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Cancer, FDA, Genetics, Research, Science, Stanford News

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

6825694281_dfb79615d6_zIf you’re a regular reader of this blog, or follow cancer literature, you’ll have heard of a signaling pathway called Hedgehog that is activated in many cancers, including brain, skin and even bladder. It’s a cute name for cellular cascade that can kill when inappropriately activated.

Neurologist Yoon-Jae Cho, MD, treats children with brain tumors called medulloblastomas. He and postdoctoral fellow in his lab, Yujie Tang, PhD, published a study yesterday in Nature Medicine that could one day help some patients whose Hedgehog-driven tumors have become resistant to available therapies.

As Cho explained in an e-mail to me:

Medulloblastomas are the most common malignant brain tumors in children. They are comprised of various subgroups, including one with activation of a strong oncogenic signal called the Hedgehog pathway. Notably, the Hedgehog pathway is also activated in several other cancers including basal cell carcinoma, the most common cancer worldwide. Therefore, pharmaceutical companies and several research groups have developed drugs to target this pathway.

The most common of these drugs targets a downstream protein component of the pathway called Smoothened, including one currently marketed by Genentechcalled vismodegib (trade name Erivedge) and an investigational drug produced by Novartis called LDE225. Blocking the activity of Smoothened stops the chain reaction leading to division of the cancer cells. You can think of it (in simplified terms) as a line of dominoes standing on end, waiting for an eager finger to begin the chain reaction. Removing one domino (nixing Smoothened activity) can sometimes stop the rest of the row from falling and block the cancerous cell from dividing. But, as Cho explained:

Unfortunately, many cancers activate the Hedgehog pathway downstream of Smoothened and are inherently resistant to these therapies. Other cancers that are initially responsive to these drugs develop resistance through activation of downstream Hedgehog pathway components.

Cho and his colleagues have now described a new, novel way to interfere with the Hedgehog pathway. They’ve found that compounds that inhibit a protein called BRD4 can stop the growth of human Hedgehog-driven cancers – even when they’re resistant to drugs blocking Smoothened activity. This is particularly interesting because the BRD family of proteins recognizes and binds to particular chemical tags on chromatin that control whether (and when) a gene is made into a protein. It’s the first time such an epigenetic regulator has been implicated as a target in the Hedgehog pathway. Additionally, it’s a new avenue to explore for patients with Hedgehog-driven medulloblastomas – as many as half of whom will be resistant to Smoothened inhibition, according to a previous study co-authored by Cho and members of the International Cancer Genome Consortium’s Pediatric Brain Tumor Project. Cho concludes, “Our study offers a promising new treatment strategy for patients with Hedgehog-driven cancers that are resistant to the currently used Smoothened antagonists.”

Previously: New skin cancer target identified by Stanford researchers, Humble anti-fungal pill appears to have noble side-effect: treating skin cancer and Studies show new drug may treat and prevent basal cell carcinoma
Photo by Phillip Taylor

Addiction, FDA, Health Policy, otolaryngology, Public Health

How e-cigarettes are sparking a new wave of tobacco marketing

e-cig tip - smallFollowing the FDA’s announcement earlier this spring that it would regulate the sale – but not marketing – of electronic cigarettes, debate has continued on the safety of using e-cigarettes and the ethics of advertising them.

In case you missed it, today’s New York Times delves into the issue and highlights how Big Tobacco is now rolling into the world of e-cigarettes, which writer Matt Richtel calls an “overnight sensation.” A subsidiary of Reynolds American plans to begin distributing its Vuse e-cigarette line nationwide on June 23 with a campaign that includes television ads (forbidden for cigarettes) in major markets, and other tobacco companies have similar entries in the works. Questions about the potentially far-reaching effects advertising of e-cigarettes, including promoting smoking tobacco and reaching child audiences, concern public-health advocates and other critics – and a U.S. Senate hearing is planned for Wednesday.

From the article:

Matthew L. Myers, [JD,] president of the Campaign for Tobacco-Free Kids, who is scheduled to testify at the Senate hearing, said the fact that the F.D.A. did not limit marketing allowed tobacco companies to return to the airwaves with ads that make e-cigarettes sexy, rebellious, glamorous — “exactly the same themes we saw work with kids in the U.S. for decades with cigarettes.”

In the absence of marketing regulation, “they will set the agenda,” Mr. Myers said of the tobacco companies. “They will drive the evolution of the product in a way that serves their interests and not public health, and that’s exactly what’s happening.”

Robert Jackler, MD, chair of otolaryngology at Stanford Medicine, is an expert on tobacco marketing who studies it through his center, the Stanford Research Into the Impact of Tobacco Advertising. Like Myers, he has vocalized his concerns about e-cigarettes and tobacco companies’ aggressive marketing tactics – especially those targeted toward teens – and you can hear more about his views and research in this recent podcast.

Previously: E-cigarettes and the FDA: A conversation with a tobacco-marketing researcherE-Cigarettes: The explosion of vaping is about to be regulatedStanford chair of otolaryngology discusses federal court’s ruling on graphic cigarette labels and What’s being done about the way tobacco companies market and manufacture products
Photo by Li Tsin Soon

Big data, Events, FDA, Public Health, Stanford News, Technology

Rising to the challenge of harnessing big data to benefit patients

Rising to the challenge of harnessing big data to benefit patients

FDA guyMuch has been written on Scope about the annual Big Data in Biomedicine conference, held here last week. My colleague Bruce Goldman was on the scene all three days, and he offers more highlights from the event in an online story.

Noting how Lloyd Minor, MD, dean of the School of Medicine,  encouraged the audience “to rise to the challenge of harnessing computer technology, biomedical informatics and social media – collectively known as big data  – to benefit clinical practice,” Goldman goes on to describe the FDA’s work in this area:

“If you eat a salad, you’re pretty much a global citizen,” said [Taha Kass-Hout, MD, chief health informatics officer at the Food and Drug Administration], noting that the ingredients of a typical salad may travel halfway around the world to get to our table. Unfortunately, the well-traveled salad can pick up a host of microbial free-riders en route. Over the last year the FDA has assembled a publicly accessible database holding the genomic sequences of more than 5,000 food-poisoning culprits such as Salmonella and listeria, he said.

In a new initiative, the FDA has been monitoring social media to enhance its surveillance capabilities. “Maybe we’ll find that we can detect outbreaks earlier that way,” he said. It may also be possible, using these methods, to draw inferences about beneficial or adverse effects of drugs prescribed for indications other than the ones for which they’ve been specifically approved. This could expedite new uses for existing drugs.

Previously: Discussing access and transparency of big data in government, U.S. Chief Technology Officer kicks off Big Data in Biomedicine, Euan Ashley discusses harnessing big data to drive innovation for a healthier world and Big laughs at Stanford’s Big Data in Biomedicine Conference
Photo of Kass-Hout by Saul Bromberger

Big data, Events, FDA, NIH, Stanford News, Technology

Discussing access and transparency of big data in government

Discussing access and transparency of big data in government

Bourne

The Big Data in Biomedicine conference of 2014 continued today with discussion around how troves of information are being stored, organized, accessed and applied in a way that’s useful to stakeholders across health care.

Yesterday afternoon, Stanford bioengineer Russ Altman, PhD, introduced keynote speaker Philip Bourne, PhD, who earlier this year began his post as the first permanent associate director for data science at the National Institutes of Health. Altman was part of the search committee that selected Bourne as part of an initiative of NIH Director Francis Collins, MD, PhD, to make use of biomedical research datasets and lead the way in coordinating effective use of Big Data.

Bourne discussed some of the factors motivating thinking on big data at the NIH, including open access to information, which was also a focus of U.S. Chief Technology Officer Todd Park‘s conference presentation. Bourne noted that currently 70 percent of research that’s funded cannot be reproduced – a statistic “of great concern to the NIH” that’s driving ongoing reproducibility studies there. But what worried him most, he said, is sustainability: How can growing databases be accommodated within the NIH’s flat budget? (“We can’t go on like this,” he said.) How can labs retain talent when competing with industry’s larger salaries offered to top scientists? (“It’s a loss to the field if you spend money making a biomedical scientist and they leave the field.”) Bourne also seeks to address “broken” areas of scholarship – a paper with “16,000 citations” that no one reads – and the reward system.

Among his solutions are applying business models to promote sustainability of research, introducing policies to ensure funding is allocated where it is most needed, sharing infrastructure where possible and treating biomedical scientists more like tenured academics. Bourne also described an NIH data commons to provide Dropbox-type storage and a collaborative compute environment for scientists.

Co-operating and data-sharing were key this morning as the conference audience heard from Taha Kass-Hout, MD, the U.S. Food and Drug Administration‘s first chief health informatics officer. He described the importance of big data to the regulatory agency’s mission “to protect and promote the public health” and in promoting information-sharing with transparency and protection of privacy. The new, scalable search and big-data analytics platform openFDA comprises more than 100 public access data sets within the FDA and  allows users to access data and run queries through APIs. ”It’s not just about the data,” Kass-Hout told the audience. Ask rather, “How can you build a community around that data?

Previously: U.S. Chief Technology Officer kicks off Big Data in BiomedicineBig Data in Biomedicine conference kicks off tomorrowBig Data in Biomedicine technical showcase to feature companies’ innovations related to big data and Euan Ashley discusses harnessing big data to drive innovation for a healthier world
Photo of Bourne by Saul Bromberger

Addiction, FDA, Health Policy, In the News, Podcasts

E-cigarettes and the FDA: A conversation with a tobacco-marketing researcher

E-cigarettes and the FDA: A conversation with a tobacco-marketing researcher

The FDA announced today its plans to regulate e-cigarettes. The news comes as little surprise to many, including Robert Jackler, MD, chair of otolaryngology at Stanford Medicine, who studies the effects of tobacco advertising, marketing, and promotion through his center, the Stanford Research Into the Impact of Tobacco Advertising. I asked Jackler this morning what he thought of the FDA’s plan, and he had this to say:

While I welcome the FDA proposal to deem electronic cigarettes as tobacco products under their regulatory authority, I’m disappointed with the narrow scope of their proposal and the snail’s pace of the process. Given its importance, I’m particularly troubled by the FDA’s failure to address the the widespread mixing of nicotine with youth-oriented flavorings (e.g. gummy bears, cotton candy, chocolate, honey, peach schnapps) in electronic cigarettes products.  Overwhelming evidence implicates such flavors as a gateway to teen nicotine addiction [which] led the FDA to ban flavors (except for menthol – which is presently under review) for cigarettes in 2009.  Give the lethargic pace of adopting new regulations, a generation of American teens is being placed at risk of suffering the ravages of nicotine addiction.

In a podcast last month, Jackler spoke in-depth about the rise of, and problems with, e-cigarettes. If you haven’t yet listened, now is a great time to.

Previously: E-Cigarettes: The explosion of vaping is about to be regulated, Stanford chair of otolaryngology discusses federal court’s ruling on graphic cigarette labels and What’s being done about the way tobacco companies market and manufacture products

Applied Biotechnology, Clinical Trials, FDA, Public Health, Research, Stanford News

The best toxicology lab: a mouse with a human liver

The best toxicology lab: a mouse with a human liver

of mice and menA few years ago, Stanford pharmacogenomic expert Gary Peltz, MD, PhD, collaborating with researchers in Japan, developed a line of bioengineered mice whose livers were largely replaced with human liver cells that recapitulate the architecture and function of a human liver. Now, in a recent study published in PLoS Medicine, Peltz’s team has shown that routine use of this altered lab mouse in standard toxicology tests preceding clinical trials would save human lives.

Among the liver’s numerous other job responsibilities, one of the most important is chemically modifying drugs in various ways to make them easier for the body to get rid of. But some of those chemical products, or metabolites, can themselves be quite toxic if they reach high levels before they’ve been excreted.

The Food and Drug Administration requires that prior to human testing, a drug’s toxicological potential be assessed in at least two mammalian species. But we humans metabolize things differently from other mammals, because our livers are different. That can make for nasty surprises. All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials due to unforeseen liver toxicity, said Peltz, a former pharmaceutical executive who is intimately familiar with established preclinical testing procedures in the industry.

That’s what happened in 1993 when, after a short safety trial of a drug called FIAU concluded without incident, the comp0und was placed in a phase-2 clinical trial of a drug for hepatitis B. FIAU belongs to a class of drugs that can interfere with viral replication, so it was considered a great candidate for treating virally induced infections such as hepatitis B.

As I wrote in my release about the new study:

“FIAU was supposed to be a revolutionary drug,” Peltz said. “It looked very promising in preclinical tests. In phase 1, when the drug was administered to subjects for a short period of time, the human subjects seemed to do fairly well.” But the phase-2 trial was stopped after 13 weeks, when it became clear that FIAU was destroying patients’ livers.

In fact, nearly half the patients treated with FIAU in that trial died from complications of liver damage. Yet, before advancing to clinical trials FIAU had been tested for as long as six months in mice, rats, dogs and monkeys without any trace of toxicity. An investigation conducted by the National Academy of Sciences later determined that the drug had shown no signs of being dangerous during those rigorous preclinical toxicology tests.

In Peltz’s new study, though, FIAU caused unmistakable early signs of  severe liver toxicity in the bioengineered mice with human livers. This observation would have served as a bright red stop signal that would have prevented the drug from being administered to people.

Bonus item: Using bioengineered mice with human livers instead of mice with murine ones would no doubt result in the clinical and commercial success of some drugs that never got to the human-testing stage because they caused liver toxicity in mice.

Previously: Fortune teller: Mice with ‘humanized’ livers predict HCV drug candidate’s behavior in humans, Alchemy: From liposuction fluid to new liver cells and Immunology escapes from the mouse trap
Photo by erjkprunczyk

Addiction, FDA, Health Policy, Podcasts, Public Health

E-Cigarettes: The explosion of vaping is about to be regulated

E-Cigarettes: The explosion of vaping is about to be regulated

E-cigarettes are about to get zapped. To date, across the globe, they’ve been largely unregulated – and their growth since they first came on the scene in 2007 has been exponential. Now, in the first big regulatory action that is sure to spur similar responses across the pond, the European Parliament approved rules last week to ban e-cigarette advertising in the 28 EU member nations beginning in mid-2016.  The strong action also requires the products to carry graphic health warnings, be childproof and contain no more than 20 milligrams of nicotine per milliliter. It’s expected that the U.S. Food and Drug Administration will soon follow suit and the days of great independence for e-cigarettes will come to a crashing halt. A few U.S. cities, Los Angeles most recently, have banned e-cigarettes in public spaces.

e-cigUntil recently, I was completely ignorant about the whole phenomenon of e-cigarettes. What is the delivery system? Where are they manufactured? Are they a safe alternative to smoking? And how are they being marketed and to whom? Well here’s an eye opener: According to the Centers for Disease Control and Prevention, e-cigarette usage more than doubled among middle and high school students users from 2011 to 2012. Altogether, nearly 1.8 million middle and high school students nationwide use e-cigarettes.

Robert Jackler, MD, chair of otolaryngology at Stanford Medicine, has long studied the effects of tobacco advertising, marketing, and promotion through his center, SRITA (Stanford Research Into the Impact of Tobacco Advertising). After years of detailing how tobacco use became ubiquitous in the U.S. he’s now tracking the marketing of e-cigarettes, and what he’s found probably won’t surprise you. The same sales techniques that brought about the explosive growth of tobacco use are being deployed again to make e-cigarettes look sexy, cool and defiant.

While there are claims by the e-cigarette industry that e-cigarettes are important tools to help people kick the tobacco habit, there’s little evidence to date to back up that claim. And Jackler isn’t completely sold on the notion that e-cigarettes will bring about a great cessation of tobacco smoking; he sees them more as a continuity product. He told me:

What the industry would like to see you do is when you go to a place that you can’t smoke, that you pick up your e‑cigarette and you vape, and you get your nicotine dose in the airport when waiting, or when you’re in your workplace, or when you’re even in school, and that way, when you leave school or the workplace, you go back to the combustible tobacco products.

Sorry if I’m a bit cynical, but as an ex-smoker I find it hard to believe that Big Tobacco – which is increasingly getting into the e-cigarette business – doesn’t also see vaping as a way to continue to keep smokers smoking. Bubble gum flavors and packaging designed to resemble lipstick containers! Who’s really being targeted here?

After my 1:2:1 podcast (above) with Jackler, I’m convinced we’ve been down this road before and it wasn’t pretty health-wise. More than 16 million Americans suffer from a disease caused by smoking. Listen to the podcast and you be the  judge about the true intentions of those promoting e-cigarettes.

Previously: Stanford chair of otolaryngology discusses federal court’s ruling on graphic cigarette labelsWhat’s being done about the way tobacco companies market and manufacture products and Image of the Week: Vintage Christmas cigarette advertisement
Photo by lindsay-fox

FDA, Health Disparities, Sexual Health, Women's Health

Female sexual health expert responds to delay in approval for “Viagra for women”

Female sexual health expert responds to delay in approval for "Viagra for women"

As announced yesterday, Sprout Pharmaceuticals, manufacturer of flibanserin, dubbed a “female Viagra,” is appealing the Food and Drug Administration‘s decision requesting more information on the drug before approving it for use in the U.S. Leah Millheiser, MD, director of Stanford’s Female Sexual Medicine Program, writes an appeal of her own on her blog, DrLeahM.com, in response to the FDA’s delay.

From the post:

Many of us in the field of female sexual medicine felt that Flibanserin had the best shot at being the first FDA-approved “Viagra for Women” – the holy grail for women with persistent low sexual desire in whom other treatments have failed (relationship therapy, sex therapy, off-label medications,etc). With this latest rejection, I ask you to consider the following: 43% of women in the US compared to 31% of men suffer from a sexual function complaint. There are currently 2 drugs that are FDA-approved for female sexual dysfunction (both for the treatment of postmenopausal painful intercourse due to vaginal dryness) compared to over 10 FDA-approved treatments available to men.

Previously: Speaking up about female sexual dysfunctionYoung, single, dating – and a breast-cancer survivorAsk Stanford Med: Director of Female Sexual Medicine Program responds to questions on sexual health and Shining the spotlight on women’s sexual health

FDA, Parenting, Pediatrics

Be in the know when it comes to kids’ cold meds, FDA reminds parents

Be in the know when it comes to kids' cold meds, FDA reminds parents

Last week, my co-worker had to ask me if I was okay after hearing me sneeze and blow my nose every 15 minutes. I immediately chalked it up to allergies and took some antihistamines. The sneezing stopped, but for the next few days I still had a runny nose and developed a sore throat. So deciding it must be the sniffles and not seasonal allergies, I tried some cold meds this time around.

Because symptoms for a cold and allergies can be very similar, choosing which medication to take can be difficult and confusing. The U.S. Food and Drug Administration is stressing the importance of paying attention to the active ingredients in medications, especially when it comes to treating kids – as mixing drugs can cause adverse reactions or serious health complications. From an agency news release:

Many medicines have just one active ingredient. But combination medicines, such as those for allergy, cough, or fever and congestion, may have more than one.

Take antihistamines taken for allergies. “Too much antihistamine can cause sedation and—paradoxically—agitation. In rare cases, it can cause breathing problems, including decreased oxygen or increased carbon dioxide in the blood, Sachs says.

“We’re just starting allergy season,” says Sachs. “Many parents may be giving their children at least one product with an antihistamine in it.” Over-the-counter (OTC) antihistamines (with brand name examples) include diphenhydramine (Benadryl), chlorpheniramine (Chlor-Trimeton), clemastine (Tavist), fexofenadine (Allegra), loratadine (Claritin, Alavert), and cetirizine (Zyrtec).

But parents may also be treating their children for a separate ailment, such as a cough or cold. What they need to realize is that more than one combination medicine may be one too many.

“It’s important not to inadvertently give your child a double dose,” Sachs says.

Via HealthDay
Previously:
CDC launches campaign to reduce accidental drug overdoses among children and New ways to prevent drug overdoses in children
Photo by anjanettew

FDA, Public Health, Research

The importance of including risk information in ads for over-the-counter medications

Findings published today in the Journal of the American Medical Association show that when prescription medications become available over-the-counter, advertisements for the products are less likely to alert consumers to potential risks or side effects.

In the study (subscription required), Brigham and Women’s Hospital researcher Jeremy Greene, MD, PhD, and colleagues examined print and broadcast advertisements for four commonly used medications that were marketed to consumers as prescription drugs and later approved for over-the-counter sale. The advertisements ran for 24 months before and six months after the switch to over-the-counter. The researchers found that when drugs required a prescription, 70 percent of the advertisements mentioned potential risks and side effects. However, once drugs were available without a doctor’s signature, this figure dropped to 11 percent.

Greene discusses the findings in a Q&A on news@JAMA. He had the following to say about why risk information in advertisements is necessary for patients and how he hopes this study will be useful to physicians:

When the average consumer thinks about an OTC drug, they think this drug has to be safe or it wouldn’t be available without a prescription. But as any pharmacologist knows, there is no such thing as a safe drug. Our most potent cures can be poison if used improperly, and that is just as true for OTC drugs.

It is increasingly important to know all of the substances a patient is taking. We understand that the total amount of acetaminophen consumed can shift it from a safe medication to one of the leading causes of emergency department visits and liver failure. It’s important for us to know the landscape of promotion and how it influences consumers’ perceptions of medication risks.

Previously: Report shows over 60 percent of Americans don’t follow doctors’ orders in taking prescription meds and One label fits all? A universal schedule for prescription drugs
Photo by PinkMoose

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