Blocking a kinase known as CDK7 sets off a chain reaction that results in the death of prostate cancer cells that have spread and are resistant to standard therapies, according to a new study from researchers in the Abramson Cancer Center at the University of Pennsylvania. The team identified the role of CDK7 as the on/off switch that controls Med-1, a process that works in partnership with the androgen receptor to drive prostate cancer growth. Researchers show turning the switch off eventually leads to the death of cancer cells in mice. Cancer Discovery published the findings today.
Androgen deprivation therapy is a standard approach to treating prostate cancer, but over the course of treatment, a majority of patients will eventually become resistant to the therapy, allowing the cancer to grow and spread. This is referred to as metastatic castration-resistant prostate cancer (CRPC). There are two drugs approved by the U.S. Food and Drug Administration for these cases, but patients see little or no long-term survival benefit from these therapies.
Since the androgen receptor (AR) continues to be the main the driver of cancer growth in CRPC, taking away its function is still critical. Given the disease’s resistance to therapies that try to take on AR directly, a new approach is needed. While these cancers do not have additional mutations or other genetic overexpression, the Penn team was still able to identify a new target thanks to what researchers called “AR’s co-pilot.”
“We know that AR does not work alone; that it needs Med-1 as its partner,” said the study’s senior author Irfan A. Asangani, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania. “Our study found a way to turn off Med-1, leaving AR without its co-pilot which means the cancer cannot grow and the cells eventually die.”
Using an inhibitor to turn off CDK7 led to the death of CRPC cells in both the lab setting and in animal models. Researchers also saw very limited off-target effects of this approach, since healthy cells have redundancies in place to deal with the loss of Med-1, meaning only the cancer cells end up dying off.
“Our theory is that these cancer cells are addicted to Med-1 and AR but other cells are not, so we’re essentially cutting them off from their addiction,” Asangani said.
CDK7 inhibitors are already being tested in phase I clinical trials for other cancers — including leukemia, lung cancer, glioblastoma, and breast cancer — but Asangani said this study shows the rationale for testing them in CRPC.
Reyaz ur Rasool, Ramakrishnan Natesan, and Qu Deng are co-first authors on the study. Other Penn authors include Shweta Aras, Priti Lal, Samuel Sander Effron, Erick Mitchell-Velasquez, Jessica M. Posimo, Lauren E. Schwartz, Daniel J. Lee, and Donita C. Brady.
Reyaz Ur Rasool, Ramakrishnan Natesan, Qu Deng, Shweta Aras, Priti Lal, Samuel Sander Effron, Erick Mitchell-Velasquez, Jessica M Posimo, Shannon Carskadon, Sylvan C Baca, Mark M Pomerantz, Javed Siddiqui, Lauren E Schwartz, Daniel J Lee, Nallasivam Palanisamy, Goutham Narla, Robert B Den, Matthew L Freedman, Donita C. Brady, Irfan A Asangani. CDK7 inhibition suppresses Castration-Resistant Prostate Cancer through MED1 inactivation. Cancer Discovery, 2019; CD-19-0189 DOI: 10.1158/2159-8290.CD-19-0189
Illicit performance-enhancing steroids can cause the heart to thicken and reduce its ability to function, according to research presented today at ESC Congress 2019 together with the World Congress of Cardiology.(1)
Use of anabolic-androgenic steroids (AAS) has long been feared to have hazardous cardiovascular effects, but only recently has this been demonstrated in studies.
The study presented today examined the effects of long-term AAS use on left ventricular systolic function by assessing the size, thickness, mass and function of the heart in male weightlifters.
“Our study found that illicit steroid use is associated with a number of worrying effects on the heart. We demonstrated that AAS-using weightlifters have a thicker heart muscle and reduced ability to contract the ventricular chambers of the heart during a cardiac cycle,” said Rang Abdullah, a third-year medical student at the University of Oslo, Norway.
“Having a heart that doesn’t contract the way it should is associated with higher mortality,” he added.
The study is part of a large multidisciplinary study on AAS use, which includes studies on brain imaging, cognitive, psychological, and other cardiovascular functions.
Study authors recruited 100 male weightlifters – 58 with more than a year of cumulative AAS use and 42 who do not use steroids – with no difference in age or BMI between the two groups.
The size, thickness, mass and function of the heart were measured with echocardiography, which uses sound waves to monitor heart and valve function, and ejection fraction, which measures how much blood the left ventricle pumps out with each contraction.
AAS-using weightlifters had a thicker heart muscle – on average, a 2 mm thicker interventricular septum, which is the wall separating the lower chambers of the heart. The left ventricular posterior wall was also, on average, 1.2 mm thicker in the steroid group.
The steroid group also showed reduced ability to contract the ventricular chambers of the heart during a cardiac cycle. Both ejection fraction and ventricular global strain, a new method to assess systolic function, were decreased in AAS-exposed weightlifters as compared to the non-steroid group, 49% vs. 53%, on average, and -15.6% vs. -18.3%.
Abdullah said, surprisingly, only a minority of steroid users in the sample had experienced cardiovascular symptoms related to their AAS use.
“Continuous, long-term use of AAS might prove to be a ‘silent killer’ but it is too early to tell,” he said.
“There are many case-studies out there on AAS-using weightlifters who end up dead or hospitalised from a heart attack or life-threatening cardiac arrhythmias. This is why prospective observational trials on this subject are so desperately needed,” he concluded.
The hashtag for ESC Congress 2019 together with the World Congress of Cardiology is #ESCCongress
Funding: The Anabolic Androgenic Steroid Research Group study is funded by a grant from the South-Eastern Norway Regional Health Authority to project leader Astrid Bjørnebekk and through the research programme at the University of Oslo (Forskerlinjen).
Cigarette maker Philip Morris International Inc has suspended a global social media marketing campaign in response to Reuters inquiries into the company’s use of young online personalities to sell its new “heated tobacco” device, including a 21-year-old woman in Russia.
The company’s internal “marketing standards” prohibit it from promoting tobacco products with youth-oriented celebrities or “models who are or appear to be under the age of 25.”
The company told Reuters of the decision late Friday, saying it had launched an internal investigation into marketing posts and photographs that Reuters sent to the company for comment earlier this week.
They included a paid post plugging the tobacco product by social media “influencer” Alina Tapilina in Moscow – who listed her age as 21 on Instagram – alongside often seductive photos of herself drinking wine, swimming and posing with little clothing in luxurious settings.
“We have taken the decision to suspend all of our product-related digital influencer actions globally,” the company told Reuters. “Whilst the influencer in question is a legal age adult smoker, she is under 25 and our guidance called for influencers to be 25+ years of age. This was a clear breach of that guidance.”
“No laws were broken,” the company told Reuters. “However, we set high standards for ourselves and these facts do not excuse our failure to meet those standards in this instance.”
The company added: “We were deeply disappointed to discover this breach and are grateful that it was brought to our attention.”
The U.S. Food and Drug Administration (FDA) last month decided it would allow sales of the IQOS device in the United States after a two-year review process in which Philip Morris repeatedly assured the regulator that it would warn young people away from the product.
The FDA declined to comment Friday evening on Philip Morris’s decision to suspend the marketing campaign. The agency earlier said it would “keep a close watch on … how the company is marketing its products.”
While most of the social media influencers hired by Philip Morris overseas did not list their ages on Instagram, a Reuters review of the firm’s social media marketing of IQOS in Japan, Italy, Switzerland, Russia and Romania shows that Tapilina’s online persona was typical of what the company called its social media “ambassadors” for the device – rail-thin young women who revel in the high life.
The company did not directly respond to additional questions Friday night regarding the intended audience for its digital influencer campaigns.
Many of the messages contained the hashtag “#IQOSambassador,” tying them into a network of social media influencers that the international tobacco giant has relied on to brand the IQOS as a safer alternative to cigarettes and a sexy fashion accessory.
“I finally have the new IQOS 3, and I can confidently say yes to change … the level of harmful substances is on average about 90 percent lower than in smoke,” Tapilina wrote in an April post. “You haven’t yet switched to IQOS?”
One Romanian IQOS marketer is 25 years old, according to a separate actress biography, but did not list her age on Instagram. Tapilina and nine other IQOS marketers did not respond to requests for comment.
Philip Morris, in its statement to Reuters, said its suspension of the social marketing campaign is “concrete proof” of its “conviction to achieve a smoke-free world through socially responsible practices.”
Matthew Myers, president of The Campaign for Tobacco-Free Kids, had a different take upon hearing of the suspension Friday night. The advocacy group collected some of the IQOS marketing images reviewed by Reuters.
Philip Morris, he said, “is changing their behavior only when caught red-handed.”
The company, Myers said, has historically been “the single most successful across the globe in making cigarettes fashionable to young people.”
HAPPY VALENTINES DAY!
Over the past year, Philip Morris has increasingly publicized its “mission” to prevent young people from using tobacco products. Last month, it issued a release calling on “all tobacco and e-cigarette companies to do their part to guard against youth nicotine use.”
“Let me be clear: We at Philip Morris International do not, and will not, market or sell our products to youth,” CEO André Calantzopoulos said during a speech in Boston earlier this month. “For Philip Morris International, age matters.”
When Philip Morris submitted marketing plans with an FDA application for IQOS in 2017, its sample advertisements featured models appearing at least a decade older and wearing modest, professional clothes.
A sample advertisement submitted to the FDA by Philip Morris as part of its IQOS application
That application, which is still pending before the FDA, seeks approval to market the IQOS as less harmful than smoking and outlines company plans to ensure it doesn’t market the device to “non-intended audiences.” The device heats up but does not burn packages of ground-up tobacco, which resemble small cigarettes, to create a nicotine-filled aerosol.
In Japan, the intended audience for IQOS marketing includes the Instagram followers of Ayame Tachibana, a 27-year-old DJ and model. In one post, she shows off a Valentine’s Day message for the IQOS device, lovingly scrawled with multicolored pens.
“Happy Valentine IQOS. Love you sooo much!” reads the Instagram post from February.
Alina Eremia, a Romanian actress and singer, holds a gold-colored IQOS in front of a Christmas tree.
“My list of resolutions contains 95% fewer moments without a smile,” says Eremia, who is 25 according to her actress biography on multiple movie and celebrity information websites.
Philip Morris says the IQOS – an acronym for “I quit ordinary smoking” – contains up to 95 percent fewer toxic compounds than cigarettes.
Vlad Parvulescu, a manager for Eremia, confirmed she had been hired to promote IQOS and said she had been contacted by a Romanian public relations agency. He did not respond to additional questions about the financial arrangement.
Marketing deals between companies and social media influencers vary widely, according to industry experts. But typically a company will work through third-party public relations or advertising firms that have relationships with online personalities. Compensation typically ranges from $20 to $25,000 or more for each post.
Corporations have become increasingly sophisticated in how they approach their social media campaigns in the past two years, said Joe Gagliese, co-founder of Viral Nation, a marketing and talent agency that works with influencers.
He once had to explain the basic concept of an “influencer” in pitch meetings. Now, companies approach him with “tailor-made decision briefs saying, ‘this is exactly what we want.’”
Reuters reviewed dozens of social media posts featuring the IQOS device. Many included hashtags such as #IQOSAmbassador, #paidad, and #notriskfree, indicating that they are IQOS marketing posts.
Many of the Instagram influencers featuring the products had tens of thousands of followers, and a few had more than a million.
VIRAL CAMPAIGNS, BLURRED LINES
Devices such as IQOS and Juul hold potential as a way for cigarette smokers to transition to less harmful nicotine products, but some public health advocates worry the sleek new devices are addicting young people who would have never smoked cigarettes. Among traditional cigarette smokers, 90 percent start smoking before the age of 18, according to federal data.
Philip Morris said there have been “no reports” of “worrisome levels” of unintended use of IQOS.
As part of the FDA review process, Philip Morris pledged to market only to adult cigarette smokers once it begins selling IQOS this summer through a partnership with Altria Group Inc, which sells Marlboro cigarettes in the U.S. IQOS delivers about the same level of nicotine as a traditional cigarette.
Altria did not respond to requests for comment.
Social media marketing has become a flashpoint in the debate over regulation of tobacco products, particularly the newest generation of products such as the wildly popular Juul e-cigarettes.
Some of Juul’s early social media and YouTube marketing included images of attractive young people, particularly at a 2015 product launch party. Twitter images from that time on Juul’s official account featured sensual images of a young woman breathing out Juul vapor in a group, next to the slogan, “Share a #Juulmoment.”
Those early campaigns sparked an explosion of video and photo posts from young people showing themselves using the product at school or with friends, often under the hashtags #doit4juul or #juullife. Juul Labs Inc has since said it stopped using social media influencers and requires anyone in its ads to be a former cigarette smoker older than 35.
Juul Labs Inc said in a statement it recognizes that “some of our earliest marketing initiatives did not fully reflect the goal of our company,” which it describes as helping cigarette smokers transition to its products.
“As a young company, we learned from our experiences and instituted changes to help ensure that we are only reaching current adult smokers,” the company said.
CONDITIONAL APPROVAL
U.S. laws governing tobacco advertising – which is banned on radio and television – were drawn up long before social media and digital advertising became a dominant force in consumer marketing.
Although no current state or federal law restricts tobacco advertising on the Internet – including for e-cigarettes and devices such as IQOS – the FDA can use its authority over new devices to assert sweeping control over a company’s marketing.
As a condition for allowing the device to be sold, the FDA is requiring Philip Morris to provide detailed analyses of the age ranges of consumers it reaches through digital advertising. Philip Morris is also required to submit any new advertising campaigns, including digital and social media efforts, to the FDA at least 30 days before it plans to launch them.
Any paid influencers promoting the product also must disclose “any relationships between you and entities that create labeling for, advertise, market, and/or promote the products, on your behalf, or at your direction.”
Those rules aim to restrict youth access to tobacco marketing, the FDA said in a statement, “especially in shared digital properties such as social media sites.”
Making complete revascularization the routine goal of percutaneous coronary intervention (PCI) conferred a benefit in hard outcomes for ST-segment myocardial infarction (STEMI) patients with multivessel disease, according to the COMPLETE trial.
The first coprimary composite outcome of cardiovascular death or MI reached 7.8% over a median 3 years follow-up among those who had complete revascularization of all angiographically significant lesions, compared with 10.5% for peers getting culprit lesion-only stenting (HR 0.74, 95% CI 0.60-0.91, P=0.004).
Notably, this was driven by fewer MIs — there was still no reduction in cardiovascular death in particular, reported Shamir Mehta, MD, of the Population Health Research Institute at McMaster University and Hamilton Health Sciences in Hamilton, Ontario.
“COMPLETE is the first randomized trial to show that complete revascularization reduces hard cardiovascular events compared to culprit-lesion only PCI in patients with STEMI and multivessel coronary artery disease,” Mehta said in a statement.
Findings from the multinational randomized trial were presented here at the 2019 European Society of Cardiology (ESC) congress and simultaneously published in the New England Journal of Medicine.
Looking at the second coprimary endpoint — combined cardiovascular death, MI, or ischemia-driven revascularization — also handed complete revascularization the edge over culprit lesion-only PCI (8.9% vs 16.7%, HR 0.51, 95% CI 0.43-0.61, P<0.001).
And there were no difference in safety events between the complete- and incomplete-revascularization arms.
“Should the consistent lack of benefit with respect to all-cause mortality discourage the strategy of routine complete revascularization?” said Lars Køber, MD, and Thomas Engstrøm, MD, both of Rigshospitalet, University of Copenhagen, in an editorial that accompanied the publication.
“It appears to be appropriate to recommend complete revascularization for patients similar to those included in the COMPLETE trial,” they wrote. “We hope that the investigators will be able to obtain data from longer follow-up in order to evaluate whether the tendency toward a small reduction in all-cause mortality becomes significant over time.”
Complete revascularization was beneficial no matter if the non-culprit lesion PCI was done during the index hospitalization or weeks after discharge (up to 45 days), Mehta said during a press briefing. The benefit also became apparent over time, with continued divergence of the Kaplan-Meier curves.
Mehta’s group reported that “over a period of 3 years, the number needed to treat to prevent cardiovascular death or MI from occurring in 1 patient is 37 patients, and the number needed to treat to prevent cardiovascular death, MI, or ischemia-driven revascularization from occurring in 1 patient is 13 patients.”
Guidelines in the U.S. and Europe currently give class IIb recommendations for PCI in non-culprit lesions.
“This is an important study which confirms our prior knowledge and is consistent with current ESC guidelines,” commented Marco Valgimigli, MD, PhD, of Inselspital University Hospital in Bern, Switzerland. [MORE]
The Bristol-Myers Squibb-Pfizer Alliance today announced findings from NAXOS (EvaluatioN of ApiXaban in strOke and Systemic embolism prevention in patients with nonvalvular atrial fibrillation in the real-life setting in France), the largest real-world data analysis on oral anticoagulant (OAC) effectiveness and safety in Europe among patients with non-valvular atrial fibrillation (NVAF). NAXOS is a retrospective cohort analysis including nearly all patients in France aged 18 years or older with NVAF newly initiating one of the OACs between 2014 and 2016 (n=321,501). In this analysis, Eliquis® (apixaban) use was associated with a lower rate of major bleeding compared to a vitamin K antagonist (VKA) (hazard ratio [HR]: 0.49, 95% confidence interval [CI]: 0.46-0.52), rivaroxaban (HR: 0.63, 95% CI: 0.58-0.67) and dabigatran (HR: 0.85, 95% CI: 0.76-0.95). These data were featured as a late-breaking oral presentation at the European Society of Cardiology (ESC) Congress 2019 in Paris, France (Abstract 1362). Anticoagulants, including Eliquis, increase the risk of bleeding and can cause serious, potentially fatal bleeding. Please see important safety information below for Eliquis, including BOXED WARNINGS.
In this analysis, Eliquis was also associated with lower rates of stroke and systemic thromboembolic events compared to VKA (HR: 0.67, 95% CI: 0.62-0.72) and rates similar to rivaroxaban (HR: 0.97, 95% CI: 0.89-1.05) or dabigatran (HR: 0.92, 95% CI: 0.81-1.06). Eliquis was associated with a lower rate of all-cause mortality compared to VKA (HR: 0.56, 95% CI: 0.54-0.58) and rivaroxaban (HR: 0.89, 95% CI: 0.85-0.93) and rates similar to dabigatran (HR: 0.94, 95% CI: 0.87-1.01). It is important to note that there are no head-to-head clinical trials comparing non-vitamin K antagonist OACs.
‘The large-scale NAXOS retrospective observational analysis is significant because it included nearly the entire French population with NVAF and is the first nationwide analysis that has evaluated the effectiveness and safety of all available OACs in France,’ said Professor Philippe Gabriel Steg, M.D., FESC, FACC, Head of Cardiology Department at Hôpital Bichat, Assistance Publique-Hôpitaux de Paris and Professor at Université de Paris. ‘Being able to analyze data from routine clinical practice from a large patient population may help characterize the effectiveness and safety of available anticoagulants.’
Entresto (sacubitril/valsartan) reduced the composite of total (first and recurrent) heart failure hospitalizations and cardiovascular death although narrowly missed statistical significance (p = 0.059)[1]
Totality of evidence, including improvement in various measures of symptoms, quality of life, and renal function, suggests clinically important benefits in HFpEF[1]
Entresto was well tolerated and the overall safety profile was comparable to previous findings in HFrEF patients
AstraZeneca today announced detailed results from the landmark Phase III DAPA-HF trial that showed FARXIGA (dapagliflozin) on top of standard of care reduced both the incidence of cardiovascular (CV) death and the worsening of heart failure.
DAPA-HF is the first outcomes trial with an SGLT2 inhibitor investigating the treatment of heart failure in patients with reduced ejection fraction (HFrEF), with and without type 2 diabetes (T2D). FARXIGAis currently approved to improve glycemic control in patients with T2D.
Top-line results announced in August 2019 showed DAPA-HF met the primary endpoint. The detailed results of the trial presented today at the ESC Congress 2019 in Paris, France, showed FARXIGAreduced the composite of CV death or worsening of heart failure by 26% (p<0.0001) and showed a reduction in each of the individual components of the composite endpoint. FARXIGA is not indicated to reduce the risk of heart failure or CV death.
In analyzing each of the components of the primary composite endpoint, there was a 30% decrease (p<0.0001) in the risk of experiencing a first episode of worsening heart failure and an 18% decrease (p=0.0294) in the risk of dying from CV causes. The effect of FARXIGA on the primary composite endpoint was generally consistent across the key subgroups examined.
The trial results also showed a significant improvement in patient reported outcomes measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score and a nominally significant reduction in all-cause mortality by 17% (7.9 vs 9.5 patients with an event per 100 patient-years) in favor of FARXIGA.
The safety profile of FARXIGA in the DAPA-HF trial was consistent with the well-established safety profile of the medicine. The proportion of patients with volume depletion (7.5% vs 6.8%) and renal adverse events (6.5% vs 7.2%), which are commonly of concern when treating heart failure, were comparable to placebo. Major hypoglycemic events (0.2% vs 0.2%) were rare in both treatment groups.
FARXIGA is also being studied in patients with heart failure with preserved ejection fraction (HFpEF) in the DELIVER and DETERMINE (HFrEF and HFpEF) trials.
