Lung cancer, Sherlock Holmes and piano

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Image of lung cancer

When we think of lung cancer we typically tend to think it’s the end result of years of smoking cigarettes. But, according to the Centers for Disease Control and Prevention, between 10 and 20 percent of cases of lung cancer (20,000 to 40,000 cases a year) happen to non-smokers, people who have either never smoked or smoked fewer than 100 cigarettes in their life. Now researchers have found that there are different genetic types of cancer for smokers and non-smokers, and that might mean the need for different kinds of treatment.

A team at the National Cancer Institute did whole genome sequencing on tumors from 232 never-smokers who had lung cancer. In an interview with STATnews, researcher Maria Teresa Landi said they called their research the Sherlock-Lung study, after the famous fictional pipe-smoking detective Sherlock Holmes. “We used a detective approach. By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease.”

They also got quite creative in naming the three different genetic subtypes they found. Instead of giving them the usual dry scientific names, they called them piano, mezzo-forte and forte; musical terms for soft, medium and loud.

Half of the tumors in the non-smokers were in the piano group. These were slow growing with few mutations. The median latency period for these (the time between being exposed to something and being diagnosed) was nine years. The mezzo-forte group made up about one third of the cases. Their cancers were more aggressive with a latency of around 14 weeks. The forte group were the most aggressive, and the ones that most closely resembled smokers’ cancer, with a latency period of just one month.

So, what is the role of stem cells in this research? Well, in the study, published in the journal Nature Genetics the team found that the piano subtype seemed to be connected to genes that help regulate stem cells. That complicates things because it means that the standard treatments for lung cancer that work for the mezzo-forte and forte varieties, won’t work for the piano subtype.

“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Dr. Landi said.

With that in mind, and because early-detection can often be crucial in treating cancer, what can non-smokers do to find out if they are at risk of developing lung cancer? Well, right now there are no easy answers. For example, the U.S. Preventive Services Task Force does not recommend screening for people who have never smoked because regular CT scans could actually increase an otherwise healthy individual’s risk of developing cancer.

A rare chance to help those in need

Recently the CIRM Board voted to support the creation of a Rare Disease Advisory Council (RDAC) in California. An RDAC is an advisory body providing a platform for the rare community to have a stronger voice in state government. They address the needs of rare patients and families by giving stakeholders an opportunity to make recommendations to state leaders on critical issues including the need for increased awareness, diagnostic tools and access to affordable treatments and cures.  

California is now in the process of creating an RDAC but, as a recent article in STAT highlighted, we are far from the only one.

Guadalupe Hayes-Mota

21 states give rare disease patients a seat at the table. The other 29 need to follow suit
By Guadalupe Hayes-Mota Originally published by STAT on July 26, 2021

A powerful movement is taking shape in the U.S. rare disease community that could transform the lives of millions of people. That’s right — millions. Even though a single rare disease may affect only a few individuals, there are several thousand of these problematic diseases that are difficult to identify and treat.

Since 2015, 21 U.S. states have passed legislation to create Rare Disease Advisory Councils that provide platforms for patients and family members to communicate with experts, policymakers, and the broader public. It’s critical to seize this hopeful moment because the needs of so many people living with rare diseases go unaddressed.

I know because I’m one of them.

I was born and raised in a small town in Mexico and diagnosed at birth with hemophilia, a rare genetic disease that prevents the blood from clotting after trauma or injury. While treatment existed in other parts of the world, I had only limited access to it, forcing me to live an isolated childhood indoors, protected and isolated from the world.

When my appendix burst at age 12, I underwent emergency surgery, followed by a desperate eight-hour ambulance ride to a hospital in another town in search of better medication to stop the bleeding. Doctors told my parents I was unlikely to survive, but against all odds I did — after clinically dying twice in the operating room. I am one of the few lucky people with my condition to have survived severe bleeding events without treatment.

After this traumatic incident, my family moved to a small town in California’s Mojave Desert. Navigating the health care system as an immigrant and not knowing the language was complicated. Accessing treatment and services for my disease was almost impossible at first. The nearest specialist was 90 minutes away. Thankfully, with help from the hemophilia association chapter in our area, I gained access to care and treatment.

Read the complete article here.

Building a new mouse, one stem cell at a time

Science is full of acronyms. There are days where it feels like you need a decoder ring just to understand a simple sentence. A recent study found that between 1950 and 2019 researchers used more than 1.1 million unique acronyms in scientific papers. There’s even an acronym for three letter acronyms. It’s TLAs. Which of course has one more letter than the thing it stands for.

I only mention this because I just learned a new acronym, but this one could help change the way we are able to study causes of infertility. The acronym is IVG or in vitro gametogenesis and it could enable scientists to create both sperm and egg, from stem cells, and grow them in the lab. And now scientists in Japan have done just that and allowed these fertilized eggs to then develop into mice.

The study, published in the journal Science, was led by Dr. Katsuhiko Hayashi of Kyushu University in Japan. Dr. Hayashi is something of a pioneer in the field of IVG. In the past his team were the first to produce both mouse sperm, and mouse eggs from stem cells. But they ran into a big obstacle when they tried to get the eggs to develop to a point where they were ready to be fertilized.

Over the last five years they have worked to find a way around this obstacle and, using mouse embryonic stem cells, they developed a process to help these stem cell-generated eggs mature to the point where they were viable.

In an article in STAT News Richard Anderson, Chair of Clinical Reproductive Science at the University of Edinburgh, said this was a huge achievement: “It’s a very serious piece of work. This group has done a lot of impressive things leading up to this, but this latest paper really completes the in vitro gametogenesis story by doing it in a completely stem-cell-derived way.”

The technique could prove invaluable in helping study infertility in people and, theoretically, could one day lead to women struggling with infertility to be able to use their own stem cells to create eggs or men their own sperm. However, the researchers say that even if that does become possible it’s likely a decade or more away.

While the study is encouraging on a scientific level, it’s raising some concerns on an ethical level. Should there be limits on how many of these manufactured embryos that a couple can create? Can someone create dozens or hundreds of these embryos and then sift through them, using genetic screening tools, to find the ones that have the most desirable traits?

One thing is clear, while the science is evolving, bioethicists, scholars and the public need to be discussing the implications for this work, and what kinds of restraints, if any, need to be applied before it’s RFPT (ready for prime time – OK, I made that one up.)

An off-the-shelf cancer killer

iPS Cell: Photo from the lab of Kathrin Plath at UCLA

One of the hottest areas in cancer research right now is the use of CAR-T treatments. These use the patient’s own re-engineered immune system cells to target and kill the tumor. But the thing that makes it so appealing – using the patient’s own cells – also makes it really complicated and expensive. Creating a custom-made therapy from each patient’s own cells takes time and costs a lot of money. But now a new approach could change that.

Fate Therapeutics has developed an off-the-shelf therapy (thanks to CIRM funding) that could, theoretically, be stored at hospitals and clinics around the country and used whenever it’s needed for anyone who needs it.

At this year’s meeting of the American Society of Hematology (ASH) Fate announced that the first patient treated with this new approach seems to be doing very well. The patient had acute myeloid leukemia and wasn’t responding to conventional treatments. However, following treatment with Fate’s FT516 the patient responded quickly and – according to STAT News’ Adam Feuerstein – was able to leave the hospital and spend Thanksgiving with his family.

Equally impressive is that 42 days after being treated with FT516, the man showed no signs of leukemia in either his bone marrow or blood.

FT516 is designed to provide a one-two combination attack on cancer. It’s made up of the wonderfully named natural killer (NK) cells, which are a critical part of our immune system defenses against cancer. These NK cells are created by using the iPSC process and have been genetically modified to express a protein that boosts their cancer-killing abilities.

Because these cells are manufactured they can, if effective, be produced in large numbers and stored for whenever needed. That would not only dramatically reduce costs but also make them more widely available when they are needed.

This is only one patient and the follow-up is still relatively short. Even so, the results are encouraging and certainly give hope that Fate is on to something big. We’ll be keeping track and let you know how things progress.

Clinical trials: separating the wheat from the chaff

What do you do when the supposed solution to a problem actually turns out to be a part of the problem? That’s the situation facing people who want to direct patients to scientifically sound clinical trials. Turns out the site many were going to may be directing patients to therapies that are not only not scientifically sound, they may not even be safe.

The site in question is the www.clinicaltrials.gov website. That’s a list of all the clinical trials registered with the National Institutes of Health. In theory that should be a rock-solid list of trials that have been given the go-ahead by the Food and Drug Administration (FDA) to be tested in people. Unfortunately, the reality is very different. Many of the trials listed there have gone through the rigorous testing and approval process to earn the right to be tested in people. But some haven’t. And figuring out which is which is not easy.

The issue was highlighted by a terrific article on STAT News this week. The article’s title succinctly sums up the piece: “Stem cell clinics co-opt clinical-trials registry to market unproven therapies, critics say.”

The story highlights how clinics that are offering unproven and unapproved stem cell therapies can register their “clinical trial” on the site, even if they haven’t received FDA approval to carry out a clinical trial.

Leigh Turner, a bioethicist at the University of Minnesota and a long-time foe of these clinics, said:

“You can concoct this bogus appearance of science, call it a clinical study, recruit people to pay to participate in your study, and not only that: You can actually register on clinicaltrials.gov and have the federal government help you promote what you’re doing. That struck me as both dangerous and brilliant.”

At CIRM this is a problem we face almost every day. People call or email us asking for help finding a stem cell therapy for everything from cancer and autism to diabetes. If we are funding something or if there is one underway at one of our Alpha Stem Cell Clinics we can direct them to that particular trial. If not, the easiest thing would be to direct them to the clinicaltrials.gov site. But when you are not sure that all the programs listed are legitimate clinical trials, that’s not something we always feel comfortable doing.

As the STAT piece points out, some of the “trials” listed on the site are even being run by companies that the FDA is trying to shut down because of serious concerns about the “therapies” they are offering. One was for a Florida clinic that had blinded four people. Despite that, the clinic’s projects remain on the site where other patients can find them.

Being listed on clinicaltrials.gov gives clinics offering unproven therapies an air or legitimacy. So how can you spot a good trial from a bad one? It’s not always easy.

One red flag is if the trial is asking you to pay for the treatment. That’s considered unethical because it’s asking you to pay to be part of an experiment. Only a very few legitimate clinical trials ask patients to pay, and even then, only with permission from the FDA.

Another warning sign is anything that has a laundry list of things it can treat, everything from arthritis to Alzheimer’s. Well-designed clinical trials tend to be targeted at one condition not multiple ones.

We have put together some useful tools for patients considering taking part in a clinical trial. Here is a link to a video and infographic that tell people the questions they need to ask, and things they need to consider, before signing up for any clinical trial.

So why does the NIH continue to allow these clinics to “advertise” their programs on its website? One reason is that the NIH simply doesn’t have the bandwidth to check every listing to make sure they are legit. They have tried to make things better by including a warning, stating:

“Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Before participating in a study, talk to your health care provider and learn about the risks and potential benefits.”

The bottom line is that if you are in the market for a stem cell therapy you should approach it the way you would any potentially life-changing decision: caveat emptor, buyer beware.