Blocking a protein could help overcome cancer resistance to PARP inhibitors

 Researchers at the Francis Crick Institute have found that blocking a specific protein could increase tumour sensitivity to treatment with PARP inhibitors. Their work published in Science , suggests combining treatments could lead to improved therapy for patients with inheritable breast cancers.

Some cancers, including certain breast, ovarian and prostate tumours, are caused by a fault in the BRCA1 or BRCA2 genes, which are important for DNA repair. Treatment for these cancers has greatly improved thanks to the discovery of PARP inhibitors, drugs which capitalise on this weakness in the cancer as they block a back-up repair mechanism. This means the cancer cells cannot repair breaks in their DNA, which stops the tumour from growing.

However, in many cases, the cancer eventually develops resistance to this treatment and the tumour starts to regrow aggressively. Finding new ways to effectively kill cancer cells before this resistance develops, or re-sensitise them to treatment, is crucial to offer patients an improved chance of survival.

In their study, the research team used human cells to screen for proteins that affect their sensitivity to PARP inhibitor drugs. They found that blocking a protein, DNPH1, sensitised BRCA-defective cancer cells to treatment with the PARP inhibitor, leading to cell death in the laboratory.

Importantly, cells that had acquired resistance to the PARP inhibitor were killed when this protein was also blocked. And, as the combination did not affect healthy cells, this discovery suggests that DNPH1 is a promising target for future drug development.

Stephen West, lead author and group leader of the DNA Recombination and Repair Laboratory at the Crick says: "PARP inhibitors were a great breakthrough in the treatment of certain cancers, extending the lives of many people. However, patients have to take these drugs for the rest of their lives which sadly gives most tumours time to mutate and eventually develop resistance.

"We want to improve treatments for these patients by finding a way to strengthen PARP inhibitors so they completely kill the cancer. While more work needs to be done, in the lab and then in clinical trials, we've found a really promising potential treatment combination."

In further experiments, the researchers characterised the role of the DNPH1 protein. It acts as a 'scavenger', removing faulty nucleotides from the pool of nucleotides which are used to build DNA. Without this process, this nucleotide 'junk' is incorporated into strands of DNA. The incorporation of faulty nucleotides is the key determinant that makes the cells more susceptible to the effects of PARP inhibitors.

Kasper Fugger, lead author and postdoc in the DNA Recombination and Repair Laboratory at the Crick says: "By investigating the function of DNPH1 and finding the molecules it interacts with, we have a good understanding of how the protein works in cells. This knowledge should help us to more effectively kill cancer cells by developing an inhibitor drug, which is specific enough to be used safely in people."

The researchers are now collaborating with pharmaceutical companies to develop an inhibitor of the DNPH1 protein which, if shown to be safe and effective in clinical trials, could be used alongside PARP inhibitors as a cancer treatment.

The topic of DNA repair in cancer was the focus of a virtual conference, Medicine at the Crick, held in February. The event was part of a series which showcases major advances in biomedical science and brings together lab-based scientists together and clinicians to consider the potential impact on patient treatment.

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Materials provided by The Francis Crick Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Fugger, K. et al. Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors. Science, 2021 DOI: 10.1126/science.abb4542

https://www.sciencedaily.com/releases/2021/04/210408153641.htm

Leisure physical activity is linked with health benefits but work activity is not

 The first large study showing that leisure time physical activity and occupational physical activity have opposite, and independent, associations with cardiovascular disease risk and longevity is published today in European Heart Journal, a journal of the European Society of Cardiology (ESC).

"We adjusted for multiple factors in our analysis, indicating that the relationships were not explained by lifestyle, health conditions or socioeconomic status," said study author Professor Andreas Holtermann of the National Research Centre for the Working Environment, Copenhagen, Denmark.

The World Health Organization (WHO) recommends physical activity during both recreation and work to improve health.* Previous studies have suggested that occupational activity is related to an increased risk for heart disease and mortality but have been too small to fully explain whether this was due to the manual work or because employees had unhealthy lifestyles or low socioeconomic status (e.g. low level of education).

This study included 104,046 women and men aged 20-100 years from the Copenhagen General Population Study with baseline measurements in 2003-2014. Participants completed questionnaires about activity during leisure and employment and were categorised as low, moderate, high, or very high activity for each.

During a median follow-up of 10 years, there were 9,846 (9.5%) deaths from all causes and 7,913 (7.6%) major adverse cardiovascular events (MACE, defined as fatal and nonfatal myocardial infarction, fatal and non-fatal stroke, and other coronary death).

Compared to low leisure time physical activity, after adjustment for age, sex, lifestyle, health, and education, moderate, high, and very high activity were associated with 26%, 41%, and 40% reduced risks of early death, respectively. In contrast, compared to low work activity, high and very high activity were associated with 13% and 27% increased risks of death, respectively.

Similarly, after adjustments, compared to low leisure activity, moderate, high, and very high levels of leisure activity were associated with 14%, 23%, and 15% reduced risks of MACE, respectively. Compared to low work activity, high and very high levels were associated with 15% and 35% increased risks of MACE, respectively.

Professor Holtermann said: "Many people with manual jobs believe they get fit and healthy by their physical activity at work and therefore can relax when they get home. Unfortunately, our results suggest that this is not the case. And while these workers could benefit from leisure physical activity, after walking 10,000 steps while cleaning or standing seven hours in a production line, people tend to feel tired so that's a barrier."

While the study did not investigate the reasons for the opposite associations for occupational and leisure time physical activity, Professor Holtermann said: "A brisk 30-minute walk will benefit your health by raising your heart rate and improving your cardiorespiratory fitness, while work activity often does not sufficiently increase heart rate to improve fitness. In addition, work involving lifting for several hours a day increases blood pressure for many hours, which is linked with heart disease risk, while short bursts of intense physical activity during leisure raises blood pressure only briefly."

Professor Holtermann's vision is to re-organise occupational activity so that it mimics the beneficial aspects of leisure exercise. Several approaches are being piloted, such as rotating between workstations on a production line so that employees do a "healthy mixture" of sitting, standing, and lifting during a shift. In another study, childcare workers play games together with children, instead of observing, so that both get their heart rate up and increase fitness. "We are trying to vary the tasks, give recovery time, or raise heart rate so there is a fitness and health benefit," he said.

Professor Holtermann concluded: "Societies need adults with sufficient health and fitness to work longer since the retirement age is increasing. We need to find ways to make active work good for health."

Funding: This work was supported by the Capital Region of Copenhagen, Danish Heart Foundation, Danish Lung Association, Velux Foundation, and Lundbeck Foundation.

* WHO Guidelines on Physical Activity and Sedentary Behaviour. Geneva: World Health Organization; 2020.

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Materials provided by European Society of Cardiology. Note: Content may be edited for style and length.

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Journal Reference:

1. Andreas Holtermann, Peter Schnohr, Børge Grønne Nordestgaard, Jacob Louis Marott. The physical activity paradox in cardiovascular disease and all-cause mortality: the contemporary Copenhagen General Population Study with 104 046 adults. European Heart Journal, 2021; DOI: 10.1093/eurheartj/ehab087

https://www.sciencedaily.com/releases/2021/04/210408212952.htm

Brazil at high risk of dengue outbreaks after droughts due to temporary water storage

 Dengue risk is exacerbated in highly populated areas of Brazil after extreme drought because of improvised water containers housing mosquitoes, suggests a new study in Lancet Planetary Health.

The research was led by the London School of Hygiene & Tropical Medicine's (LSHTM) Centre on Climate Change & Planetary Health and Centre for the Mathematical Modelling of Infectious Diseases. Using advanced statistical modelling techniques, the team predicted the timing and intensity of dengue risk in Brazil from extreme weather patterns.

The risk of dengue was high in urban areas three to five months after extreme drought. Extremely wet conditions increased dengue risk in the same month and up to three months later. In rural areas, dengue risk was more readily associated with very wet conditions.

Dengue fever is caused by a virus carried by mosquitoes and is considered one of the top ten threats to global health. Brazil has the greatest number of dengue cases in the world, reporting more than two million cases of dengue in 2019 alone.

Increasing levels of severe droughts and flooding episodes due to climate change has led to interruptions in water supply networks in Brazil. The improvised water storage containers used to combat this have become breeding grounds for mosquitoes.

Dr Rachel Lowe from LSHTM who led the study, said: "The dengue situation in Brazil is extremely concerning. Our work highlights that risk is not only related to extreme weather, but also linked to water management systems and human behaviour in densely populated urban areas."

In Brazil, large dengue outbreaks are typically observed after wet and warm periods and most interventions are targeted at these times. No studies have previously determined exact timeframes for dengue outbreaks following extreme weather events like droughts and floods across a large and diverse geographical area, although this work confirms initial findings from Barbados.

In this new study, the team combined dengue case data in 558 regions of Brazil between January 2001 and 2019, with information on droughts and wet conditions to assess the dengue risk differences in urban and rural areas.

The results suggest dengue interventions should be timed appropriately in poorly serviced urban areas and not only implemented during the wet and warm season.

In the short term, these include eliminating breeding sites around the home to prevent additional mosquito larval habitats during drought periods. During wet periods, outdoor water storage containers should be well covered and maintained, and discarded waste should be cleared to avoid collecting water.

Dr Lowe said: "It's imperative that governments invest in local infrastructure to ensure permanent water supply and promote better environmental hygiene in areas prone to epidemics of mosquito-borne diseases."

The study carries some limitations as the dengue data was obtained from the passive surveillance system, where only a fraction of cases are laboratory confirmed and mild or asymptomatic cases are not accounted for.

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Story Source:

Materials provided by London School of Hygiene & Tropical Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Rachel Lowe, Sophie A Lee, Kathleen M O'Reilly, Oliver J Brady, Leonardo Bastos, Gabriel Carrasco-Escobar, Rafael de Castro Catão, Felipe J Colón-González, Christovam Barcellos, Marilia Sá Carvalho, Marta Blangiardo, Håvard Rue, Antonio Gasparrini. Combined effects of hydrometeorological hazards and urbanisation on dengue risk in Brazil: a spatiotemporal modelling study. The Lancet Planetary Health, 2021; 5 (4): e209 DOI: 10.1016/S2542-5196(20)30292-8

https://www.sciencedaily.com/releases/2021/04/210408212957.htm

Toward reliable oral treatment for sickle cell disease

For the millions of people worldwide who have sickle cell disease, there are only a few treatment options, which include risky bone marrow transplants, gene therapy or other treatments that address a subset of symptoms. Today, researchers will describe the discovery of a small molecule with the potential to address the root cause of sickle cell disease by boosting levels of fetal hemoglobin, a healthy form that adults normally do not make. The drug could be formulated into a convenient daily tablet.

The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). ACS Spring 2021 is being held online April 5-30. 

"Using our proprietary small molecule probe and CRISPR guide RNA libraries, we screened a disease-relevant cell model that allowed us to pinpoint a treatment target," says Ivan V. Efremov, Ph.D., senior director, head of medicinal chemistry of Fulcrum Therapeutics, who is presenting the work.

Sickle cell disease occurs when the gene responsible for instructing cells to produce two of hemoglobin's four proteins contains an error. The mutation causes hemoglobin to adopt a rigid, sickle-like shape, which results in reduced oxygen transport throughout the body. The irregularly shaped cells get stuck in the blood vessels, causing painful episodes known as vaso-occlusive crises. The cells also die much sooner than normal red blood cells, leading to anemia. In addition to these symptoms, patients are at high risk of developing stroke, heart disease, kidney failure and other life-threatening conditions.

Interestingly, sickle cell patients don't begin life with malfunctioning hemoglobin. While in the womb, humans make "fetal" hemoglobin that carries oxygen normally. Three or four months after birth, however, cells stop expressing fetal hemoglobin and switch to an adult version. The adult hemoglobin expressed by sickle cell patients is defective, but they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin.

Patients that have what is called a hereditary persistence of fetal hemoglobin tap this resource automatically. "They have the sickle cell mutation, but additional mutations result in continued expression of fetal hemoglobin into adulthood," says Christopher Moxham, Ph.D., chief scientific officer of Fulcrum Therapeutics. With fetal hemoglobin levels around 25-30%, he says, enough red blood cell function is restored so that these patients may become asymptomatic.

The team developed a drug, called FTX-6058, that mimics the effect seen in patients with the hereditary persistence of fetal hemoglobin, as demonstrated in human-derived cell assay systems and mouse models. The drug attaches to a protein inside bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression. "What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution," Efremov says. "If some red blood cells did not express this, they could still sickle and cause disease symptoms." Fulcrum began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments showed an increase in fetal hemoglobin levels to around 25-30%.

"What distinguishes FTX-6058 is that we are targeting the root cause of sickle cell disease," Moxham says. "Other drugs approved in this space, particularly since 2019, are treating the disease's symptoms, either the anemia or the vaso-occlusive crises." Preclinical experiments comparing FTX-6058 with another fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment and, according to Moxham, offers the potential for a transformative therapy.

The team is currently designing a phase 2 clinical trial for people living with sickle cell disease that they plan to initiate by the end of 2021. They are also in the process of characterizing the therapeutic molecule further, using genomic technologies and additional cell assay systems to fill in the details of exactly how it works. Beyond sickle cell disease, Fulcrum is also considering a clinical strategy to explore the use of FTX-6058 in people living with ?-thalassemia, a blood disorder in which hemoglobin production is reduced.

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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

https://www.sciencedaily.com/releases/2021/04/210409093609.htm

Materials developed for oral delivery of insulin

 A revolutionary technology developed within the Trabolsi Research Group at NYU Abu Dhabi (NYUAD) could dramatically improve the well-being of diabetic patients through a simple and straightforward way: an insulin oral delivery system that could replace traditional subcutaneous injections without the side effects caused by frequent injection.

Using prepared layers of nanosheets with insulin loaded in between layers to protect it, researchers developed gastro-resistant imine-linked-covalent organic framework nanoparticles (nCOFs) that exhibited insulin protection in the stomach as well in diabetic test subjects whose sugar levels completely returned to normal within two hours after swallowing the nanoparticles. Led by NYUAD's Research Scientist Farah Benyettou and Program Head of Chemistry Ali Trabolsi, the findings were published today in Chemical Science.

Compared to the two FDA-approved technologies for the oral delivery of insulin, the system developed at NYUAD is biocompatible, highly stable in the stomach, specific, and able to deliver the right amount of insulin based on the diabetic subject's blood sugar levels. This treatment represents a step forward in treating this disease that is the seventh leading cause of death worldwide.

"Our work overcomes insulin oral delivery barriers by using insulin-loaded nCOF nanoparticles which exhibit insulin protection in the stomach as well as a glucose-responsive release," said Benyettou. "This technology responds quickly to an elevation in blood sugar, but would promptly shut off to prevent insulin overdose and will dramatically improve the well-being of diabetic patients across the UAE and worldwide," she added.

The development of this treatment was in collaboration with an international team of researchers from Algeria, Spain, Saudi Arabia, and the United Kingdom. The project was completed with the help of NYUAD's Core Platform Technology. A US patent application is pending for this innovative technology.

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Story Source:

Materials provided by New York University. Note: Content may be edited for style and length.

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Journal Reference:

1. Farah Benyettou, Nawel Kaddour, Thirumurugan Prakasam, Gobinda Das, Sudhir Kumar Sharma, Sneha Ann Thomas, Fadia Bekhti-Sari, Jamie Whelan, Mohammed A. Alkhalifah, Mostafa Khair, Hassan Traboulsi, Renu Pasricha, Ramesh Jagannathan, Nassima Mokhtari-Soulimane, Felipe Gándara, Ali Trabolsi. In vivo oral insulin delivery via covalent organic frameworks. Chemical Science, 2021; DOI: 10.1039/D0SC05328G

https://www.sciencedaily.com/releases/2021/04/210406084048.htm

Metabolic changes in fat tissue in obesity tied to adverse health effects

 Researchers at the Obesity Research Unit of the University of Helsinki have found that obesity clearly reduces mitochondrial gene expression in fat tissue, or adipose tissue. Mitochondria are important cellular powerplants which process all of our energy intake. If the pathways associated with breaking down nutrients are lazy, the changes can often have health-related consequences.

A total of 49 pairs of identical twins discordant for body weight participated in the study conducted at the University of Helsinki: their body composition and metabolism were studied in detail, and biopsies from adipose and muscle tissue were collected. Multiple techniques for analysing the genome-wide gene expression, the proteome and the metabolome were used in the study.

The study was recently published in the journal Cell Reports Medicine.

According to the findings, the pathways responsible for mitochondrial metabolism in adipose tissue were greatly reduced by obesity. Since mitochondria are key to cellular energy production, their reduced function can maintain obesity. For the first time, the study also compared the effects of obesity specifically on the mitochondria in muscle tissue in these identical twin pairs: muscle mitochondria too were found to be out of tune, but the change was less distinct than in adipose tissue.

The study provided strong evidence of a connection between the low performance of adipose tissue mitochondria and a proinflammatory state. Furthermore, the findings indicate that metabolic changes in adipose tissue are associated with increased accumulation of fat in the liver, prediabetic disorders of glucose and insulin metabolism as well as cholesterol.

"If mitochondria, the cellular powerplants, are compared to the engine of a car, you could say that the power output decreases as weight increases. A low-powered mitochondrial engine may also generate toxic exhaust fumes, which can cause a proinflammatory state in adipose tissue and, consequently, the onset of diseases associated with obesity," says Professor Kirsi Pietiläinen from the Obesity Research Unit, University of Helsinki.

"What was surprising was that the mitochondrial pathways in muscle had no association with these adverse health effects," Pietiläinen adds.

Obesity also affected amino acid metabolism

In the study, changes in mitochondrial function were also seen in amino acid metabolism. The metabolism of branched-chain amino acids, which are essential to humans, was weakened in the mitochondria of both adipose tissue and muscle tissue.

"This finding was of particular significance because the reduced breakdown of these amino acids and the resulting heightened concentration in blood have also been directly linked with prediabetic changes and the accumulation of liver fat in prior twin studies," says Pietiläinen.

Obesity, with its numerous associated diseases, is a common phenomenon that is continuously increasing in prevalence. While lifestyle influence the onset of obesity, genes also have a significant role.

"Identical twins have the same genes, and their weight is usually fairly similar. In fact, studying twins is the best way to investigate the interplay between genes and lifestyle. In spite of their identical genome, the genes and even mitochondria of twins can function on different activity levels. We utilised this characteristic in our study when looking into the effects of weight on tissue function," Pietiläinen says.

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Story Source:

Materials provided by University of Helsinki. Note: Content may be edited for style and length.

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Journal Reference:

1. Birgitta W. van der Kolk, Sina Saari, Alen Lovric, Muhammad Arif, Marcus Alvarez, Arthur Ko, Zong Miao, Navid Sahebekhtiari, Maheswary Muniandy, Sini Heinonen, Ali Oghabian, Riikka Jokinen, Sakari Jukarainen, Antti Hakkarainen, Jesper Lundbom, Juho Kuula, Per-Henrik Groop, Taru Tukiainen, Nina Lundbom, Aila Rissanen, Jaakko Kaprio, Evan G. Williams, Nicola Zamboni, Adil Mardinoglu, Päivi Pajukanta, Kirsi H. Pietiläinen. Molecular pathways behind acquired obesity: adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI. Cell Reports Medicine, 2021; 100226 DOI: 10.1016/j.xcrm.2021.100226

https://www.sciencedaily.com/releases/2021/04/210409104457.htm

Aptevo: AACR sessions detail T-cell, immunity benefits of candidates

 Aptevo Therapeutics Inc. (NASDAQ: APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIR^TM and ADAPTIR-FLEX^TM platform technologies, today announced that it will present two new posters at the American Association for Cancer Research Virtual Annual Meeting, to be held in two virtual sessions - Saturday, April 10^th to Thursday, April 15^th, 2021 and Monday, May 17^th to Friday, May 21^st, 2021.

The posters will provide preclinical updates on APVO603 and Aptevo's newest pipeline candidate, APVO442.

Title: APVO603: A Dual 4-1BB and OX40 bispecific approach utilizing ADAPTIR technology designed to deliver a conditional T cell/NK response against solid tumors (LB173)

Summary: The data to be presented will highlight the potential benefits of dual targeting of 4-1BB and OX40 by APVO603. In vitro data includes demonstration of APVO603's ability to reduce or reverse the negative effects of T-cell exhaustion and suppressive immune responses by augmenting cytokine production and reducing markers of T-cell exhaustion following repeat stimulation. In preclinical in vivo studies, APVO603 therapy induced a dose-dependent anti-tumor response and significantly increased the survival of mice in a murine bladder cancer model. A non-GLP NHP PK/Tox study was completed and it was found that APVO603 had a favorable safety profile without liver toxicity and a PK profile that supports clinical dosing. CMC activities are in progress and IND-enabling studies are underway to progress the program towards clinical development.

Title: APVO442: A bispecific T cell-engaging candidate utilizing the ADAPTIR-FLEX platform technology with unique properties designed to optimize drug tumor distribution and cytotoxic response against PSMA-expressing solid tumors

Summary: The data to be presented will highlight the unique properties of APVO442, Aptevo's first molecule utilizing our ADAPTIR-FLEX technology, designed with low affinity, monovalent targeting of CD3 and high affinity, bivalent targeting of PSMA to potentially reduce safety signals and improve efficacy for treatment of a solid tumor. In vitro, APVO442 retains strong binding to tumor cell lines with a range of (high to low) surface PSMA expression, and demonstrates reduced binding to CD3+ T cell lines when compared to higher affinity CD3 binding molecules. In vitro efficacy studies show that, despite lower CD3 binding affinity, APVO442 elicits equivalent T-cell activation, proliferation, and cytotoxicity against PSMA+ tumor cells, while limiting cytokine release, when compared to higher affinity CD3 engaging molecules. In vivo, APVO442 demonstrated a dose-dependent ability to limit tumor burden at responses comparable to a high affinity T-cell engager response in a murine xenograft PSMA+ prostate cancer model. APV0442 retains key manufacturability characteristics of the ADAPTIR platform and preclinical data to support the potential for a beneficial safety and efficacy profile. Continued pre-clinical evaluation and CMC efforts are ongoing to progress APVO442 toward clinical development.

Details of the e-Poster Presentations: The abstracts and the accompanying e-posters will be available in the Virtual Poster Hall to registered attendees from 8:30 am EST on Saturday, April 10^th, 2021, until the Virtual Poster Hall closes on Monday June 21^st, 2021. Chat and live meeting requests will be available for questions and discussion with the presenters. Details can be found on the AACR abstract website and will also be posted on the Aptevo Therapeutics website.

https://www.streetinsider.com/Accesswire/Aptevo+Therapeutics+to+Present+at+the+American+Association+for+Cancer+Research+Virtual+Annual+Meeting/18243637.html