Taking a new approach to fighting a deadly brain cancer

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Christine Brown, Ph.D., City of Hope researcher

CIRM’s 2017 Annual Report will be going live online very soon. In anticipation of that we are highlighting some of the key elements from the report here on the Stem Cellar.

One of the most exciting new approaches in targeting deadly cancers is chimeric antigen receptor (CAR) T-cell therapy, using the patient’s own immune system cells that have been re-engineered to help them fight back against the tumor.

Today we are profiling City of Hope’s Christine Brown, Ph.D., who is using CAR-T cells in a CIRM-funded Phase 1 clinical trial for an aggressive brain cancer called malignant glioma.

“Brain tumors are the hardest to treat solid tumors. This is a project that CIRM has supported from an early, pre-clinical stage. What was exciting was we finished our first milestone in record time and were able to translate that research out of the lab and into the clinic. That really allowed us to accelerate treatment to glioblastoma patients.

I think there are glimmers of hope that immune based therapies and CAR-T based therapies will revolutionize therapy for patients with brain tumors. We’ve seen evidence that these cells can travel to the central nervous system and eliminate tumors in the brain.

We now have evidence that this approach produces a powerful, therapeutic response in one group of patients. We are looking at why other patients don’t respond as well and the CIRM funding enables us to ask the questions that will, we hope, provide the answers.

Because our clinical trial is a being carried out at the CIRM-supported City of Hope Alpha Stem Cell Clinic this is a great example of how CIRM supports all the different ways of advancing therapy from early stage research through translation and into clinical trials in the CIRM Alpha Clinic network.

There are lots of ways the tumor tries to evade the immune system and we are looking at different approaches to combine this therapy with different approaches to see which combination will be best.

It’s a challenging problem and it’s not going to be solved with one approach. If it were easy we’d have solved it by now. That’s why I love science, it’s one big puzzle about how do we understand this and how do we make this work.

I don’t think we would be where we are at without CIRM’s support, it really gave the funding to bring this to the next level.”

Dr. Brown’s work is also creating interest among investors. She recently partnered with Mustang Bio in a $94.5 million agreement to help advance this therapy.

CIRM-Funded Clinical Trials Targeting Cancers

Welcome to the Month of CIRM!

As we mentioned in last Thursday’s blog, during the month of October we’ll be looking back at what CIRM has done since the agency was created by the people of California back in 2004. To start things off, we’ll be focusing on CIRM-funded clinical trials this week. Supporting clinical trials through our funding and partnership is a critical cornerstone to achieving our mission: to accelerate stem cell treatments to patients with unmet medical needs.

Over the next four days, we will post infographics that summarize CIRM-funded trials focused on therapies for cancer, neurologic disorders, heart and metabolic disease, and blood disorders. Today, we review the nine CIRM-funded clinical trial projects that target cancer. The therapeutic strategies are as varied as the types of cancers the researchers are trying to eradicate. But the common element is developing cutting edge methods to outsmart the cancer cell’s ability to evade standard treatment.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

Scientists use human stem cell models to target deadly brain cancer

Malignant brain cancer is a devastating disease and it’s estimated that more than 16,000 patients will die of it this year. One of the most aggressive forms of brain cancer is gliomas, which originate from the support cells in the brain or spine that keep nerve cells happy and functioning. Unfortunately, there is no cure for gliomas and common treatments involving surgery, radiation and chemotherapy are not effective in fully eradicating these tumors.

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Brain CT scan of human glioma.

In hopes of finding a cure, scientists have turned to animal models and human cell models derived from tumor biopsies or fetal tissue, to gain understanding of how gliomas form and what makes these type of tumors so deadly and resistant to normal cancer treatments.  These models have their limitations, and scientists continue to develop more relevant models in hopes of identifying new potential treatments for brain cancer.

Speaking of which, a CIRM-funded research team from the Salk Institute recently reported a new human stem cell-based model for studying gliomas in Nature Communications. The team figured out how to transform human induced pluripotent stem cells (iPS cells) into glioma tumor-initiating cells (GTICs) that they used to model how gliomas develop and to screen for drugs that specifically target this deadly form of cancer.

Making the Model

One theory for how gliomas form is that neural progenitor cells (brain stem cells) can transform and take on new properties that turn them into glioma tumor-initiating cells or GTICs, which are a subpopulation of cancer stem cells that are really good at staying alive and reproducing themselves into nasty tumors.

The Salk team created a stem cell model for glioma by generating GTICs in a dish from human iPS cells. They genetically manipulated brain progenitor cells (which they called induced neural progenitor cells or iNPCs) derived from human iPS cells to look and behave like GTICs. Building off of previous studies reporting that a majority of human gliomas have genetic mutations in the p53 and Src-family kinase (SFK) genes, they developed different iNPC lines that either turned off expression of p53, a potent tumor suppressor, or that ramped up expression of SFKs, whose abnormal expression are associated with tumor expansion.

The team then compared the transformed iNPC lines to primary GTICs isolated from human glioma tissue. They found that the transformed iNPCs shared many similar characteristics to primary GTICs including the surface markers they expressed, the genes they expressed, and their metabolic profiles.

Their final test of their stem cell model determined whether transformed iNPCs could make gliomas in an animal model. They transplanted normal and transformed iNPC lines into the brains of mice and saw aggressive tumors develop only in mice that received transformed cells. When they dissected the gliomas, they found a mixture of GTICs, more mature brain cells produced from GTICs, and areas of dead cells. This cellular makeup was very similar to that of advanced grade IV primary glioblastomas.

Screening for drugs that target glioma initiating cells

Now comes the applied part of this study. After developing a new and relevant stem cell model for glioma, the team screened their transformed iNPC lines with a panel of 101 FDA-approved anti-cancer drugs to see if any of them were effective at stopping the growth and expansion of GTICs. They identified three compounds that were able to target and kill both transformed iNPCs and primary GTICs in a dish. They also tested these compounds on living brain slices that were injected with GTICs to form tumors and saw that the drugs worked well at reducing tumor size.

The authors concluded that their transformed iNPCs are appropriate for modeling certain features of how GTICs develop into adult gliomas. Their hope is that this model will be useful for developing new targeted therapies for aggressive forms of brain cancer.

“Our results highlight the potential of hiPSCs for studying human tumourigenesis. Similar to conventional disease modeling strategies based on the use of hiPSCs, the establishment of hiPSC cancer models might facilitate the future development of novel therapeutics.”


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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.