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Cancer, Dermatology, Research, Science

Common skin cancer evades treatment via specific mutations

Common skin cancer evades treatment via specific mutations

Anthony OroBasal cell carcinoma is the most common type of skin cancer. It is also one of the most treatable. But people with advanced cases of the disease often experience only a temporary response to the drug vismodegib, and their tumors recur within a few months as the cancer becomes resistant to the drug.

Now dermatologists Anthony Oro, MD, PhD; Jean Tang, MD, PhD; and Anne Chang, MD, have identified the specific mutations involved in the development of vismodegib resistance, and identified another treatment that may be successful even on vismodegib resistant tumors. They’ve recently published their findings in Cancer Cell (with an accompanying companion paper and commentary).

From our release:

Approximately 2 million new cases of basal cell carcinoma are diagnosed each year in the United States, making it the most common cancer in the country. About half of patients with advanced basal cell carcinomas will respond to vismodegib, which belongs to a class of drug compounds called Smoothened inhibitors. About 20 percent of these responders will go on to quickly develop resistance to the drug.

Basal cell carcinomas are uniquely dependent on the inappropriate activation of a cellular signaling cascade called the Hedgehog pathway. Blocking signaling along this pathway will stop the growth and spread of the cancer cells. The Hedgehog pathway plays a critical role in normal development. It’s also been found to be abnormally active in many other cancers, including pancreatic, colon, lung and breast cancers, as well as in a type of brain cancer called medulloblastoma.

The researchers found two classes of mutations in the Smoothened gene that inhibit vismodegib’s effectiveness by keeping the Smoothened protein active. Treating the cells with inhibitors that target a portion of the pathway downstream of Smoothened blocked the activation of the pathway even in cells with the mutations. These inhibitors, called Gli antagonists, could be an effective way to treat vismodegib-resistant tumors, the researchers said.

As Oro told me, “This research sheds new light on mechanisms of how tumors evolve to develop drug resistance, and has already helped us with personalized cancer genetics and therapy for our patients. It is now possible for us to identify those people who may benefit from a combination therapy even before they begin treatment.”

Previously: Studies show new drug may treat and prevent basal cell carcinoma, New skin cancer target identified by Stanford researchers and Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers
Photo of Anthony Oro by Steve Fisch

Cancer, Stanford News

Stanford neurosurgeon Paul Kalanithi, who touched countless lives with his writing, dies at 37

Stanford neurosurgeon Paul Kalanithi, who touched countless lives with his writing, dies at 37

Paul K and daughter - fixedNeurosurgeon and writer Paul Kalanithi, MD, passed away on Monday. A death is almost always sad, but for me this one is indescribably so – though if he were alive he might convince me of a positive angle.

Kalanithi died at 37 of lung cancer less than a year after finishing his neurosurgery residency at Stanford. During the roughly two years between his diagnosis and death, he spent time as a surgeon saving lives and passing his skills and insights to neurosurgery trainees. But I came to meet him through my work as editor of Stanford Medicine magazine, which published an essay he crafted. His words changed how I think about my life – and, based on the many letters and emails I’ve received, changed how many people looked at theirs as well.

After his diagnosis he wrote essays for The New York Times and Stanford Medicine about his changing perception of mortality and time and the joy he continued to find in life. I interviewed him for a video produced for our magazine, talking with him at his apartment and meeting his wife and baby girl. My colleagues also got to know him by working on stories about his life and illness; just a few days ago, Paul Costello shared on Scope a 45-minute conversation the two had last fall.

Kalanithi’s message, to appreciate every moment, sounds corny when I write it, but in his eloquent words it hits home. In the obituary I wrote today, I shared this excerpt from his Stanford Medicine essay – words he wrote for his infant daughter:

When you come to one of the many moments in life when you must give an account of yourself, provide a ledger of what you have been, and done, and meant to the world, do not, I pray, discount that you filled a dying man’s days with a sated joy, a joy unknown to me in all my prior years, a joy that does not hunger for more and more, but rests, satisfied. In this time, right now, that is an enormous thing.

Previously: Stanford neurosurgeon/cancer patient Paul Kalanithi: “I can’t go on. I will go on.”For this doctor couple, the Super Bowl was about way more than football, A neurosurgeon’s journey from doctor to cancer patient, Stop skipping dessert:” A Stanford neurosurgeon and cancer patient discusses facing terminal illness and No one wants to talk about dying but we all need to
Image – a screenshot from a Stanford Medicine video – from Mark Hanlon

Cancer, Medicine and Society, Patient Care, Public Health, Videos

March marks National Colon Cancer Awareness Month: The takeaway? It’s preventable

March marks National Colon Cancer Awareness Month: The takeaway? It's preventable

What is the leading, preventable cause of death in the United States? I suppose the headline gave away my punchline, but remembering that colon cancer is both deadly and preventable is a timely exercise during March, which is National Colon Cancer Awareness Month.

Here’s what you need to know: Don’t wait until your colon hurts to come to the doctor. That won’t work. “Polyps and early tumors are often not symptomatic,” said gastroenterologist Uri Ladabaum, MD, in the above Stanford Health Care video.

It’s best to catch cancer 10 years before it appears, making 50 a key age to spot a cancer that often appears in the 60s,  said endoscopy director Subhas Banerjee, MD.

And a prime screening procedure, colonoscopy, “is no big deal,” said oncologist Mark Welton, MD. “They give you a little sedation and the next thing you know is you’re saying, ‘Are we done?'”

If physicians do spot the cancer early — or even later — they can often remove it, the physicians agreed. Chemotherapy and surgery are continuing to improve, making it more likely that patients can continue to live long, healthy lives.

Family history and race can leave you more vulnerable to colon cancer — African Americans are more likely to get, and die from, the disease — but in general, a fruit-and-vegetable packed diet, avoiding smoking and getting regular exercise can help stave off colon cancer.

Previously: The Big Bang model of human colon cancer, Stanford researchers explore new ways of identifying colon cancer and Study shows evidence-based care eliminates racial disparity in colon-cancer survival rates 

Cancer, Podcasts, Stanford News

Stanford neurosurgeon/cancer patient Paul Kalanithi: “I can’t go on. I will go on.”

Stanford neurosurgeon/cancer patient Paul Kalanithi: "I can't go on. I will go on."

Kalanthi and childEditor’s note: Paul Kalanithi passed away on March 9, after this post was published.

Frankly, I didn’t quite know how to begin my conversation with Paul Kalanithi, MD. How do you talk to a 37–year-old man about his terminal illness and facing death? A conversation with someone so young who’s the father of a small child is supposed to be ebullient, not dark.

Kalanithi, a Stanford Medicine neurosurgeon and fellow with Stanford Neurosciences Institute, was diagnosed with advanced stage lung cancer in 2013. His illness is terminal. While he’s hopeful that a treatment may extend his life, there is no cure. He faces big questions and small ones. And he wonders: “How do I talk about myself – in the present, past or future tense? When someone says, ‘See you next year,’ will I?”

It all began with back pain, night sweats, weight loss and fever. His neurosurgical training prepared him for what he reviewed on his CT scan. Metastatic cancer. He responded well to his initial treatment plan, but a second round of chemotherapy last spring led to a number of complications and setbacks. Though he finished his residency he’s now taking time off to recover and regain his strength. He remains hopeful about a return to neurosurgery, yet he has to prepare for an end. He’s spoken with a palliative-care expert. He’s mulling the existential questions and trying to grapple with moving on while not giving up. He takes comfort in the words of the Irish novelist and playwright, Samuel Beckett: “I can’t go on. I can go on.” They’ve become sort of his mantra.

Still, he knows he faces the inevitable and whether it’s a year, two years or five, terminal is the diagnosis. He’s trying to find a way to leave a trail of bread crumbs to his life so his child will know she was loved deeply when his presence is all but a shadow.

I spoke with him last November for a 1:2:1 podcast while he was in the throes of writing a book proposal. It was hard for me at points in our conversation to keep it together as our talk pried open my own grief over my brother’s death to cancer at age 48.

Kalanithi also wrote a beautiful piece for Stanford Medicine magazine. It’s magical. It’s lyrical. It touches the heart. And it’s clear, no matter what his health status, no matter what the outcome, he will live on.

Previously: Stanford Medicine magazine reports on time’s intersection with health, For this doctor couple, the Super Bowl was about way more than football, A neurosurgeon’s journey from doctor to cancer patient, Stop skipping dessert:” A Stanford neurosurgeon and cancer patient discusses facing terminal illness and No one wants to talk about dying but we all need to
Photo by Gregg Segal

Cancer, Stanford News, Stem Cells, Videos

A look at stem cells and “chemobrain”

A look at stem cells and "chemobrain"

As many as 75 percent of cancer patients experience memory and attention problems during or after their treatment, and up to 3.9 million are afflicted by long-term cognitive dysfunction. This foggy mental state, often referred to as “chemobrain,” can also affect cancer survivors’ fine motor skills, information processing speed, concentration and ability to calculate.

In this recently posted California Institute for Regenerative Medicine video, Stanford physician-scientist Michelle Monje, MD, PhD, explains the role that damage to stem cells in the brain plays in the condition, outlines some of the interventions that can mitigate patients’ symptoms, and highlights efforts to develop effective regenerative therapies.

Previously: Stanford brain tumor research featured on “Bay Area Proud”, Emmy nod for film about Stanford brain tumor research – and the little boy who made it possible and Stanford study shows effects of chemotherapy and breast cancer on brain function

Applied Biotechnology, Cancer, Evolution, Immunology, Research, Stanford News

Corrective braces adjust cell-surface molecules’ positions, fix defective activities within cells

Corrective braces adjust cell-surface molecules' positions, fix defective activities within cells

bracesStanford molecular and cellular physiologist and structural biologist Chris Garcia, PhD, and his fellow scientists have tweaked together a set of molecular tools that work like braces of varying lengths and torque to fix things several orders of magnitude too small to see with the naked eye.

Like faulty cell-surface receptors, for instance, whose aberrant signaling can cause all kinds of medical problems, including cancer.

Cell-surface receptors transmit naturally occurring signals from outside cells to the insides of cells. Molecular messengers circulating in the blood stumble on receptors for which they’re a good fit, bind to them, and accelerate or diminish particular internal activities of cells, allowing the body to adjust to the needs of the minute.

Things sometimes go wrong. One or another of the body’s various circulating molecular messengers (for example, regulatory proteins called cytokines) may be too abundant or scarce. Alternatively, a genetic mutation may render a particular receptor type overly sluggish, or too efficient. One such mutation causes receptors for erythropoietin – a cytokine that stimulates production of certain blood-cell types – to be in constant overdrive, resulting in myeloproliferative disorders. Existing drugs for this condition sometimes overshoot, bringing the generation of needed blood-cell types to a screeching halt.

Garcia’s team took advantage of the fact that many receptors – erythropoietin receptors, for example – don’t perform solo, but instead work in pairs. In a proof-of-principle study in Cell, Garcia and his colleagues made brace-like molecular tools composed of stitched-together antibody fragments (known in the trade as diabodies). They then showed that these “two-headed beasts” can selectively grab on to two members of a mutated receptor pair and force the amped-up erythropoietin receptors into positions just far enough apart from, and at just the right angles to, one another to slow down their hyperactive signaling and act like normal ones.

That’s a whole new kind of therapeutic approach. Call it “cellular orthopedics.”

Previously: Souped-up super-version of IL-2 offers promise in cancer treatment and Minuscule DNA ring tricks tumors into revealing their presence
Photo by Zoe

Cancer, Evolution, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Bubble, bubble, toil and trouble – yeast dynasties give up their secrets

Bubble, bubble, toil and trouble - yeast dynasties give up their secrets

yeasty brew

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Their research was published today in Nature.

From our release:

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

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Applied Biotechnology, Bioengineering, Cancer, Genetics, Research, Stanford News

Minuscule DNA ring tricks tumors into revealing their presence

Minuscule DNA ring tricks tumors into revealing their presence

cool minicirclesAn animal study just published in Proceedings of the National Academy of Sciences shows how, in the not-distant future, doctors may be able to not only detect tumors early in humans, but also monitor the effectiveness of cancer drugs in real time, guide clinical trials of new drugs, and even screen entire populations of symptom-free people for nascent tumors that could have otherwise slipped under the radar.

The potential is huge. And the principal investigator, Sam Gambhir, MD, PhD, is credible: He chairs Stanford’s radiology department, directs the Canary Center at Stanford for Cancer Early Detection and has authored or co-authored nearly 600 peer-reviewed research publications.

From my news release about the study:

Imagine: You pop a pill into your mouth and swallow it. It dissolves, releasing tiny particles that are absorbed and cause only cancerous cells to secrete a specific protein into your bloodstream. Two days from now, a finger-prick blood sample will expose whether you’ve got cancer and even give a rough idea of its extent. That’s a highly futuristic concept. But its realization may be only years, not decades, away.

The key to early cancer detection lies in finding valid biomarkers: substances whose presence in a person’s blood or urine flags a probable tumor. (High blood levels of the molecule known as PSA, for example, can signify prostate cancer.) But although various tumor types indeed secrete characteristic substances into the blood, these same substances typically are made in healthy tissues, too, albeit usually in smaller amounts. So a positive test result for, say, PSA doesn’t necessarily mean the person has cancer. Contrariwise, a small tumor just may not secrete enough of the trademark substance to be detectable.

Gambhir’s team appears to have found a way to force any of numerous tumor types to produce a biomarker whose presence in the blood unambiguously signifies cancer, because no adult tissues – cancerous or otherwise – would normally be making it. This particular substance is a protein naturally present in human embryos as they’re forming and developing, but absent in adults.

The scientists designed a genetic construct, called a DNA minicircle, that contains a single gene coding for the telltale substance. DNA minicircles are tiny, artificial, single-stranded DNA rings about 4,000 nucleotides in circumference – roughly one-millionth as long as the strand that you’d get if you stretched the DNA in all 23 chromosomes of the human genome end to end.

Gambhir and his colleagues rigged their minicircles so that this sole gene would be “turned on” only inside cancer cells. (For more details on how to do this, please see my release.) They injected the minicircles into mice who had small tumors and mice who didn’t. Within 48 hours, a simple blood test indicated the presence of the biomarker in the blood of mice with tumors, but not in the blood of the tumor-free mice.The bigger the tumor volume, the more of the biomarker in the blood.

The technique will likely apply to a broad range of cancers, and can possibly be modified to help pinpoint budding tumors’ location in the body.

Previously: Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later, Nanoparticles home in on human tumors growing in mice’s brains, increase accuracy of surgical removal and Nanomedicine moves one step closer to reality
Photo by Jim Strommer

Aging, Cancer, Emergency Medicine, Medical Education, Pregnancy, Stanford News

Stanford Medicine magazine reports on time’s intersection with health

Stanford Medicine magazine reports on time's intersection with health

Why is it that giant tortoises typically live for 100 years but humans in the United States are lucky to make it past 80? And why does the life of an African killifish zip past in a matter of months?

I’ve often mused about the variability of life spans and I figure pretty much everyone else has too. But while editing the new issue of Stanford Medicine magazine’s special report on time and health, “Life time: The long and short of it,” I learned that serious scientists believe the limits are not set in stone.

“Ways of prolonging human life span are now within the realm of possibility,” says professor of genetics Anne Brunet, PhD, in “The Time of Your Life,” an article on the science of life spans. My first thought was, wow! Then I wondered if some day humans could live like the “immortal jellyfish,” which reverts back to its polyp state, matures and reverts again, ad infinitum. Now that would be interesting.

Also covered in the issue:

  • “Hacking the Biological Clock”: An article on attempts to co-opt the body’s timekeepers to treat cancer, ease jetlag and reverse learning disabilities.
  • “Time Lines”: A Q&A with bestselling author and physician Abraham Verghese, MD, on the timeless rituals of medicine. (The digital edition includes audio of an interview with Verghese.)
  • “Tick Tock”: A blow-by-blow account of the air-ambulance rescue of an injured toddler.
  • “Before I Go”: An essay about the nature of time from a young neurosurgeon who is now living with an advanced form of lung cancer. (The neurosurgeon, Paul Kalanithi, MD, is featured in the video above, and our digital edition also includes audio of an interview with him.)

The issue also includes a story about the danger-fraught birth of an unusual set of triplets and an excerpt from the new biography of Nobel Prize-winning Stanford biochemist Paul Berg, PhD, describing the sticky situation he found himself in graduate school.

Previously Stanford Medicine magazine traverses the immune system, Stanford Medicine magazine opens up the world of surgery and Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions.

Cancer, Imaging, In the News, Research, Technology

Stanford instructor called out for his innovative – and beautiful – imaging work

Stanford instructor called out for his innovative - and beautiful - imaging work

breast cancer cells

I’ll skip the name word play – it’s just too obvious – but I won’t skip Michael Angelo’s work. Angelo, MD, a pathology instructor at Stanford, developed a new imaging technique that labels antibodies with metallic elements, then uses an ion beam to scan the tissue, revealing up to 100 proteins at once in a single cancer cell.

This technique, called multiplexed ion beam imaging, or MIBI, captured the attention of the National Institutes of Health, which featured Angelo in its NIH Director’s Blog this week. The images are lovely to look at, but also quite useful to learn more about tissue types.

Here’s Angelo describing the image above:

Angelo used MIBI to analyze a human breast tumor sample for nine proteins simultaneously—each protein stained with an antibody tagged with a metal reporter. Six of the nine proteins are illustrated here. The subpopulation of cells that are positive for three proteins often used to guide breast cancer treatment (estrogen receptor a, progesterone receptor, Ki-67) have yellow nuclei, while aqua marks the nuclei of another group of cells that’s positive for only two of the proteins (estrogen receptor a, progesterone receptor). In the membrane and cytoplasmic regions of the cell, red indicates actin, blue indicates vimentin, which is a protein associated with highly aggressive tumors, and the green is E-cadherin, which is expressed at lower levels in rapidly growing tumors than in less aggressive ones.

Taken together, such “multi-dimensional” information on the types and amounts of proteins in a patient’s tumor sample may give oncologists a clearer idea of how quickly that tumor is growing and which types of treatments may work best for that particular patient.  It also shows dramatically how much heterogeneity is present in a group of breast cancer cells that would have appeared identical by less sophisticated methods.

Angelo was given a NIH Director’s Early Independence Award last fall, and he’s ramping up his investigations of breast cancer.

Stanford Medicine Resources: