New way to understand tumor diversity combines CRISPR with genetic barcodes

Photo courtesy of PIXNIO

The growth of a particular tumor depends on multiple genetic factors, so it is difficult for cancer researchers to recreate and study this genetic diversity in the lab.

“Human cancers don’t have only one tumor-suppression mutation [which fuels tumor growth] — they have combinations. The question is, how do different mutated genes cooperate or not cooperate with one another?” said Monte Winslow, PhD, a Stanford assistant professor of genetics and of pathology, in a recent Stanford news release.

Now, Winslow and his colleagues have discovered a way to modify cancer-related gene and then track how these combinations of mutations impact tumor growth, as recently reported in Nature Genetics.

The researchers used a powerful gene-editing tool, called CRISPR-Cas9, to introduce multiple, genetically distinct tumors in the lungs of mice. They also attached short, unique DNA sequences to individual tumor cells — which acted as genetic barcodes and multiplied in number as the tumors grew. By counting the different barcodes, they were able to accurately and simultaneously track tumor growth.

“We can now generate a very large number of tumors with specific genetic signatures in the same mouse and follow their growth individually at scale and with high precision. The previous methods were both orders of magnitude slower and much less quantitative,” said Dmitri Petrov, PhD, a senior author of the study and an evolutionary biologist at Stanford, in the release.

The study showed that many tumor-suppressor genes only drive tumor growth when other specific genes are present. The researchers hope to use their new methodology to better understand why tumors with the same mutations sometimes grow to be very large in some patients and remain small in others, they said.

Their technique may also speed up cancer drug development, allowing a drug to be tested on thousands of tumor types simultaneously. Petrov explained in the release:

“We can help understand why targeted therapies and immunotherapies sometimes work amazingly well in patients and sometimes fail. We hypothesize that the genetic identify of tumors might be partially responsible, and we finally have a good way to test this.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

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Oncologist disagree on use of value to guide cancer treatments

Photo by Nick Youngson

Cancer care is expensive, with the cost of new chemotherapies exceeding  $100,000 annually and the growth in cancer care costs increasing faster than the growth in general medical care costs. In addition, there is a widely acknowledged mismatch between the costs and benefits of treatment.

“The pricing of cancer drugs doesn’t appear to be related to their health benefit. This is problematic and unaffordable both for the health care system and for patients, who are expected to engage in not-insubstantial cost sharing,” explained Risha Gidwani-Marszowski, DrPH, a health economist at the VA Palo Alto Health Care System and at Stanford.

In response to this gap, oncology professional societies now recommend that oncologists consider the value of a treatment when making clinical recommendations, a major shift in clinical practice. But how are oncologists defining whether a therapy has “high value?” And how are they using this information?

Gidwani-Marszowski investigated these questions in a new study recently published in Value in Health. Her multi-institutional research team conducted in-depth interviews with 31 U.S. oncologists who practiced in a diverse range of environments, including academic medical centers, community medical centers and the Veterans Health Administration.

The researchers asked oncologists open-ended questions about larger questions regarding value – specifically,  about the oncologists’ definitions and measurements of value, as well as about their value-based choices.

“We didn’t want to operate under the erroneous assumption that we knew everything there is to know about the relevant features of the value problem,” said Gidwani-Marszowski. “We felt it would be better to keep things open-ended, so that practicing oncologists could tell us the aspects of value that were most relevant or salient to them.”

Once these in-depth conversations were transcribed, two independent investigators qualitatively assessed the transcripts to identify themes — pinpointing and recording patterns. Their analyses revealed that oncologist have wide ranging views. Gidwani-Marszowski explained:

“One of the most interesting things we found through this work is that the divergent views exist at a very basic level — the definition of value.  For example, in defining value, some oncologists said cost was one of multiple factors that should be considered, while others said cost had no role at all to play in value.”

Additionally, some oncologists looked at cost in relation to a patient’s quality of life, while others looked at quality of life alone to measure value. One oncologist explained in the paper, “I think [value] shouldn’t just be measured by overall survival, but quality of life has to really be integrated into that. I’m extending the patient’s life by two months, if they’re filled with chemotherapy side effects and toxicity, have we increased the value?”

The oncologists also disagreed on how value should be measured, who should assess the value of a treatment and whether value should be discussed with the patient.

For one oncologist, conversations about costs are important: “I tend to explain to them what the cost is and what the benefit is. And some patients actually say, ‘I don’t think it’s worth it.’ … So I will give them [information about the] cost and the side effects and the benefit and we’ll make the decision together.”

For another oncologist, the conversations don’t work well: “Most of the time we don’t [discuss the cost of care] because then the patients and families think hey, these guys are looking at dollars and not providing the care… So that’s kind of really controversial. Plus it’s very uncomfortable even to talk about the money and the care we provide to them…”

Now, the team is using the results from these in-depth interviews to design a closed-ended survey, which they plan to disseminate to a large sample of oncologists across the country. Gidwani-Marszowski explained:

“Oncologists often have the best understanding of the effectiveness of a particular drug in a specific patient and largely guide the purchasing of care for cancer patients. Thus, it is partly through understanding their perspectives that we can improve the value of cancer care.”

Gidwani-Marszowski also told me that for value efforts to be successful, a critical first step is to make sure all of the relevant stakeholders — oncologists, patients, caregivers, other health care providers, payers, health economists and policy makers  — are able to reach a consensus on the definition of value in cancer care.  That will build a foundation for efforts to establish thresholds for value, mechanisms to measure value, and ultimately, efforts to improve the value of cancer care, she said.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Developing “guided missiles” to attack cancer: A podcast featuring a Stanford bioengineer

Photo by Allocer

Chemotherapy attacks cancer by killing cells that are rapidly dividing. But this leads to serious side effects, like intestinal upset and hair fallout, because these normal cells grow quickly.

So researchers like Jennifer Cochran, PhD, a professor and the chair of bioengineering at Stanford, are developing more targeted cancer therapies, dubbed “guided missiles.” She recently described her work to professor and radio show Russ Altman, MD, PhD, on an episode of the Sirius radio show The Future of Everything.

“We, and others, have developed novel proteins that can selectively target cancer cells and then we can attach cargo to them — this is where the missile analogy comes in,” Cochran told Altman. “The cargo that we attach, things like chemotherapy, can then be selectively targeted to the tumor.” The idea is to precisely deliver to the tumor a more poisonous dose than you could deliver systemically, she said.

One way to do this is to bioengineer antibodies, which are molecules that recognize and help neutralize foreign substances like bacteria. However, Cochran’s lab took a slightly different approach. She explained to Altman:

“As amazing as antibodies are, they can have some limitations in that they are very large in terms of molecular size so they have trouble wiggling into a tumor. So we’ve created smaller versions of tumor-targeting proteins that can hopefully penetrate into tumors better. And we’ve then chemically attached chemotherapy molecules to deliver a punch to the cancer cells.”

In order to develop these proteins, her team is expediting protein evolution in a test tube — making favorable properties that would normally evolve over millions of years happen in just a few weeks. To do this, the team uses genetic manipulation to create millions of slightly different protein variants, tests them with high-throughput screening in just a few hours, identifies the ones most desirable for a certain task, and then determines these variants’ DNA sequences.

For example, they used this evolutionary process on a peptide, a small fragment of protein, from the seeds of a plant known as a squirting cucumber to turn the molecule into a favorable drug scaffold. “We ran the protein through this evolution process to create a tumor-targeting protein that we then hooked the chemotherapy agents on to,” said Cochran.

Cochran’s group is also investigating immunotherapy applications for her proteins. She is teaming up with Dane Wittrup, PhD, a professor in chemical engineering and biological engineering at Massachusetts Institute of Technology, who has developed new ways to use the immune system. By combining Cochran’s tumor-targeting technology with Wittrup’s insights into immunotherapy, they are able to give a “one-two punch” and activate multiple factors of the immune system to more effectively attack cancer, she said.

Her research team is also interested in applying their work to other diseases. She explained to Altman:

“We’ve been applying them for cancer, but you can use the same approach to deliver therapies to other types of disease tissue. We have really only just scratched the surface of what we can do. A big driver of this has been the interdisciplinary culture of collaborative research at Stanford. We’ve been working together with physicians, clinicians, scientists, engineers and physicists to tackle really challenging problems.”

Cochran’s bioengineered proteins are not yet available to patients. However, some tumor-targeting molecules are already approved by the U.S. Food and Drug Administration and many more are in the pipeline. “There are a number of molecules that are FDA approved and you might have heard commercials for them,” she told Altman. “But they only work for a subset of patients. So the question is: how do we make them work better for a larger subset of patients?”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Living with cancer: A Q&A with comedian Fred Reiss

Photo by Ben Moon

Cancer isn’t what comes to mind when I think of stand-up comedy, but Fred Reiss may change that. A three-time cancer survivor, Reiss shares at Comedy Day 37 what it’s like to go for a follow-up PET scan to find out if your cancer is back, also joking that they found a computer chip in his neck and returned him to his original owner. I recently spoke with Reiss, who is also an inspirational wellness speaker and novelist, to learn more. 

When were you diagnosed and treated with cancer?

“I was diagnosed with testicular cancer when I was 28 in 1982. Then about 4 years ago, I was diagnosed again with testicular cancer and treated at Stanford — I should have gone for the 2-for-1 deal on testicular removal and saved myself some money. And then a year ago when going for a routine endoscope, I found out I had esophageal cancer. Fortunately Stanford caught it early, and it’s gone now with treatment. So I’ve had cancer three times. I guess I’ll keep on doing this until I get it right.

I started wearing boxing gloves to chemo during my second bout of testicular cancer. I thought of the scene in “Rocky” when he throws the first punch and knocks Apollo down in the first round. I kept thinking: I need to be in shape to throw that punch. I need to fight for my life. So I decided to wear boxing gloves. Why should I be self-conscious? And the first day, I had someone take a photo in a fighting stance with the gloves. The nurses loved that.”

Why do you do stand-up comedy?

“The genesis was when I was 28 with testicular cancer. I was lying there with an IV in my soft blue vein and I thought: If I’m here again, who will I be? Who will be lying in this bed? And I decided to move from the East Coast to California, go do stand-up comedy and write books.

Later, after I had cancer again, no one wanted to hire a two-time cancer survivor in his 50s to do comedy, radio, journalism, public relations or administration. I had to become Fred 2.0. So I thought, what do I have to say about going through all of this? And I headed back to the stage.

I started going to open mics to use the gravitas of my own mortality to help other people and explore myself. People in the audience wondered why I was there, because I’ve been on national TV, but you have to develop material at smaller clubs — the only way to find out if something works is by saying it. I’ve been on a billboard on Times Square to promote the film, “This is Living with Cancer.” That was the result of two to three years of going to open mics and working on material. I know I’m betraying myself if I don’t go out and perform. I’m betraying the person that I vowed to be.”

How did you become a cancer advocate?

“My cancer advocacy grew out of my suffering and watching other people suffering — it alters you. When I first had cancer, I went through self-actualization to figure out what I wanted to do. The second time, I thought about what I was going to do and what I’d done. And the third time, my ego was completely gone and I thought about other people.

So I decided to travel two tracks — comedy and cancer patient advocacy. I started doing “Fred talks” (my brand of motivational Ted-style talks) and speaking to hospital groups, offering myself to people. In comedy, the audience wants jokes. But if I’m speaking to groups, the audience wants to know how I feel; it’s enormously satisfying. If they can help me out financially when I speak, that’s great. But if they can’t afford it, I don’t mind speaking for free.

During my talks, I use jokes, personal anecdotes and photographs to tell my story of being diagnosed and at the end overcoming cancer. I stress how to draw on your personality, passion, humor and the character of your life to overcome it. I also give practical tips on how to reduce your suffering. My main message is that you can’t let cancer define you; you have to let the spirit that enabled you to overcome it be given to others to help them prevail over the disease too.

In that spirit, I still visit Stanford when I can, giving out my books, CDs and food. I can’t do it every day, but it’s a temple that I have to respect. It’s a way to pay homage and show that I haven’t forgotten the oncologists, nurses and all the people that made a difference. It’s not out of a sense of duty. These people did great things for me, so I’m trying to propel that toward the other people around me.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Stanford chemists produce chemical — originally from marine creature — needed for new drugs

Photo by Fitzgerald Marine Reserve Docent

One person’s weed is another’s flower. A good example of this is spiral-tufted bryozoan, an invasive marine organism that fouls up marine environments. Although considered a pest by many, spiral-tufted bryozoan is much sought after by researchers since it can produce biostatin 1 — a chemical critical to the development of promising new drugs to treat HIV/AIDS, Alzheimer’s disease and cancer.

Although this bryozoan is abundant, bryostatin 1 is very scarce because it’s difficult to harvest from the sea creature and complex to synthesize. In fact, the National Cancer Institute’s stock of bryostatin 1 is nearly depleted from supplying over 40 clinical trials. So Stanford chemists have developed a new, easier way to synthesize bryostatin 1, as recently reported in Science.

Paul Wender, PhD, a professor of chemistry and of chemical and systems biology at Stanford, has been working for years to develop bryostatin analogs that are more effective for drug development. However, the dwindling supply of bryostatin 1 inspired him to synthesize the drug itself.

“Ordinarily, we’re in the business of making chemicals that are better than the natural products,” Wender said in a recent Stanford news release. “But when we started to realize that clinical trials a lot of people were thinking about were not being done because they didn’t have enough material, we decided, ‘That’s it, we’re going to roll up our sleeves and make bryostatin because it is now in demand.’”

The researchers devised a much simpler synthesize process, cutting the steps down from 57 to 29. They also dramatically increased the yield, making it tens of thousands of times more efficient than extracting bryostatin from spiral-tufted bryozoan and significantly more efficient than the previous synthetic approaches. And they confirmed with a wide range of tests that their synthetic bryostatin was identical to a natural sample supplied by NCI.

So far, the team has produced over two grams of bryostatin 1, and a single gram can treat about 1000 cancer patients or 2000 Alzheimer’s patients, according to their paper. After scaling up production, they expect manufacturers to produce about 20 grams per year to meet clinical and research needs, Wender said in the news release.

They also expect their work could facilitate research using bryostatin analogs derived from their synthesis process. The paper explains that these analogs “are proving to be more effective and better tolerated in comparative studies with cells, disease models in animals, and ex vivo samples taken from HIV-positive patients.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Detecting single cancer cells with light: A podcast

Photo by Burak Kebapci

When cancer is spotted early, it’s much easier to thwart. So researchers, including Stanford’s Jennifer Dionne, PhD, are working to detect cancer more effectively. Dionne, an associate professor of materials science and engineering, is developing a nanomaterial-based probe that may be able to detect a single cancer cell.

She described her work in a recent episode of the Future of Everything radio show, hosted by Russ Altman, MD, PhD, a Stanford professor of bioengineering, of genetics, of medicine and of biomedical data science.

“What our lab is trying to do is create light-emitting nanoparticles that change their color when there is an applied force on the nanoparticles. So that way we can make mechanical forces visually perceptible,” she explained to Altman. These nanoparticle already change color in response to the tiny forces generated by cells and groups of cells, she said, and cancer cells are known to exert more force on their environment than healthy cells.

Dionne explained: “Generally a cancer cell wants to take up a lot of nutrients and it’s basically growing and dividing more quickly than a healthy cell. You can imagine given the speed of replication that it’s going to exert a higher force on its environment than a healthy cell. So our nanoparticles offer the ability to detect even a single cancer cell based on the forces that that cancer cell is exerting on its environment.”

That could help pathologists spot abnormal cells in a biopsy sample, she said. “This could be a really cool in vitro probe of whether or not in a biopsy [sample] you have even one cancer cell, which you can tell just by looking at the color the nanoparticles are emitting,” she told Altman.

Although their primary focus was on the development of nanomaterials with energy and biomedical applications, the conversation did take a few interesting twists. I particularly enjoyed their discussion on the design challenges behind making a Harry Potter invisibility cloak. Hint: Like water waves flowing around a rock, you need to create a cloak that allows light waves to flow smoothly around the hidden object so they emerge on the other side as if they hadn’t passed through the object — it’s difficult, but they’re working on it.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Mowing down cancer: A podcast featuring Stanford chemist Carolyn Bertozzi

To explain her work, Stanford chemistry professor Carolyn Bertozzi, PhD, often turns to analogies. Cancer cells, she says, are like M&Ms with a hard sugar coating. As she recently explained on the “Future of Everything” radio show, the coating’s function has remained a mystery for years, but now researchers are making real progress.

“We have come to think of these sugars as kind of a 2D barcode. The patterns are different on different cell types, and yet all of the cells of a certain type have a common pattern,” Bertozzi told show host Russ Altman, MD, Phd. “So there is a code there, but we don’t quite have the means to scan it and we don’t yet understand it.”

So what do the barcodes look like on cancer cells? Bertozzi describes them as a superposition of two barcodes — the original cell’s barcode and a new cancerous one. And the cancerous barcode looks similar for many different cancers. Researchers have found that these sugar barcodes on cancer cells can promote disease progression by turning off the immune system. “They basically tell immune cells, ‘There’s nothing to see here. Move along. I’m perfectly fine and healthy,’” Bertozzi said.

Using an analogy, she explained in the podcast that the cancer cells put on makeup to look fabulous and mesmerize the immune system, fooling it into thinking that the cells are healthy so the cancer can progress unimpeded. Her lab is developing a way to strip off this makeup.

Her team has developed a way to use enzymes to cut off the sugars, making the cells available for immune cells to target. She explained: “They were enzymes that normally play a role in digesting sugars. So what we’ve done is repurposed these enzymes so we can target them right to the surface of the cancer cell. And literally they’ll just go across the surface of the cell mowing off the sugars, like stripping off the makeup. And then the cells can be seen for what they truly are.”

Bertozzi is also involved in a company that hopes to bring this “lawn mower” technology to the clinic within the next two years, but they first need to get good preclinical data as proof-of-concept. The company is currently focused on developing new treatments for breast, lung and kidney cancers.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.