives hope to the future of cell-based therapies for liver disease and avoids the current hurdles associated with iPSC-based therapy. In a press release from UCSD, Dr. Karin succinctly summarized the implications of their findings.

“Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation.”

This exciting and potentially game-changing research was supported by CIRM funding. The first author, Dr. Joan Font-Burgada, was a CIRM postdoctoral scholar from 2012-2014. He reached out to CIRM regarding his publication and provided the following feedback:

CIRM Postdoctoral Fellow Jean Font-Burgada

CIRM postdoctoral scholar Joan Font-Burgada

“I’m excited to let you know that work CIRM funded through the training program will be published in Cell. I would like to express my most sincere gratitude for the opportunity I was given. I am convinced that without CIRM support, I could not have finished my project. Not only the training was excellent but the resources I was offered allowed me to work with enough independence to explore new avenues in my project that finally ended up in this publication.”

 

We at CIRM are always thrilled and proud to hear about these success stories. More importantly, we value feedback from our grantees on how our funding and training has supported their science and helped them achieve their goals. Our mission is to develop stem cell therapies for patients with unmet medical needs, and studies such as this one are an encouraging sign that we are making progress towards to achieving this goal.


Related links:

UCSD Press Release

CIRM Spotlight on Liver Disease Research

CIRM Spotlight on Living with Liver Disease

Stem cell stories that caught our eye: shutting down cancer stem cells, safer BMT, better gene therapy and a 3rd ear

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.

A new route to shut down cancer stem cells. A team at Texas A&M University has discovered a specific protein’s role in keeping cancer stem cells active and shown the pathway it uses to do its dirty deed. That pathway immediately became a target for future cancer therapy.

Although not universally accepted by all cancer researchers, the theory that cancer stem cells circumvent traditional therapy and keep cancers coming back is gaining credence through studies like the current one. The Texas team looked at the protein FGF that has been implicated in cancer but has not been a target of drug research because it is involved in so much of normal cell processes. It has seemed impossible to halt its bad behavior without inhibiting its good behavior. They tracked down its impact on cells believed to be cancer stem cells and found the pathway it uses for that effect. So, future teams can target this pathway rather than FGF itself and its many roles.

“If we understand how to keep these cells dormant it means that although we may have to live with the presence of cancer stem cells, we can prevent them from causing the cancer to come back,” said one of the study lead authors, Fen Wang. “That’s what we are trying to understand. That is the future of cancer therapy.”

The NewsMedical web portal picked up the university’s release about the research published in The Journal of Biological Chemistry.  CIRM funds several teams trying to thwart cancer stem cells both in blood cancers and in solid tumors.

 

Safer bone marrow transplant. The most common stem cell therapy, commonly called bone marrow transplant, has a more than three-decade record of success treating cancer patients. As doctors have grown more comfortable with the procedure, they expanded its use beyond using a person’s own stem cells and stem cells from immunologically well-matched donors to using cells from only partially matched donors. As this has increased the number of lives saved it has also increased the number of patients put at risk for the horrible complication known as graft versus host disease (GVHD). Besides being painful and debilitating, GVHD frequently ends in death.

A team at Seattle’s Fred Hutchinson Cancer Center completed a genetic analysis of transplant patients that did and did not develop GVHD. They found a specific gene marker that increases the risk of the complication by more than 50 percent and the risk of death by 25 percent. The results should push physicians with patients who have the at-risk gene to search harder for a matching donor before they resort to a mismatched transplant.

“Our data provide new information on the role of HLA-DPB1 expression in transplantation associated risks that can be used to guide the selection of donors for future transplant recipients in order to minimize the risk of acute GVHD,” said Effie Petersdorf, one the study authors in an article in MEDPAGETODAY.

The study appears in this week’s New England Journal of Medicine, but anyone who does not want to climb the journal’s pay wall, can get considerable more detail in the MEDPAGE article written by a former colleague from my days editing a national medical magazine, Charles Bankhead. You can trust Charlie to get the story right.

 

Using evolution science to improve gene therapy. The field of gene therapy—providing a correct copy of a gene to someone born with a mutation or using a gene to deliver a desired protein—is finally starting to take off. But one of the oldest tools for getting desired genes into cells, a family of viruses called adeno-associated viruses (AAVs) has serious limitations when trying to directly deliver the gene into people. Most of us have been infected with various AAVs and developed immunity to them. So, our immune system may wipe out the virus carrying the desired payload before it can deliver its goods.

Many teams have developed various forms of AAV that help a bit; making the viruses a little less likely to be recognized. Now, a team at the Harvard Stem Cell Institute has taken a major step down that path using evolutionary science. They used existing records of how the virus has changed over time to construct surface proteins that would not be recognized by the immune systems of most people alive today. Bionity.com wrote about the research that appeared in the journal Cell Reports.

 

ear on arm jpegListen up for the week’s oddest story. An Australian performance artist who goes by the name Stelarc has worked with a team of surgeons to grow an ear on his forearm, which he intends to implant with a microphone connected to the internet so followers of his art can hear what he hears 24/7. Not surprisingly, his family is a little skeptical.

Surgeons built the main part of the ear by implanting a scaffold made from standard materials used in plastic surgery and the artist’s own cells populated it with blood vessels and other tissues. But to grow the exterior ear lobe he intends to work with a team using stem cells, which is why this story appeared in my news feed dozens of times this week.

CNN Style did one of the most thorough write-ups including a good discussion of the ethics of wasting valuable time of medical professionals, something Stelarc himself discussed. He concluded that the value grew from getting the science world and art world to intermingle and better understand each other, something that has been on our soapbox for years.

“But I’ve found there’s a lot of goodwill from people who ordinarily would not have contact with an artist, and ordinarily would not see the reason for wasting time and money and their expertise on doing something like this, and that’s heartening,” Stelarc said.

Sonic Hedgehog provides pathway to fight blood cancers

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Dr. Catriona Jamieson:
Photo courtesy Moores Cancer Center, UCSD

For a lot of people Sonic Hedgehog is a video game. But for stem cell researcher Dr. Catriona Jamieson it is a signaling pathway in the body that offers a way to tackle and defeat some deadly blood cancers.

Dr. Jamieson – a researcher at the University of California, San Diego (UCSD) – has a paper published online today in The Lancet Haematology that highlights the safety and dosing levels for a new drug to treat a variety of blood cancers. CIRM funding helped Dr. Jamieson develop this work.

The drug targets cancer stem cells, the kind of cell that is believed to be able to lie dormant and evade anti-cancer therapies before springing back into action, causing a recurrence of the cancer. The drug coaxes the cancer stem cells out of their hiding space in the bone marrow and gets them to move into the blood stream where they can be destroyed by chemotherapy.

In a news release Dr. Jamieson says the drug – known by the catchy name of PF-04449913 – uses the sonic Hedgehog signaling pathway, an important regulator of the way we develop, to attack the cancer:

“This drug gets that unwanted house guest to leave and never come back. It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily oral tablet.”

The goal of this first-in-human study was to test the drug for safety; so 47 adults with blood and marrow cancer were given daily doses of the drug for up to 28 days. Those who were able to tolerate the dosage, without experiencing any serious side effects, were then given a higher dose for the next 28 days. Those who experienced problems were taken off the therapy.

Of the 47 people who started the trial in 2010, 28 experienced side effects. However, only three of those were severe. The drug showed signs of clinical activity – meaning it seemed to have an impact on the disease – in 23 people, almost half of those enrolled in the study.

Because of that initial promise it is now being tested in five different Phase 2 clinical trials. Dr. Jamieson says three of those trials are at UCSD:

“Our hope is that this drug will enable more effective treatment to begin earlier and that with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation. It’s all about reducing the burden of disease by intervening early.”

Two studies show genes and their switches critical to brain cancer’s resistance to therapy

Two California teams discovered genetic machinery that cancer stem cells in high-grade brain cancers use to evade therapy. One CIRM-funded team at Cedars-Sinai in Los Angeles pinpointed a family of genes that turn off other genes that chemotherapy targets —effectively hiding them from the chemo. The other team at the University of California, San Diego (UCSD), found a culprit switch among the molecules that surround genes in the DNA.

Chemical switches like those found at UCSD control much of how our cells function. These so called epigenetic markers can toggle between on and off states and result in two cells with the same genes behaving differently. That is what the San Diego team found when they transplanted cells from the same glioblastoma brain cancer into different mice. Some readily formed new tumors and some did not.

“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Clark Chen. “This plasticity represents a mechanism by which glioblastoma develops resistance to therapy.”

The switch the cancer stem cells used in this case is called LSD1 and the researchers hope to be able to learn how to manipulate that switch to make the brain cancer stem cells more vulnerable to therapy.

Brain caner cells (left) that don’t readily form new tumors can spontaneously acquire cancer stem cell characteristics (right).

Brain caner cells (left) that don’t readily form new tumors can spontaneously acquire cancer stem cell characteristics (right).

The family of genes fingered by the Cedars team control the on-off status of a number of genes associated with cancer stem cells. That family, called Ets factors, is quite large but the brain tumor model used by the team allows them to quickly determine which genes are being impacted by the Ets factors.

“The ability to rapidly model unique combinations of driver mutations from a patient’s tumor enhances our quest to create patient-specific animal models of human brain tumors,” said Moise Danielpour the senior author on the study

The team’s next step: testing the function of the various Ets factors to see what their specific roles are in tumor progression.

Given the dismal five-year survival rate for high-grade brain cancers these advances in understanding their genetic machinery should push the field toward better therapy.

The Cedars team published in the journal Cell Reports and Health Canal picked up the hospital’s press release. The UCSD team published in the Proceedings of the National Academy of Sciences and Science Daily picked up the university’s press release. CIRM funds a number of projects working on new therapies for brain cancer.

Partnering with Big Pharma to benefit patients

Our mission at CIRM is to accelerate the development of stem cell therapies for patients with unmet medical needs. One way we have been doing that is funding promising research to help it get through what’s called the “Valley of Death.” This is the time between a product or project showing promise and the time it shows that it actually works.

Many times the big pharmaceutical companies or deep pocketed investors, whose support is needed to cover the cost of clinical trials, don’t want to get involved until they see solid proof that this approach works. However, without that support the researchers can’t do the early stage clinical trials to get that proof.

The stem cell agency has been helping get these projects through this Catch 22 of medical research, giving them the support they need to get through the Valley of Death and emerge on the other side where Big Pharma is waiting, ready to take them from there.

We saw more evidence that Big Pharma is increasingly happy doing that this week with the news that the University of California, San Diego, is teaming up with GSK to develop a new approach to treating blood cancers.

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Dr. Catriona Jamieson:
Photo courtesy Moores Cancer Center, UCSD

Dr. Catriona Jamieson is leading the UCSD team through her research that aims at killing the cancer stem cells that help tumors survive chemotherapy and other therapies, and then spread throughout the body again. This is work that we have helped fund.

In a story in The San Diego Union Tribune, reporter Brad Fikes says this is a big step forward:

“London-based GSK’s involvement marks a maturation of this aspect of Jamieson’s research from basic science to the early stages of discovering a drug candidate. Accelerating such research is a core purpose of CIRM, founded in 2004 to advance stem cell technology into disease therapies and diagnostics.”

The stem cell agency’s President and CEO, Dr. C. Randal Mills, is also quoted in the piece saying:

“This is great news for Dr. Jamieson and UCSD, but most importantly it is great news for patients. Academic-industry partnerships such as this bring to bear the considerable resources necessary to meaningfully confront healthcare’s biggest challenges. We have been strong supporters of Dr. Jamieson’s work for many years and I think this partnership not only reflects the progress that she has made, but just as importantly it reflects how the field as a whole has progressed.”

As the piece points out, academic researchers are very good at the science but are not always as good at turning the results of the research into a marketable product. That’s where having an industry partner helps. The companies have the experience turning promising therapies into approved treatments.

As Scott Lippman, director of the Moores Cancer Center at UCSD, said of the partnership:

“This is a wonderful example of academia-industry collaboration to accelerate drug development and clinical impact… and opens the door for cancer stem cell targeting from a completely new angle.”

With the cost of carrying out medical research and clinical trials rising it’s hard for scientists with limited funding to go it alone. That’s why these partnerships, with CIRM and industry, are so important. Working together we make it possible to speed up the development and testing of therapies, and get them to patients as quickly as possible.

Stem cell stories that caught our eye: Immune therapy for HIV, nerves grown on diamonds and how stem cells talk

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.

Trendy CAR T therapy tried on HIV.  The hottest trend in cancer therapy today is using CAR-T cells to attack and rid the body of cancer. Technically called chimeric antigen receptors the technology basically provides our own immune system with directions to cancer cells and keys to get inside them and destroy them. A CIRM-funded team at the University of California, Los Angeles, has now tried that same scheme with HIV.

Jerome Zack (left) and Scott Kitchen, found that the technique decreased HIV levels in mice by 80 to 95 percent.

Jerome Zack (left) and Scott Kitchen, found that the technique decreased HIV levels in mice by 80 to 95 percent.

The researchers worked with mice bred to have a human immune system so that HIV affects them similarly to humans. They harvested their blood-forming stem cells and inserted a CAR that recognized HIV. After giving the stem cells back to the mice they produced T cells capable of seeking out and destroying about 90 percent of the virus. The technique has a ways to go, but the study’s lead author noted their ultimate goal in a University press release picked up by HealthCanal:

“We hope this approach could one day allow HIV-positive individuals to reduce or even stop their current HIV drug regimen and clear the virus from the body altogether,” said Scott Kitchen. “We also think this approach could possibly be extended to other diseases.”

Nerves grown on diamonds. Diamonds are so chemically non-reactive our bodies would not recognize them as foreign. But they can also be made to conduct electricity, which could make nerves grown on their surface able to be turned on and off with electrical impulses. When developing cell therapy for several neurologic diseases the ability to control the activity of replacement cells could be critical to success—making new research by a team in Britain and Ireland intriguing, if very preliminary.

They doped diamonds with boron to make them able to conduct electricity and then used them as a surface for growing nerve stem cells that could later be turned into nerves. They then succeeded in growing nerves long term on the diamonds.

“We still have a lot more fundamental studies of the neuron/diamond interface to perform,” said Paul May of the University of Bristol. “[But] the long term possibilities for this work are exciting.  Long-lifetime diamond bio-implants may offer treatments for Parkinson’s, Alzheimer’s, stroke or even epilepsy.”

Materials Today wrote a piece explaining the work.

Some stem cells talk over “land lines.” Most cellular communication works through chemical signals that get dispatched by one cell and received by others. It turns out that some types of stem cells communicate by sending out tiny nanotubes, sort of a cellular land line.

A team at the University of Michigan and the University of Texas Southwestern Medical Center found the new form of communication working with fruit flies. Yukiko Yamashita, a senior author of the paper from Michigan explained why it is so important to get a better understanding of cell-to-cell communication in a university press release picked up by ScienceNewsline:

“There are trillions of cells in the human body, but nowhere near that number of signaling pathways. There’s a lot we don’t know about how the right cells get just the right messages to the right recipients at the right time.”

In a classic example of the beauty of young minds in science, prior images of these stem cells had shown the nanotubes, but they had been overlooked until a graduate student asked what they were.

Phase 3 melanoma trial explained. When a new therapy gets into its third and final phase of testing it is make or break for the company developing the therapy and for patients who hope it will become broadly available. CIRM recently provided funding to our first phase three clinical trial, one aimed at metastatic melanoma being conducted by Caladrius Biosciences.

The CEO of the company, David Mazzo, gave an interview with The New Economy this week that does a nice job of explaining the goal of the therapy and how it is different from other therapies currently used or being developed. The therapy’s main difference is its ability to target the cancer-inducing cells thought to responsible for the spread of the disease.

One man’s story points to hope against a deadly skin cancer

One of the great privileges and pleasures of working at the stem cell agency is the chance to meet and work with some remarkable people, such as my colleagues here at CIRM and the researchers we support. But for me the most humbling, and by far the most rewarding experience, is having a chance to get to know the people we work for, the patients and patient advocates.

Norm Beegun, got stem cell therapy for metastatic melanoma

Norm Beegun, got stem cell therapy for metastatic melanoma

At our May Board meeting I got to meet a gentleman who exemplifies everything that I truly admire about the patients and patient advocates. His name is Norm Beegun. And this is his story.

Norm lives in Los Angeles. In 2002 he went to see his regular doctor, an old high school friend, who suggested that since it had been almost ten years since he’d had a chest x-ray it might be a good idea to get one. At first Norm was reluctant. He felt fine, was having no health problems and didn’t see the need. But his friend persisted and so Norm agreed. It was a decision that changed, and ultimately saved, his life.

The x-ray showed a spot on his lung. More tests were done. They confirmed it was cancer; stage IV melanoma. They did a range of other examinations to see if they could spot any signs of the cancer on his skin, any potential warnings signs that they had missed. They found nothing.

Norm underwent surgery to remove the tumor. He also tried several other approaches to destroy the cancer. None of them worked; each time the cancer returned; each time to a different location.

Then a nurse who was working with him on these treatments suggested he see someone named Dr. Robert Dillman, who was working on a new approach to treating metastatic melanoma, one involving cancer stem cells.

Norm got in touch with Dr. Dillman and learned what the treatment involved; he was intrigued and signed up. They took some cells from Norm’s tumor and processed them, turning them into a vaccine, a kind of personalized therapy that would hopefully work with Norm’s own immune system to destroy the cancer.

That was in 2004. Once a month for the next six months he was given injections of the vaccine. Unlike the other therapies he had tried this one had no side effects, no discomfort, no pain or problems. All it did was get rid of the cancer. Regular scans since then have shown no sign that the melanoma has returned. Theoretically that could be because the new therapy destroyed the standard tumor cells as well as the cancer stem cells that lead to recurrence.

Norm says when you are diagnosed with an incurable life-threatening disease, one with a 5-year survival rate of only around 15%, you will try anything; so he said it wasn’t a hard decision to take part in the clinical trial, he felt he had nothing to lose.

“I didn’t know if it would help me. I didn’t think I’d be cured. But I wanted to be a guinea pig and perhaps help others.”

When he was diagnosed his son had just won a scholarship to play football at the University of California, Berkeley. Norm says he feared he would never be able to see his son play. But thanks to cleverly scheduling surgery during the off-season and having a stem cell therapy that worked he not only saw his son play, he never missed a game.

Norm returned to Berkeley on May 21st, 2015. He came to address the CIRM Board in support of an application by a company called NeoStem (which has just changed its name to Caladrius Biosciences). This was the company that had developed the cell therapy for metastatic melanoma that Norm took.

“Talking about this is still very emotional. When I got up to talk to the CIRM Board about this therapy, and ask them to support it, I wanted to let them know my story, the story of someone who had their life saved by this treatment. Because of this I am here today. Because of this I was able to see my son play. But just talking about it left me close to tears.”

It left many others in the room close to tears as well. The CIRM Board voted to fund the NeoStem application, investing $17.7 million to help the company carry out a Phase 3 clinical trial, the last hurdle it needs to clear to prove to the Food and Drug Administration that this should be approved for use in metastatic melanoma.

Norm says he is so grateful for the extra years he has had, and he is always willing to try and support others going through what he did:

“I counsel other people diagnosed with metastatic melanoma. I feel that I want to help others, to give them a sense of hope. It is such a wonderful feeling, being able to show other people that you can survive this disease.”

When you get to meet people like Norm, how could you not love this job.

Stem cell stories that caught our eye: sickle cell patient data, vaccine link to leukemia protection, faster cell analysis

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.

Good news from sickle cell clinical trial. It is always satisfying to report positive results from human clinical trials using stem cells even when we don’t fund the work. Bluebird Bio released the first data on a patient treated for sickle cell anemia using the same procedure the company had earlier used to get good outcomes for two patients with beta thalassemia.

Both diseases result from defects—though different defects—in the gene for hemoglobin, the protein our red blood cells use to carry needed oxygen. So, in both cases they use a modified, deactivated virus to carry a correct version of the gene into patients’ own blood-forming stem cells in the lab. They then re-infused those cells into the patients to provide a ready supply of cells able to make the needed protein.

In the sickle cell patient, after the transplant a third of his red cells were making the right protein and that was enough to wean him off blood transfusions that had been keeping him alive and prevented any further hospitalizations due to the disease. The company also announced that the two previously reported patients treated for beta thalassemia had continued to improve. Reuters ran a story on the new data.

CIRM funds a similar project about to begin treating patients for sickle cell disease (link to video), also using a viral vector but a somewhat different one, so it is reassuring to see viral gene carriers working without side effects.

Another reason to vaccinate, prevent leukemia. While it has been known for some time that infant vaccination seems to have driven down the rate of childhood leukemia, no one has known why. A CIRM-funded team at the University of California, San Francisco, thinks they have figured it out. Viral infections trigger inflammation and the production of enzymes in cells that cause genetic mutations that lead to the cancer.

They worked with Haemophilus influenza Type b (Hib) vaccine but suggest a similar mechanism probably applies to other viral infections, and correspondingly, protection from other vaccines. The senior author on the paper, Marcus Muschen, explained the process in a university press release posted at Press-News.org

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy. Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

Barcoding individual cells. Our skin cells all pretty much look the same, but in the palm of your hand there are actually several different types of cells, even a tiny scratch of the fingernail. As scientist work to better understand how cells function, and in particular how stem cells mature, they increasingly need to know precisely what genes are turned on in individual cells.

Both techniques use tiny channels to isolate individual cells and introduce beads with "bar codes."

Both techniques use tiny channels to isolate individual cells and introduce beads with “bar codes.”

Until recently, all this type of analysis blended up a bunch of cells and asked what is in the collective soup. And this did not get the fine-tuned answers today’s scientists are seeking. Numerous teams over the past couple years have reported on tools to get down to single-cell gene analysis. Now, two teams at Harvard have independently developed ways to make this easier. They both use a type of DNA barcode on tiny beads that gets incorporated into individual cells before analysis.

Allan Klein, part of one team based at the Harvard Medical School’s main campus, described why the work is needed in a detailed narrative story released by the school:

“Does a population of cells that we initially think is uniform actually have some substructure. What is the nature of an early developing stem cell? . . . How is [a cell’s] fate determined? “

Even Macosko who worked with the other team centered at the Broad Institute of Harvard and MIT, noted the considerable increase in ease and decrease in cost with the new methods compared to some of the early methods of single cell gene analysis:

“If you’re a biologist with an interesting question in mind, this approach could shine a light on the problem without bankrupting you. It finally makes gene expression profiling on a cell-by-cell level tractable and accessible. I think it’s something biologists in a lot of fields will want to use.”

The narrative provides a good example of what we called the “bump rate” when I was at Harvard Med. Good science often moves forward when scientists bump into each other, and with Harvard Medical faculty scattered at 17 affiliated hospitals and research institutes scattered across Boston and Cambridge we were always looking for ways to increase the bump rate with conferences and cross department events. Macosko and Klein found out they were both working on similar systems at a conference.

Brain’s Own Activity Can Fuel Growth of Deadly Brain Tumors, CIRM-Funded Study Finds

Not all brain tumors are created equal—some are far more deadly than others. Among the most deadly is a type of tumor called high-grade glioma or HGG. Most distressingly, HGG’s are the leading cause of brain tumor death in both children and adults. And despite extraordinary progress in cancer research as a whole, survival rates for those diagnosed with an HGG have yet to improve.

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But recent research from Stanford University scientists could one day help move the needle—and give renewed hope to the patients and their families affected by this devastating disease.

The study, published today in the journal Cell, found that one key driver for HGG’s deadly diagnosis is that the tumor can be stimulated to grow by the brain’s own neural activity—specifically the nerve activity in the brain’s cerebral cortex.

Michelle Monje, senior author of the study that was funded in part by two grants from CIRM, was initially surprised by these results, as they run counter to how most types of tumors grow. As she explained in today’s press release:

“We don’t think about bile production promoting liver cancer growth, or breathing promoting the growth of lung cancer. But we’ve shown that brain function is driving these brain cancers.”
 


By analyzing tumor cells extracted from HGG patients, and engrafting it onto mouse models in the lab, the researchers were able to pinpoint how the brain’s own activity was driving tumor growth.

The culprit: a protein called neuroligin-3 that appeared to be calling the shots. There are four distinct types of HGGs that affect the brain in vastly different ways—and have vastly different molecular and genetic characteristics. Interestingly, says Monje, neuroligin-3 played the same role in all of them.

What was so disturbing to the research team, says Monje, is that neuroligin-3 is an essential protein for overall brain development. Specifically, it helps maintain healthy growth and repair of brain tissue over time. In order to grow, HGG tumors hijack this critical protein.

The research team came to this conclusion after a series of experiments that delved deep into the molecular mechanisms that guide both brain activity and brain tumor development. They first employed a technique called optogenetics, whereby scientists use genetic manipulation to insert light-sensitive proteins into the brain cells, or neurons, of interest. This allowed scientists to activate these neurons—or deactivate them—at the ‘flick of a switch.’

When applying this technique to the tumor-engrafted mouse models, the team could then see that tumors grew significantly better when the neurons were switched on. The next step was to narrow it down to why. Additional biochemical analyses and testing on the mouse models confirmed that neuroligin-3 was being hijacked by the tumor to spur growth.

And when they dug deeper into the connection between neuroligin-3 and cancer, they found something even more disturbing. A detailed look at the Cancer Genome Atlas (a large public database of the genetics of human cancers), they found that HGG patients with higher levels of neuroligin-3 in their brain had shorter survival rates than those with lower levels of the same protein.

These results, while highlighting the particularly nefarious nature of this class of brain tumors, also presents enormous opportunity for researchers. Specifically, Monje hopes her team and others can find a way to block or nullify the presence of neuroligin-3 in the regions surrounding the tumor, creating a kind of barrier that can keep the size of the tumor in check.