A new study has shown that a small molecule inhibitor drug, with the unwieldy designation of PF05175157, originally developed to treat diabetes by Pfizer, may help in the treatment of breast cancer by blocking a key enzyme.
“Our research shows the preclinical, anti-cancer activity using PF05175157 may lead us to bring this drug back into the clinic to help treat patients with breast cancer,” said lead study author Julia Foldi, MD, PhD, a clinical fellow at Yale Cancer Center and Smilow Cancer Hospital. “More studies are needed, but our initial data looks very promising.”
Cancer cells are characterised by altered metabolism. In this study, the Yale team identified new metabolic vulnerabilities in cancer cells that are based on a loss of enzyme diversity. They found that an enzyme called acetyl-CoA-carboxylase-1 (ACC1), is critical for the survival of breast cancer cells. The ACC1 enzyme is the key initial step in fatty acid synthesis. Fatty acids are building blocks of the various types of lipids and fat that are the critical ingredients of cell membranes and play an important role in energy generation in cells. The team’s analysis demonstrated that blocking ACC1 using PF05175157 can inhibit the growth of breast cancer cells grown in mice and also in patient-derived cancer models.
“We are currently testing this drug in combination with other approved breast cancer drugs to see if it could improve their activity, with the hope to bring the most promising combinations to the clinic to help patients with breast cancer,” added Lajos Pusztai, MD, DPhil, Professor of Medicine (Medical Oncology), Director of Breast Cancer Translational Research at Yale Cancer Center, and senior author of the study.
Researchers have identified a new group of molecules with an antibacterial effect against many antibiotic-resistant bacteria. Since the properties of the molecules can easily be altered chemically, the hope is to develop new, effective antibiotics with few side effects. The study appears in PNAS.
Increasing antibiotic resistance is a great concern as few new antibiotics have been developed in the past 50 years.
Most antibiotics work by inhibiting the bacteria’s ability to form a protective cell wall, causing the bacteria to crack (cell lysis). Besides the well-known penicillin, which inhibits enzymes building up the wall, newer antibiotics such as daptomycin or the recently discovered teixobactin bind to a special molecule, lipid II. All bacteria need lipid II as a building block for the cell wall. Antibiotics that bind to Lipid II are usually very large and complex molecules and therefore more difficult to improve with chemical methods. These molecules are in addition mostly inactive against a group of problematic bacteria, which are surrounded by an additional layer, the outer membrane, that hinders penetration of these antibacterials.
“Lipid II is a very attractive target for new antibiotics. We have identified the first small antibacterial compounds that work by binding to this lipid molecule, and in our study, we found no resistant bacterial mutants, which is very promising,” says Birgitta Henriques Normark, professor at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and one of the article’s three corresponding authors.
For this study, published in PNAS, researchers tested a large number of chemical compounds for their ability to lyse pneumococci – the most common cause of community-acquired pneumonia. After a careful follow-up of active compounds from this screening, the researchers found that a group of molecules called THCz inhibits the formation of the cell wall of the bacterium by binding to lipid II. The molecules could also prevent the formation of the sugar capsule that pneumococci need to escape the immune system and to cause disease.
Small molecules offer several benefits, noted Fredrik Almqvist, professor at Umeå University and one of the corresponding authors: “The advantage of small molecules like these is that they are more easy to change chemically. We hope to be able to change THCz so that the antibacterial effect increases and any negative effects on human cells decrease.”
Laboratory work with THCz showed it has an antibacterial effect against many antibiotic-resistant bacteria, such as methicillin-resistant staphylococci (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant pneumococci (PNSP). An antibacterial effect was also found against gonococci, which causes gonorrhoea, and mycobacteria, bacteria that can cause severe diseases such as tuberculosis in humans. None of the bacteria managed to develop resistance to THCz in a laboratory environment.
“We will now also initiate attempts to change the THCz molecule, allowing it to penetrate the outer cell membrane found in some, especially intractable, multi-resistant bacteria,” says Tanja Schneider, professor at the Institute of Pharmaceutical Microbiology at the University of Bonn and one of the corresponding authors.
The end of a longstanding “therapeutic drought” in atopic dermatitis (AD) is in sight as improved understanding of the pathogenesis and pathophysiology has stoked development of multiple drug candidates, according to a leading expert in the field.
“We did have treatments like cyclosporine, that are not specific as we know, and they are not treatments we can give our patients for long-term disease control,” said Emma Guttman-Yassky, MD, of the Icahn School of Medicine at Mount Sinai, during the Inflammatory Skin Diseases Summit.
She said that overcoming this drought was not easy, mostly because “we didn’t have enough understanding of the disease and its pathogenesis, really preventing therapeutic development for patients with atopic dermatitis,” she said.
New AD therapies built on the trail made for psoriasis treatment, starting with basic studies that produced insights into pathogenesis, leading to hypotheses that eventually could be tested in clinical trials, she said. Progress was accompanied by many failures in early stages of therapeutic development in psoriasis.
“One failure that I remember very vividly from psoriasis was the failure of interferon-gamma targeting,” Dr Guttman-Yassky recounted. “In atopic dermatitis, we also had our share of this type of failure, but these failures really helped shape therapeutic directions for all the diseases we are now targeting, including atopic dermatitis.”
This rocky development has led to recognition that AD is a complex disease involving multiple pathogenetic components, including barrier dysfunction, immune abnormalities, disruption of the dermal microbiome, and the peripheral and central nervous systems that play a central role in itch and other disease manifestations.
“Of all the major components involved in AD pathogenesis, immune targeting is the most tractable,” said Dr Guttman-Yassky. “Immune abnormalities are the most important because they perpetuate the disease phenotype of atopic dermatitis, from the nonlesional skin to acute disease and chronic lesions.”
In contrast to psoriasis, AD is a more heterogeneous disease with multiple clinical phenotypes that correlate with differences in immune polarisation and barrier dysfunction. All of the phenotypes exhibit activation of the type 2 inflammatory pathway as a common feature. Across the spectrum of clinical phenotypes, additional cytokine targeting may be required to achieve disease control.
Understanding that AD arises from systemic inflammation has also helped therapy development. Several studies have suggested that, compared to psoriasis, AD is associated with higher levels of immune activation. Blood samples of patients with AD have shown increased levels of activated T cells, circulatory cytokines, and cardiovascular markers. The accumulation of new insights into AD pathogenesis added no fewer than a dozen viable therapeutic candidates to the pipeline. Dupilumab (Dupixent) led the way in providing the proof of principle that Th2-specific targeting reverses key pathogenetic factors that drive the disease process in AD.
Dr Guttman-Yassky pointed out how targeting Th2 inflammation with dupilumab led to reversal of barrier defects and lichenisation typical of AD as early as 4 weeks, and that by 16 weeks lesional and nonlesional skin looked similar. Furthermore, markers of epidermal hyperplasia and proliferation were “completely wiped out.”
Dr Guttman-Yassky highlighted several key classes of AD drug candidates with potential to build on the success of targeting inflammation: Interleukin-13 inhibition, OX40 inhibition and JAK/STAT inhibition, which showed promising results.
“With these types of response rates, our treatment goals for our patients are evolving,” said Dr Guttman-Yassky.
Using a virus that grows in black-eyed pea plants, nanoengineers developed a new treatment that could keep metastatic cancers at bay from the lungs.
Not only did the treatment slow tumour growth in the lungs of mice with either metastatic breast cancer or melanoma, it also prevented or drastically minimised the spread of these cancers to the lungs of healthy mice that were challenged with the disease. The research was published in Advanced Science.
Researchers developed an experimental treatment that combats metastatic spread. This involves a plant virus called the cowpea mosaic virus, harmless to animals and humans, but which the body still registers as a foreign invader, thus triggering an immune response that could also boost the body’s cancer-fighting ability.
The idea is to use the plant virus to help the body’s immune system recognise and destroy cancer cells in the lungs. The virus itself is not infectious in our bodies, but it has all these danger signals that alarm immune cells to go into attack mode and search for a pathogen, said Nicole Steinmetz, professor of nanoengineering at the University of California San Diego.
To draw this immune response to lung tumours, Prof Steinmetz’s lab engineered nanoparticles made from the cowpea mosaic virus to target a protein in the lungs. The protein, called S100A9, is expressed and secreted by immune cells that help fight infection in the lungs. Overexpression of S100A9 has been observed to play a role in tumour growth and spread.
“For our immunotherapy to work in the setting of lung metastasis, we need to target our nanoparticles to the lung,” said Prof Steinmetz. “Therefore, we created these plant virus nanoparticles to home in on the lungs by making use of S100A9 as the target protein. Within the lung, the nanoparticles recruit immune cells so that the tumors don’t take.”
“Because these nanoparticles tend to localise in the lungs, they can change the tumor microenvironment there to become more adept at fighting off cancer — not just established tumors, but future tumors as well,” said Eric Chung, a bioengineering PhD student in Steinmetz’s lab who is one of the co-first authors on the paper.
To make the nanoparticles, the researchers infected black-eyed pea plants with cowpea mosaic virus, and harvested the virus in the form of ball-shaped nanoparticles. They then fixed S100A9-targeting molecules to the particles’ surfaces.
The researchers performed both prevention and treatment studies. In the prevention studies, they first injected the plant virus nanoparticles into the bloodstreams of healthy mice, and then later injected either triple negative breast cancer or melanoma cells into these mice. Treated mice showed a dramatic reduction in the cancers spreading to their lungs compared to untreated mice.
In the treatment studies, the researchers administered the nanoparticles to mice with metastatic tumours in their lungs. The treated mice exhibited smaller lung tumours and survived longer than untreated mice.
Prof Steinmetz envisions that the treatment could be useful after tumourectomy. “It wouldn’t be meant as an injection that’s given to everyone to prevent lung tumours. Rather, it would be given to patients who are at high risk of their tumors growing back as a metastatic disease, which often manifests in the lung. This would offer their lungs protection against cancer metastasis,” she said.
More detailed immunotoxicity and pharmacology studies are needed before this can progress to a treatment. Future studies will also explore combining this with standard cancer therapies such as chemotherapy.
Researchers have shown that the antiviral drug molnupiravir, currently in clinical trials as a COVID treatment, works by inducing mutations in SARS-CoV-2 which prevent the coronavirus from replicating further.
Since the onset of the corona pandemic, researchers have been developing various vaccines and drugs to varying degrees of success. Previous studies have shown why the antiviral drug remdesivir, the first one approved against COVID, has a rather weak effect on the virus. “Remdesivir does interfere with the [viral] polymerase while doing its work, but only after some delay. And the drug does not fully stop the enzyme,” said Max Planck Director Patrick Cramer.
Molnupiravir was originally developed to treat influenza and in preliminary clinical trials, the compound is promising against SARS-CoV-2. “Knowing that a new drug is working is important and good. However, it is equally important to understand how molnupiravir works at the molecular level in order to gain insights for further antiviral development,” explained Cramer. “According to our results, Molnupiravir acts in two phases.”
Induced RNA mutations halt replication Molnupiravir, an orally available drug, becomes activated through metabolisation in the body. When it enters the cell, it is converted into RNA-like building blocks. In the first phase, viral RNA polymerase incorporates the building blocks into the virus’ own RNA. However, unlike remdesivir, which merely slows the viral RNA polymerase, molnupiravir does not interfere with its copying functions. Instead, in the second phase, the RNA-like building blocks connect with the building blocks of the viral genetic material. “When the viral RNA then gets replicated to produce new viruses, it contains numerous errors, so-called mutations. As a result, the pathogen can no longer reproduce,” explained Florian Kabinger, a doctoral student in Cramer’s department. Molnupiravir also appears to do this for other viruses “The compound could potentially be used to treat a whole spectrum of viral diseases,” said Höbartner, a professor of chemistry at the University of Würzburg. “Molnupiravir has a lot of potential.” Currently, molnupiravir is in phase III studies, where it is being tested on a large number of patients and is being evaluated for safety. The US government has already secured 1.7 million doses, at a cost of US$1 billion. However, working out at a cost of nearly US$600 per dose, it will not be cheap.
Two new molecules that release tiny quantities of hydrogen sulfide have been found to prevent skin from ageing after being exposed to ultraviolet light found in sunlight. The study was published in Antioxidant and Redox Signalling.
For the study, the researchers exposed adult human skin cells and the skin of mice to ultraviolet radiation (UVA). UVA causes skin ageing by turning on collagenases, enzymes which eat away at the natural collagen, causing the skin to lose elasticity, sag and wrinkle. UVA also penetrates deeper into skin than the UV radiation that causes sunburns (UVB), and it also damages cellular DNA, leading to mutations that can contribute to some skin cancers. Typical sun creams sit on top of the skin and absorb UV radiation, but they do not penetrate the skin where the long-lasting damage occurs.
For deeper protection, the researchers came up with a new way to protect the deeper layers of skin using two compounds invented at the University of Exeter: AP39 and AP123. The compounds do not protect the skin in the same way traditional sun creams prevent sunburn, but instead penetrate the skin to correct how skin cells’ energy production and usage was turned off by UVA exposure. This then prevented the activation of skin-degrading collagenase enzymes.
The compounds used in this study were previously shown to have impressive effects in reducing skin inflammation and skin damage after burn injury and atopic dermatitis (eczema). In an anti-ageing context, they prevented human skin cells in test tube experiments from ageing, but this is the first time the effects of photo-ageing have been seen in animals.
The important observation noted was that the compounds only regulated energy production, PGC-1α and Nrf2 in skin that was exposed to UVA. This suggests a novel approach to treating skin that has already been damaged by UV radiation, and could potentially reverse, as well as limit, that damage.
While further research is needed, there could be medical as well as cosmetic implications from this work, where protecting skin from UV light is important. For example, not only premature skin ageing and skin cancers, but UV light allergies, solar urticaria and rare hereditary skin diseases such as xeroderma pigmentosum. The researchers are currently partway through testing newer and more potent molecules able to do the same task using newer approaches.
AstraZeneca announced that its type 1 interferon receptor antagonist anifrolumab (Saphnelo) has received approval from the US Food and Drug Administration for the treatment of moderate-to-severe systemic lupus erythematosus alongside standard therapy.
“This is wonderful, exciting news, and is great for the lupus community — patients, family members, and clinicians who treat patients,” said Richard Furie, MD, chief of rheumatology at Northwell Health in Great Neck, New York, in an interview.
Only belimumab (Benlysta) in 2011 and voclosporin (Lupkynis) for lupus nephritis a few months ago had been approved in the past decades. “And that represents 25 years of trying,” Dr Furie said.
Significant benefits were reported in 2016 in a phase IIb trial known as MUSE. In that trial, 62.6% of patients receiving 300 mg intravenous anifrolumab every 4 weeks had an SLE Responder Index score of 4 (SRI-4) plus a reduction in the steroid dose to less than 10 mg/day compared with only 17.6% of patients in the placebo group, which was a significant difference — the best lupus trial data so far, according to Dr Furie.
Two pivotal phase III trials, TULIP-1 and TULIP-2, followed, with conflicting results.
In TULIP-1, the primary endpoint of Systemic Lupus Erythematosus Responder Index (SRI-4) was not met. After a year, an SRI-4 response was seen in 36% of patients receiving anifrolumab and in 40% on placebo. Some secondary endpoints suggested benefits, including the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA).
In TULIP-2, patients were randomised 300 mg intravenous anifrolumab or placebo every 4 weeks for 48 weeks, with a BICLA response as the primary endpoint. After a year, 47.8% of patients in the anifrolumab group achieved a BICLA response compared with 31.5% of placebo patients.
“We were all shocked when TULIP-1 failed,” said Dr Furie, who is also a leading member of the Lupus Research Alliance’s Lupus Clinical Investigators Network. “But it didn’t really fail — it depends on how you define failure. It did not reach the primary endpoint, but on the other composite, BICLA, it was successful, as well as on a lot of the key secondary endpoints. The totality of the data, I think, is the key phrase,” he said.
“I think the two studies were more similar than dissimilar. You have to have an appreciation of how difficult it is doing clinical trials in lupus. For every one trial that has been successful, there have probably been 10 that were unsuccessful,” he said.
This was not the first time discordant results had been seen in lupus trials. “We also saw discordance between the BICLA and SRI in the ustekinumab phase II trial,” he noted.
Of 253 drugs approved via the FDA’s accelerated approval pathway, clinical effectiveness has been confirmed in 112, according to a new investigation by The BMJ.
Clinical reporter Elisabeth Mahase found that, as of the end of last year, 24 of those 112 drugs have been on the market for more than 5 years, and some have been on the market for more than 2 decades — often with a high price tag, according to.
Though the accelerated approval pathway allows drugs onto the market before efficacy has been established, the manufacturer has to perform confirmatory trials or else the approval will be rescinded.
However, Mahase noted that only 16 drugs authorised through the accelerated approval pathway have been withdrawn since its creation in 1992 . Most of those were shown to lack efficacy, but in some cases, confirmatory trials were simply never done. Celecoxib (Celebrex), for example, was given accelerated approval in 1999 for the treatment of familial adenomatous polyposis, a genetic disorder that carries a high risk of bowel cancer if untreated, remained on the market for about 12 years before the FDA asked Pfizer to voluntarily withdraw it for this specific indication because efficacy trials were never completed.
The BMJ asked the manufacturers of 24 drugs that have been on the market for more than 5 years if they had conducted phase IV trials. Six drugs had been withdrawn, approved, or postponed. Of the remaining 18 drugs, relevant trial information was provided for a third. Four manufacturers of those six drugs were recruiting participants, and two reported talking to the FDA about final trial design. Eleven companies representing 12 drugs did not respond.
FDA response
“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” an FDA spokesperson said in a statement provided to MedPage Today. “The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies.”
The FDA could choose to initiate proceedings to withdraw a drug’s approval should post-marketing trials show no benefit or not be performed in time, added the spokesperson.
“Because the FDA continues to use this pathway to accelerate access to drugs for serious and life-threatening diseases for which there is an unmet medical need, at any point in time there will be drugs that are not converted because the confirmatory trials are ongoing,” the spokesperson said.
“Despite the pathway’s good intentions to accelerate ‘the availability of drugs that treat serious diseases,’ experts are concerned that it is now being exploited, to the detriment of patients — who may be given a drug that offers little benefit and possible harm — and of taxpayers,” she continued.
Fixing the accelerated approval pathway
Concerns about the accelerated approval pathway include a lack of threats from the FDA to withdraw a drug should confirmatory trials not be done, the agency’s use of indirect (or surrogate) measures of clinical benefit in some cases, and the potential for drug manufacturers to take advantage of the pathway when it comes to actual measures of safety and effectiveness, Mahase wrote.
Nevertheless, experts still agree that the accelerated approval pathway is of benefit, she noted. Suggested changes to the pathway include planning or starting confirmatory trials as part of the approval as well as closer examination of surrogate measures.
A recent example is Biogen’s controversial Alzheimer’s disease treatment aducanumab (Aduhelm) received FDA approval via the process last month, which was based on the surrogate endpoint of reduction of amyloid-beta plaque in the brain.
The drug has attracted criticism since its recent fast-track approval, with critics pointing out that the drug has not been proven effective and its $56 000 annual price is unreasonable.
Journal information: Mahase E “FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway” BMJ 2021; DOI: 10.1136/bmj.n1898.
Neurologist Daniel Gibbs, MD, PhD, related his experiences of having been diagnosed with Alzheimer’s disease and taking part in clinical trials of possible treatments for it.
Dr Gibbs stumbled upon his diagnosis accidentally, when he and his wife tested their DNA to learn about their ancestry that he discovered he had two copies of the APOE4 allele, the most common genetic risk factor for Alzheimer’s disease.
Because he had an early diagnosis, Dr Gibbs has volunteered to participate in several Alzheimer’s clinical trials in recent years, including one for aducanumab, the controversial Alzheimer’s treatment the FDA is expected to decide upon in June.
During a trial of aducanumab, he developed a serious amyloid-related imaging abnormality (ARIA) involving both brain oedema and intracerebral haemorrhage, which he recovered from. Dr Gibbs went on to co-author a case report about the clinical course and treatment of his complication. In the wake of much controversy, aducanumab has today received FDA approval.
MedPage Today interviewed Dr Gibbs on his experiences and perspectives since his Alzheimer’s diagnosis.
Dr Gibbs said that “as a patient and as a neurologist” it is a coping mechanism which gives hime “a huge advantage” to be able to look at the disease through his two “masks”. “Looking at it from the neurologist scientist’s point of view is a lot less threatening and is intellectually very satisfying. I enjoy reading and writing about it,” he said.
Regarding his future, he said: “One of the messages I try to get across in the book is that you need to plan for the future while you are still cognitively intact, and make very clearly known what you want done when you’re unable to give instructions about your care. I’ve done that. My family knows, my doctor knows: I don’t want anything done if I can’t participate in making decisions.”
Dr Gibbs said he was excited to volunteer for the aducanumab study partly because of the way aducanumab was discovered; a reverse-engineered antibody found in cognitively normal aged people. Another reason was the more aggressive nature of the trial. He explained the meaning of “tattoo on my brain” alluded to in the title of his book, an adverse effect of the experimental drug.
“For me, a ‘tattoo on my brain’ has two forms. In the ARIA — the amyloid-related imaging abnormality complication I had from aducanumab — there was both leakage of fluid causing swelling in my brain and leakage of blood, microhaemorrhages. Those went away, as did the swelling in my brain, but they left behind this haemosiderin, this iron-containing pigment which is not dissimilar to tattoo ink, if you will.
“I haven’t had a recent MRI scan, but at least the last one I looked at a year or two ago still showed those little dots of hemosiderin. In a literal sense, that is the tattoo on my brain. In the figurative sense, the tattoo is a symbol of a kind of coming out of the closet and showing something that you’re not ashamed of.”
The book, he said, is about people with early disease and the children of people with Alzheimer’s disease because they’re at risk. The aim is to “loosen up the conversation” so that interventions such as lifestyle changes can take place.
He suspects that the first disease-modifying drugs will be effective in early stages, which are going to be really hard studies to do. Recruiting participants without cognitive impairment but the pathology of of Alzheimer’s disease is extremely difficult. Finally, he offered some advice on dealing with Alzheimer’s.
“What I would recommend is for everybody to start doing things that are good for them. A heart-healthy diet is good for you in so many ways. It’s hard to say that’s not a good idea, although we’re a country of hamburger-loving people. And exercise — I don’t know how you overcome that bar of convincing people if you want to be a healthy 70- or 80-year-old, you have to exercise and get a good diet. And good sleep.”
A clinical trial of olaparib has been shown to help keep certain early-stage, hard-to-treat breast cancers at bay after initial treatment in promising early findings.
The results were so promising they were published early, ahead of the American Society of Clinical Oncology’s annual meeting and published in the New England Journal of Medicine.
Olaparib, sold under the name Lynparza, was found to help breast cancer patients with harmful mutations have a longer disease-free survival after their cancers had been treated with standard surgery and chemotherapy.
It was studied in patients with BRCA1 and BRCA2 gene mutations, which can not only predispose people to breast cancer if they don’t work properly, but who did not have a gene flaw that can be targeted by the drug Herceptin.
Most patients in the study also had tumours not fuelled by oestrogen or progesterone. Triple negative breast cancers are not fuelled by these two hormones nor by the gene Herceptin targets.
The new study tested Lynparza in 1836 women and men with early-stage disease who were given the drug or placebo pills for one year after surgery and chemotherapy. About 82% of participants had triple-negative breast cancer.
Independent monitors advised releasing the results after observing clear benefit from Lynparza. After three years, 86% of patients on it were alive without cancer recurrence compared to 77% in the placebo group.
The results suggest more patients should get their tumours tested for BRCA mutations to help guide treatment decisions, said ASCO president Dr Lori Pierce, a cancer radiation specialist at the University of Michigan.
Serious side effects were rare, and other less serious side effects included anaemia, fatigue and blood cell count abnormalities.
Lynparza, which is marketed by AstraZeneca and Merck, is already sold in the United States and elsewhere for treating metastatic breast cancers and for treating certain cancers of the ovaries, prostate and pancreas. It costs roughly US$14 000 per month, though what patients pay out of pocket varies depending on income, insurance and other factors.
