Johns Hopkins Medicine researchers have added to evidence that a gene responsible for turning off a cells natural suicide signals may also be the culprit in making breast cancer and melanoma cells resistant to therapies that use the immune system to fight cancer. A summary of the research, conducted with mice and human cells, appeared in Cell Reports.When the gene, called BIRC2, is sent into overdrive, it makes too much, or an overexpression, of protein levels. This occurs in about 40% of breast cancers, particularly the more lethal type called triple negative, and it is not known how often the gene is overexpressed in melanomas.

If further studies affirm and refine the new findings, the researchers say, BIRC2 overexpression could be a key marker for immunotherapy resistance, further advancing precision medicine efforts in this area of cancer treatment. A marker of this kind could alert clinicians to the potential need for using drugs that block the genes activity in combination with immunotherapy drugs to form a potent cocktail to kill cancer in some treatment-resistant patients. Cancer cells use many pathways to evade the immune system, so our goal is to find additional drugs in our toolbox to complement the immunotherapy drugs currently in use, says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Genetic Medicine, Pediatrics, Oncology, Medicine, Radiation Oncology and Biological Chemistry at the Johns Hopkins University School of Medicine, and director of the Vascular Program at the Johns Hopkins Institute for Cell Engineering.

Semenza shared the 2019 Nobel Prize in Physiology or Medicine for the discovery of the gene that guides how cells adapt to low oxygen levels, a condition called hypoxia.

In 2018, Semenzas team showed that hypoxia essentially molds cancer cells into survival machines. Hypoxia prompts cancer cells to turn on three genes to help them evade the immune system by inactivating either the identification system or the eat me signal on immune cells. A cell surface protein called CD47 is the only dont eat me signal that blocks killing of cancer cells by immune cells called macrophages. Other cell surface proteins, PDL1 and CD73, block killing of cancer cells by immune cells called T lymphocytes.

These super-survivor cancer cells could explain, in part, Semenza says, why only 20% to 30% of cancer patients respond to drugs that boost the immune systems ability to target cancer cells.

For the current study, building on his basic science discoveries, Semenza and his team sorted through 325 human genes identified by researchers at the Dana Farber Cancer Institute in Boston whose protein products were overexpressed in melanoma cells and linked to processes that help cancer cells evade the immune system.

Semenzas team found that 38 of the genes are influenced by the transcription factor HIF-1, which regulates how cells adapt to hypoxia; among the 38 was BIRC2 (baculoviral IAP repeat-containing 2), already known to prevent cell suicide, or apoptosis, in essence a form of programmed cell death that is a brake on the kind of unchecked cell growth characteristic of cancer.

BIRC2 also blocks cells from secreting proteins that attract immune cells, such as T-cells and natural killer cells.

First, by studying the BIRC2 genome in human breast cancer cells, Semenzas team found that hypoxia proteins HIF1 and HIF2 bind directly to a portion of the BIRC2 gene under low oxygen conditions, identifying a direct mechanism for boosting the BIRC2 genes protein production.

Then, the research team examined how tumors developed in mice when they were injected with human breast cancer or melanoma cells genetically engineered to contain little or no BIRC2 gene expression. In mice injected with cancer cells lacking BIRC2 expression, tumors took longer to form, about three to four weeks, compared with the typical two weeks it takes to form tumors in mice.

The tumors formed by BIRC2-free cancer cells also had up to five times the level of a protein called CXCL9, the substance that attracts immune system T-cells and natural killer cells to the tumor location. The longer the tumor took to form, the more T-cells and natural killer cells were found inside the tumor.

Semenza notes that finding a plentiful number of immune cells within a tumor is a key indicator of immunotherapy success.

Next, to determine whether the immune system was critical to the stalled tumor growth they saw, Semenzas team injected the BIRC2-free melanoma and breast cancer cells into mice bred to have no functioning immune system. They found that tumors grew at the same rate, in about two weeks, as typical tumors. This suggests that the decreased tumor growth rate associated with loss of BIRC2 is dependent on recruiting T-cells and natural killer cells into the tumor, says Semenza.

Finally, Semenza and his team analyzed mice implanted with human breast cancer or melanoma tumors that either produced BIRC2 or were engineered to lack BIRC2. They gave the mice with melanoma tumors two types of immunotherapy FDA-approved for human use, and treated mice with breast tumors with one of the immunotherapy drugs. In both tumor types, the immunotherapy drugs were effective only against the tumors that lacked BIRC2.

Experimental drugs called SMAC mimetics that inactivate BIRC2 and other anti-cell suicide proteins are currently in clinical trials for certain types of cancers, but Semenza says that the drugs have not been very effective when used on their own.

These drugs might be very useful to improve the response to immunotherapy drugs in people with tumors that have high BIRC2 levels, says Semenza.Reference: Samanta D, Huang TYT, Shah R, Yang Y, Pan F, Semenza GL. BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy. Cell Rep. 2020;32(8). doi:10.1016/j.celrep.2020.108073

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Excerpt from:

Cell Suicide Gene Further Linked to Immunotherapy Response - Technology Networks

Visit the News Hub

Gene in fruit flies, worms, zebrafish, mice and people may help explain some fertility issues

Researchers at Washington University School of Medicine in St. Louis have identified a gene that plays an important role in fertility across multiple species. Pictured is a normal fruit fly ovary (left) and a fruit fly ovary with this gene dialed down (right). Male and female animals missing this gene had substantially defective reproductive organs. The study could have implications for understanding human infertility and early menopause.

A new study from Washington University School of Medicine in St. Louis identifies a specific genes previously unknown role in fertility. When the gene is missing in fruit flies, roundworms, zebrafish and mice, the animals are infertile or lose their fertility unusually early but appear otherwise healthy. Analyzing genetic data in people, the researchers found an association between mutations in this gene and early menopause.

The study appears Aug. 28 in the journal Science Advances.

The human gene called nuclear envelope membrane protein 1 (NEMP1) is not widely studied. In animals, mutations in the equivalent gene had been linked to impaired eye development in frogs.

The researchers who made the new discovery were not trying to study fertility at all. Rather, they were using genetic techniques to find genes involved with eye development in the early embryos of fruit flies.

We blocked some gene expression in fruit flies but found that their eyes were fine, said senior author Helen McNeill, PhD, the Larry J. Shapiro and Carol-Ann Uetake-Shapiro Professor and a BJC Investigator at the School of Medicine. So, we started trying to figure out what other problems these animals might have. They appeared healthy, but to our surprise, it turned out they were completely sterile. We found they had substantially defective reproductive organs.

Though it varied a bit by species, males and females both had fertility problems when missing this gene. And in females, the researchers found that the envelope that contains the eggs nucleus the vital compartment that holds half of an organisms chromosomes looked like a floppy balloon.

This gene is expressed throughout the body, but we didnt see this floppy balloon structure in the nuclei of any other cells, said McNeill, also a professor of developmental biology. That was a hint wed stumbled across a gene that has a specific role in fertility. We saw the impact first in flies, but we knew the proteins are shared across species. With a group of wonderful collaborators, we also knocked this gene out in worms, zebrafish and mice. Its so exciting to see that this protein that is present in many cells throughout the body has such a specific role in fertility. Its not a huge leap to suspect it has a role in people as well.

To study this floppy balloon-like nuclear envelope, the researchers used a technique called atomic force microscopy to poke a needle into the cells, first penetrating the outer membrane and then the nucleuss membrane. The amount of force required to penetrate the membranes gives scientists a measure of their stiffness. While the outer membrane was of normal stiffness, the nucleuss membrane was much softer.

Its interesting to ask whether stiffness of the nuclear envelope of the egg is also important for fertility in people, McNeill said. We know there are variants in this gene associated with early menopause. And when we studied this defect in mice, we see that their ovaries have lost the pool of egg cells that theyre born with, which determines fertility over the lifespan. So, this finding provides a potential explanation for why women with mutations in this gene might have early menopause. When you lose your stock of eggs, you go into menopause.

On the left is a normal fruit fly ovary with hundreds of developing eggs. On the right is a fruit fly ovary that is totally missing the NEMP gene. It is poorly developed and no eggs are visible.

McNeill and her colleagues suspect that the nuclear envelope has to find a balance between being pliant enough to allow the chromosomes to align as they should for reproductive purposes but stiff enough to protect them from the ovarys stressful environment. With age, ovaries develop strands of collagen with potential to create mechanical stress not present in embryonic ovaries.

If you have a softer nucleus, maybe it cant handle that environment, McNeill said. This could be the cue that triggers the death of eggs. We dont know yet, but were planning studies to address this question.

Over the course of these studies, McNeill said they found only one other problem with the mice missing this specific gene: They were anemic, meaning they lacked red blood cells.

Normal adult red blood cells lack a nucleus, McNeill said. Theres a stage when the nuclear envelope has to condense and get expelled from the young red blood cell as it develops in the bone marrow. The red blood cells in these mice arent doing this properly and die at this stage. With a floppy nuclear envelope, we think young red blood cells are not surviving in another mechanically stressful situation.

The researchers would like to investigate whether women with fertility problems have mutations in NEMP1. To help establish whether such a link is causal, they have developed human embryonic stem cells that, using CRISPR gene-editing technology, were given specific mutations in NEMP1 listed in genetic databases as associated with infertility.

We can direct these stem cells to become eggs and see what effect these mutations have on the nuclear envelope, McNeill said. Its possible there are perfectly healthy women walking around who lack the NEMP protein. If this proves to cause infertility, at the very least this knowledge could offer an explanation. If it turns out that women who lack NEMP are infertile, more research must be done before we could start asking if there are ways to fix these mutations restore NEMP, for example, or find some other way to support nuclear envelope stiffness.

This work was supported by the Canadian Institutes of Health, research grant numbers 143319, MOP-42462, PJT-148658, 153128, 156081, MOP-102546, MOP-130437, 143301, and 167279. This work also was supported, in part, by the Krembil Foundation; the Canada Research Chair program; the National Institutes of Health (NIH), grant number R01 GM100756; and NSERC Discovery grant; and the Medical Research Council, unit programme MC_UU_12015/2. Financial support also was provided by the Wellcome Senior Research Fellowship, number 095209; Core funding 092076 to the Wellcome Centre for Cell Biology; a Wellcome studentship; the Ontario Research FundsResearch Excellence Program. Proteomics work was performed at the Network Biology Collaborative Centre at the Lunenfeld-Tanenbaum Research Institute, a facility supported by Canada Foundation for Innovation funding, by the Ontarian Government, and by the Genome Canada and Ontario Genomics, grant numbers OGI-097 and OGI-139.

Tsatskis Y, et al. The NEMP family supports metazoan fertility and nuclear envelope stiffness. Science Advances. Aug. 28, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

Visit link:

Genetic mutations may be linked to infertility, early menopause - Washington University School of Medicine in St. Louis

What should a precision medicine approach be in a pandemic? The gene-centric vision of precision medicine encourages people to expect individualised gene-targeted fixes

Tom Hanks and his wife, Rita Wilson, were among the earliest celebrities to catch the novel coronavirus. In an interview at the beginning of July, Hanks described how differently COVID-19 had affected each of them in March.

My wife lost her sense of taste and smell, she had severe nausea, she had a much higher fever than I did. I just had crippling body aches, he said. I was very fatigued all the time and I couldnt concentrate on anything for more than about 12 minutes.

Why does COVID-19 present such different symptoms or none at all in different people?

Preexisting conditions can only be part of the story. Hanks is over 60 and is a Type 2 diabetic, putting him in a high-risk group. Nevertheless, he survived his brush with the virus with no pneumonia and apparently without any long-lasting effects. Knowing what causes variation in different patients could help physicians tailor their treatments to individual patients an approach known as precision medicine.

In recent years, a gene-centric approach to precision medicine has been promoted as the future of medicine. It underlies the massive effort funded by the US National Institutes of Health to collect over a million DNA samples under the All of Us initiative that began in 2015.

But the imagined future did not include COVID-19. In the rush to find a COVID-19 vaccine and effective therapies, precision medicine has been insignificant. Why is this? And what are its potential contributions?

We are a physician geneticist and a philosopher of science who began a discussion about the promise and potential pitfalls of precision medicine before the arrival of COVID-19. If precision medicine is the future of medicine, then its application to pandemics generally, and COVID-19 in particular, may yet prove to be highly significant. But its role so far has been limited. Precision medicine must consider more than just genetics. It requires an integrative omic approach that must collect information from multiple sources beyond just genes and at scales ranging from molecules to society.

From genetics to microbes

Inherited diseases such as sickle cell anemia and Tay-Sachs disease follow a predictable pattern. But such direct genetic causes are perhaps the exception rather than the rule when it comes to health outcomes. Some heritable conditions for instance, psoriasis or the many forms of cancer depend on complex combinations of genes, environmental and social factors whose individual contributions to the disease are difficult to isolate. At best, the presence of certain genes constitutes a risk factor in a population but does not fully determine the outcome for an individual person carrying those genes.

The situation becomes yet more complicated for infectious diseases.

Viruses and bacteria have their own genomes that interact in complex ways with the cells in the people they infect. The genome of SARS-CoV-2 underlying COVID-19 has been extensively sequenced. Its mutations are identified and traced worldwide, helping epidemiologists understand the spread of the virus. However, the interactions between SARS-CoV-2 RNA and human DNA, and the effect on people of the viruss mutations, remain unknown.

The importance of multi-scale data

Tom Hanks and his wife caught the virus and recovered in a matter of weeks. Presumably each was infected over the course of a few minutes of exposure to another infected person, involving cellular mechanisms that operate on a timescale of milliseconds.

But the drama of their illness, and that of the many victims with far worse outcomes, is taking place in the context of a global pandemic that has already lasted months and may continue for years. People will need to adopt changes in their behavior for weeks or months at a time.

What should a precision medicine approach be in a pandemic? The gene-centric vision of precision medicine encourages people to expect individualised gene-targeted fixes. But, genes, behavior and social groups interact over multiple timescales.

To capture all the data needed for such an approach is beyond possibility in the current crisis. A nuanced approach to the COVID-19 pandemic will depend heavily on imprecise population level public health interventions: mask-wearing, social distancing and working from home. Nevertheless, there is an opportunity to begin gathering the kinds of data that would allow for a more comprehensive precision medicine approach one that is fully aware of the complex interactions between genomes and social behavior.

How to use precision medicine to understand COVID-19

With unlimited resources, a precision medicine approach would begin by analyzing the genomes of a large group of people already known to be exposed to SARS-CoV-2 yet asymptomatic, along with a similar-sized group with identified risk factors who are dying from the disease or are severely ill.

An early study of this kind by Precisionlife Ltd data mined genetic samples of 976 known COVID-19 cases. Of these, 68 high-risk genes were identified as risk factors for poor COVID-19 outcomes, with 17 of them deemed likely to be good targets for drug developments. But, as with all such statistical approaches, the full spectrum of causes underlying their association with the disease is not something the analysis provides. Other studies of this kind are appearing with increasing frequency, but there is no certainty in such fast-moving areas of science. Disentangling all the relevant factors is a process that will take months to years.

To date, precision medicine has proven better suited to inherited diseases and to diseases such as cancer, involving mutations acquired during a persons lifetime, than to infectious diseases. There are examples where susceptibility to infection can be caused by malfunction of unique genes such as the family of inherited immune disorders known as agammaglobulinemia, but these are few and far between.

Many physicians assume that most diseases involve multiple genes and are thus not amenable to a precision approach. In the absence of the kind of information needed for a multi-omic approach, there is a clear challenge and opportunity for precision medicine here: If it is to be the future of medicine, in order to complement and expand our existing knowledge and approaches, it needs to shift from its gene-centric origins toward a broader view that includes variables like proteins and metabolites. It must consider the relationships between genes and their physical manifestations on scales that range from days to decades, and from molecules to the global society.

Colin Allen, Distinguished Professor of History & Philosophy of Science, University of Pittsburgh and David Finegold, Professor, Department of Human Genetics, Pitt Public Health, University of Pittsburgh

This article is republished from The Conversation under a Creative Commons license. Read the original article.

We are a voice to you; you have been a support to us. Together we build journalism that is independent, credible and fearless. You can further help us by making a donation. This will mean a lot for our ability to bring you news, perspectives and analysis from the ground so that we can make change together.

Read more here:

How to use precision medicine to personalise COVID-19 treatment according to the patient's genes - Down To Earth Magazine

Normal blood cells (left) and the blood cells in sickle cell disease, which do not flow through the circulatory system smoothly. (Credit: Darryl Leja, NHGRI, CC BY 2.0)

First published by GroundUp.

A study performed in Cameroon by a University of Cape Town (UCT) professor may offer hope of treatment for people with sickle cell anaemia (SCA), a disease which affects hundreds of thousands in Africa.

Professor Ambroise Wonkam, principal investigator and director of Genetic Medicine of African Populations in the Division of Human Genetics at UCT, says though the condition was identified more than 100 years ago, a definitive treatment is still not widely available.

Sickle cell anaemia is the most serious in a group of disorders known as sickle cell disease. It is an inherited red blood cell disorder in which there arent enough healthy red blood cells to carry oxygen throughout the body. It is caused by a mutation in a single gene, responsible for production of the protein, haemoglobin. Making up 70% of the content of red blood cells, haemoglobin is essential for transporting oxygen throughout the body.

Normally, the flexible, round red blood cells move easily through blood vessels. In sickle cell anaemia, the red blood cells are shaped like sickles or crescent moons. These rigid, sticky cells can become stuck in small blood vessels, which can slow or block blood flow and oxygen to other parts of the body. (Read this for more information.)

Among the 300,000 babies that are born with the condition every year, 80% are in sub-Saharan Africa, says Wonkam. It is, in essence, an African disease.

Despite the prevalence of SCA in Africa, medical care has been less than optimal. According to Wonkam, it has been shown that, due to the lack of medical interventions, in most African settings, at least 50% of African children with SCA will die before they turn five years old.

However, the same regions of sub-Saharan Africa are also home to SCA patients who are 50 or 60 years old.

Why is it that some people who live in an environment that is not favourable in terms of healthcare access, and stressors including high temperatures, malaria and other infections manage to survive while others die at a much younger age? Wonkam asks. Our hypothesis is that these long survivors living with SCA may be protected by some genetic factors.

To test this, Wonkam and his team recruited SCA patients of 40 years or older, who had received minimal medical intervention, as well as a control group who had suffered strokes, which is one of the severe effects of SCA, and an intermediate group who were under 40 and never had a stroke. The research took place in Cameroon.

In the study, published in the journal Clinical and Translational Medicine, Wonkam and his team found genetic modifiers of long-term survival in individuals with SCA.

People who had survived longer had recurrent changes in specific genes. And patients who had strokes had a mutation in the blood coagulation pathway.

Another finding in the long-term survivor group was that they metabolised the micronutrient selenium efficiently. They also have genes that assist in keeping blood pressure low. Wonkam says that selenium supplementation is worth investigating.

Also, the study found, some patients were protected from some of the vascular complications of the disease by their ability to produce an amino acid called glutamine. Glutamine helps to protect the body against stress due to low oxygen which is one of the side effects of SCA. This ability to produce glutamine can also now be studied further as a possible treatment in other people with the disorder. Glutamine supplements could be one of the options.

It is possible that genes with recurrent mutations that we found in numerous patients provide some protection, and have become prevalent in people with SCA by natural selection. This information can be used in future in gene-modifying therapy.

Modifier genes, which change the actions of other genes, can be beneficial to the health of the patients by countering some of the negative effects of the disorder.

By identifying novel modifier genes, our research is providing additional mechanisms to explain the long-term survival, or complications such as stroke in some patients, says Wonkam.

I believe this is probably one of the landmark findings that have been performed in Africa where most of these patients live, he says. DM

Please note you must be a Maverick Insider to comment. Sign up here or if you are already an Insider.

See the original post here:

UCT professors research offers hope of treatment for sickle cell anaemia - Daily Maverick

1. Environmental liability for schizophrenia moderated the association of stressful life events with mental and physical health.

Evidence Rating Level: 2 (Good)

Schizophrenia research has elucidated the roles of environmental and genetic liability as well as stressful life events (SLEs) in schizophrenia pathogenesis. However, few studies have illustrated the interactions of these risk factors and how they impact mental and physical health. This population-based prospective cohort study investigated the prevalence, incidence, course, and consequences of psychiatric disorders in the Netherlands. A total of 6,646 (M [SD] age = 44.26 [12.54] years, 55.25% female) participants were enrolled between November 5, 2007 and July 31, 2009, being followed up with by three assessments across nine years. Follow-ups included recent SLEs and aggregate scores of environmental and genetic liabilities (polygenic risk score for schizophrenia [PRS-SCZ]; exposome score for schizophrenia [ES-SCZ]). SLEs were significantly associated with reduced mental (B = -3.68, 95% CI -4.05 to -3.32) and physical health (B = -3.22, 95% CI -3.66 to -2.79). Genetic and environmental liabilities were associated with poorer mental health (PRS-SCZ: B = -0.93, 95% CI -1.31 to -0.54; ES-SCZ: B = -3.07, 95% CI -3.35 to -2.79), with environmental liability also being associated with reduced physical health (B = -3.19, 95% CI -3.56 to -2.82). The interaction model suggested that ES-SCZ moderated the association of SLEs with physical (B = -0.64, 95% CI -1.11 to -0.17) and mental health (B = -1.08, 95% CI -1.47 to -0.69). PRS-SCZ, however, did not moderate this relationship. Overall, both genetic and environmental liabilities for schizophrenia resulted in mental health outcomes across the population. Exposure to SLEs, specifically in the context of these liabilities, were further associated with poorer health outcomes. Thus, it is important to consider the environmental factors impacting schizophrenia, such that modifiable risk factors should be targets of prevention and ongoing treatment.

Click to read the study in JAMA Psychiatry

Image: PD

2020 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.

Go here to read the rest:

Association of recent stressful life events with mental and physical health in the context of genomic and exposomic liability for schizophrenia - 2...

Scientists observed that different cancers undergo the same genetic mutations at similar stages of evolution, the findings could become part of an evolutionary rule book which would theoretically enable the prediction and prevention of cancers next evolutionary move.

Researchers have identified that there is an element of order to the seemingly chaotic changes to chromosomes that give tumours their heterogeneity. In their paper, the team report that mutations in the chromosomes of cancer cells happen frequently and throughout the development of a tumour; however, some are more likely to occur in the early stages of cancer development and others in the later stages, once a tumour has metastasised.

One of the difficulties in treating cancers is that the genetic make-up of tumours evolves over time. Scientists believe these changes result from errors made in DNA replication, which are more frequent in cancers due to the upregulation of various cell survival pathways and the speed with which cancer cells divide. Unfortunately, the more heterogeneous a tumour is (in other words, the greater the genetic variability of cells within a single tumour), the less likely a patient is to respond successfully to treatment, which ultimately makes recovery less likely and survival shorter.

In their paper published in Nature, researchers at the Francis Crick Institute (the Crick) and the University College London (UCL) Cancer Institute, both UK, sought to identify why these mutations occur and if there is a pattern or order to them.

In collaboration with Germanys Max Delbrck Center for Molecular Medicine, the team developed a technique that analyses multiple samples from a single tumour and used it to identify chromosomal changes in 1421 tumour samples taken from 394 patients with 22 different types of tumours.

They observed that often similar chromosomal changes had taken place in different subclones within a tumour from the same patient. Subclones are different groups of cells within a single tumour. The team found evidence of subclones evolving in parallel in samples taken from 37 percent of patients (146 patients).

The scientists also identified certain chromosomal changes that occurred in multiple tumour types at particular stages of cancer evolution, including changes that could aid in immune evasion or promote tumour growth despite a lack of oxygen.

Thomas Watkins, lead author and PhD student in the Cancer Evolution and Genome Instability Laboratory at the Crick, said: In a tumour there are lots of genetic changes taking place. The fact we saw similar chromosomal changes take hold independently within a tumour in separate subclones suggests these changes are important for the tumour and might lead to subclones with them out-competing other subclones without them.

Professor Charles Swanton, senior group leader at the Crick and UCL, Cancer Research UKs chief clinician and consultant oncologist at UCL Hospital, added: The presence of common changes supports the theory that there are a number of genetic pathways through which tumours must evolve. Identifying these would move us a step closer to writing cancers evolutionary rule book.

The studys authors also revealed that some changes were common in the early stages of a cancers development, while others were more frequent later on, after it metastasised. They added that there were certain events that acted as a catalyst for mutations; for example, whole genome doubling where every chromosome is duplicated appears to open up new evolutionary solutions for the tumour, leading to a wave of late-stage mutations.

Nicholas McGranahan, group leader of the Cancer Genome Evolution Group at the UCL Cancer Institute, commented: There was a sense of order in the mutations we identified, with different mutations likely to appear at different points. So, these changes, which may seem like chromosomal chaos, could actually be something we could predict. Of course, if you could predict them, this opens the door to scientists and doctors developing new treatments which could block these evolutionary pathways.

The team are continuing to leverage their analysis technique on samples taken from patients with lung cancer, as part of Cancer Research UKs TRACERx project. They said that they hope this will lead to new insights about the genetic changes that drive the spread of lung cancer as well as understanding what changes help these tumours to evade the immune system.

More:

Finding order in the chaos of cancer mutations - Drug Target Review

WORCESTER, Mass., Sept. 02, 2020 (GLOBE NEWSWIRE) -- Mustang Bio, Inc. (Mustang) (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to MB-107, Mustangs lentiviral gene therapy for the treatment of X-linked severe combined immunodeficiency (XSCID), also known as bubble boy disease, in newly diagnosed infants under the age of two. The FDA previously granted Rare Pediatric Disease Designation in August 2020 and Regenerative Medicine Advanced Therapy designation in August 2019 to MB-107 for the treatment of XSCID in newly diagnosed patients. Additionally, the European Medicines Agency granted Advanced Therapy Medicinal Product classification to MB-107 in April 2020.

The FDA grants Orphan Drug Designation to drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation provides certain incentives, such as tax credits toward the cost of clinical trials and prescription drug user fee waivers. If a product holding Orphan Drug Designation receives the first FDA approval for the disease in which it has such designation, the product is entitled to seven years of market exclusivity, which is independent from intellectual property protection.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, Mustang has had a productive quarter on the regulatory front. We are very pleased to achieve another significant milestone and receive Orphan Drug Designation for MB-107 for the treatment of XSCID in newly diagnosed patients. This designation for MB-107, in addition to its Rare Pediatric Disease Designation, Regenerative Medicine Advanced Therapy designation and Advanced Therapy Medicinal Product classification, continues to enhance our regulatory pathway for a much-needed treatment option to address this devastating rare disease that affects children. We look forward to initiating our pivotal clinical programs for MB-107 in newly diagnosed infants with XSCID and MB-207 in previously transplanted patients with XSCID very soon.

MB-107 is currently being assessed in a Phase 1/2 clinical trial for XSCID in newly diagnosed infants under the age of two at St. Jude Childrens Research Hospital (St. Jude), UCSF Benioff Childrens Hospital in San Francisco and Seattle Childrens Hospital. In May 2020, Mustang submitted an investigational new drug application (IND) to the FDA to initiate a multi-center Phase 2 clinical trial of MB-107 in newly diagnosed infants with XSCID who are between two months to two years of age. The trial is expected to enroll 10 patients who, together with 15 patients enrolled in the current multi-center trial led by St. Jude, will be compared with 25 matched historical control patients who have undergone hematopoietic stem cell transplantation (HSCT). The primary efficacy endpoint will be event-free survival. The initiation of this trial is expected early in the fourth quarter of 2020. Mustang is targeting topline data from this trial in the second half of 2022.

Another Phase 1/2 clinical trial for XSCID in patients over the age of two years, who have received prior HSCT, is underway at the National Institutes of Health, and Mustang expects to file an IND to the FDA to initiate a multi-center Phase 2 clinical trial in this population in the fourth quarter of 2020. This product candidate for XSCID in patients over the age of two years, who have received prior HSCT, is designated MB-207. The FDA granted a Rare Pediatric Disease Designation to MB-207 in August 2020.

About X-linked Severe Combined Immunodeficiency (XSCID)X-linked severe combined immunodeficiency is a rare genetic disorder that occurs in approximately 1 per 225,000 births. It is characterized by the absence or lack of function of key immune cells, resulting in a severely compromised immune system and death by one year of age if untreated. Patients with XSCID have no T-cells or natural killer cells. Although their B-cells are normal in number, they are not functional. As a result, XSCID patients are usually affected by severe bacterial, viral or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea and failure to thrive.

The specific genetic disorder that causes XSCID is a mutation in the gene coding for the common gamma chain (c), a protein that is shared by the receptors for at least six interleukins. These interleukins and their receptors are critical for the development and differentiation of immune cells. The gene coding for c is known as IL-2 receptor gamma, or IL2RG. Because IL2RG is located on the X-chromosome, XSCID is inherited in an X-linked recessive pattern, resulting in almost all patients being male.

About Mustang BioMustang Bio, Inc. is a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR T therapies across multiple cancers, as well as a lentiviral gene therapy for XSCID. Mustang is registered under the Securities Exchange Act of 1934, as amended, and files periodic reports with the U.S. Securities and Exchange Commission (SEC). Mustang was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visit http://www.mustangbio.com.

ForwardLooking StatementsThis press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on managements current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under, and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; risks relating to the timing of starting and completing clinical trials; uncertainties relating to preclinical and clinical testing; our dependence on third-party suppliers; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Company Contacts:Jaclyn Jaffe and William BegienMustang Bio, Inc.(781) 652-4500ir@mustangbio.com

Investor Relations Contact:Daniel FerryLifeSci Advisors, LLC(617) 430-7576daniel@lifesciadvisors.com

Media Relations Contact:Tony Plohoros6 Degrees(908) 591-2839tplohoros@6degreespr.com

Here is the original post:

Mustang Bio Announces Orphan Drug Designation for MB-107 for the Treatment of X-linked Severe Combined Immunodeficiency in Newly Diagnosed Infants -...

GAITHERSBURG, Md., Sept. 02, 2020 (GLOBE NEWSWIRE) -- Novavax, Inc. (Nasdaq: NVAX), a late stage biotechnology company developing next-generation vaccines for serious infectious diseases, today announced the publication in The New England Journal of Medicine of Phase 1 data from its Phase 1/2 clinical trial of NVXCoV2373, its COVID19 vaccine candidate adjuvanted with MatrixM, in healthy adults 18-59 years of age. The publication offers further detail on the previously announced results, in which NVXCoV2373 demonstrated a reassuring safety and reactogenicity profile and induced robust antibody responses numerically superior to that seen in human convalescent sera. The manuscript is available at https://www.nejm.org/doi/full/10.1056/NEJMoa2026920?query=featured_coronavirus.

The rapid publication of Phase 1 results from our trial in a prestigious peer-reviewed journal reflects both the importance of the data and the urgent need for an effective vaccine to slow the COVID-19 pandemic, said Gregory M. Glenn, M.D., President of Research and Development at Novavax. Based on the positive Phase 1 results, we have begun multiple Phase 2 clinical trials, from which we expect to collect preliminary efficacy. Novavax is committed to generating the safety, immunogenicity and efficacy data that will support confident usage of the vaccine, both in the US and globally, and the data published today further bolsters our conviction that this is possible.

The Phase 1 portion of the Phase 1/2 clinical trial was randomized, observer-blinded, and placebo-controlled.

NVX-CoV2373 is currently in multiple Phase 2 clinical trials. The Phase 2 portion of the Phase 1/2 clinical trial to evaluate the safety and immunogenicity of NVX-CoV2373 began in August inthe United StatesandAustralia, and expands on the age range of the Phase 1 portion by including older adults 60-84 years of age as approximately 50 percent of the trial population. Secondary objectives include preliminary evaluation of efficacy. In addition, a Phase 2b clinical trial to assess efficacy began inSouth Africain August.

The trial was supported by funding from the Coalition for Epidemic Preparedness Innovations (CEPI) and was conducted at two sites in Australia.

Phase 1 Results Summary

Further details may be found in Novavax August 4 announcement of Phase 1 results and may be accessed here.

About NVX-CoV2373

NVXCoV2373 is a vaccine candidate engineered from the genetic sequence of SARSCoV2, the virus that causes COVID-19 disease. NVXCoV2373 was created using Novavax recombinant nanoparticle technology to generate antigen derived from the coronavirus spike (S) protein and contains Novavax patented saponin-based Matrix-M adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies. In preclinical trials, NVXCoV2373 demonstrated indication of antibodies that block binding of spike protein to receptors targeted by the virus, a critical aspect for effective vaccine protection. In its Phase 1 portion of the Phase 1/2 clinical trial, NVXCoV2373 was generally well-tolerated and elicited robust antibody responses numerically superior to that seen in human convalescent sera. Phase 2 clinical trials began in August 2020. Novavax has secured $2 billion in funding for its global coronavirus vaccine program, including up to $388 million in funding from the Coalition for Epidemic Preparedness Innovations (CEPI).

About Matrix-M

Novavax patented saponin-based Matrix-M adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen-presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune response.

About Novavax

Novavax, Inc. (Nasdaq:NVAX) is a late-stage biotechnology company that promotes improved health globally through the discovery, development, and commercialization of innovative vaccines to prevent serious infectious diseases. Novavax is undergoing clinical trials for NVX-CoV2373, its vaccine candidate against SARS-CoV-2, the virus that causes COVID-19. NanoFlu, its quadrivalent influenza nanoparticle vaccine, met all primary objectives in its pivotal Phase 3 clinical trial in older adults. Both vaccine candidates incorporate Novavax proprietary saponin-based Matrix-M adjuvant in order to enhance the immune response and stimulate high levels of neutralizing antibodies. Novavax is a leading innovator of recombinant vaccines; its proprietary recombinant technology platform combines the power and speed of genetic engineering to efficiently produce highly immunogenic nanoparticles in order to address urgent global health needs.

For more information, visit http://www.novavax.com and connect with us on Twitter and LinkedIn.

Novavax Forward-Looking Statements

Statements herein relating to the future of Novavax and the ongoing development of its vaccine and adjuvant products are forward-looking statements. Novavax cautions that these forward-looking statements are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include those identified under the heading Risk Factors in the Novavax Annual Report on Form 10-K for the year ended December 31, 2019, and Quarterly Report on Form 8-K for the period ended June 30, 2020, as filed with the Securities and Exchange Commission (SEC). We caution investors not to place considerable reliance on forward-looking statements contained in this press release. You are encouraged to read our filings with the SEC, available at sec.gov, for a discussion of these and other risks and uncertainties. The forward-looking statements in this press release speak only as of the date of this document, and we undertake no obligation to update or revise any of the statements. Our business is subject to substantial risks and uncertainties, including those referenced above. Investors, potential investors, and others should give careful consideration to these risks and uncertainties.

Contacts:

Novavax

InvestorsSilvia Taylor and Erika Trahanir@novavax.com240-268-2022

MediaBrandzone/KOGS CommunicationEdna Kaplankaplan@kogspr.com617-974-8659

See the article here:

Novavax Announces Publication of Phase 1 Data for COVID-19 Vaccine Candidate in The New England Journal of Medicine - GlobeNewswire