PGRMC1

A new study identified a set of 140 genes that may help predict enhanced disease-free survival in patients with non-small cell lung cancer (NSCLC) treated with a combination of immunotherapy and low-dose radiation. The results suggested that this 'gene signature' could be used to identify a subclass of lung tumors that is more likely to be eradicated by immunotherapies. A new study identified a set of 140 genes that may help predict enhanced disease-free survival in patients with non-small cell lung cancer (NSCLC) treated with a combination of immunotherapy and low-dose radiation. The results, published in Cell Reports Medicine on Feb. 23, suggested that this "gene signature" could be used to identify a subclass of lung tumors that is more likely to be eradicated by immunotherapies. Immunotherapy has saved countless lives but only 20 to 25 percent of patients respond to this treatment that activates a person's own immune system to attack their cancer. Predicting who would benefit from this approach and why could help patients who have exhausted other options such as chemotherapy. Studying a cohort of 60 patients with NSCLC, the team determined previously that adding a low dose of radiation to a course of durvalumab, an immune-boosting drug, promoted cancer-free survival in most of these individuals. Now, to assess why some tumors didn't respond to the therapy, the researchers examined pretreatment tumor biopsies from this study cohort. They determined the gene expression pro which showed the specific genes that are turned up and those that turned down in each sample. They compared the gene expression profiles of ten tumors that reached major pathologic response (MPR) -- the elimination of more than 90 percent of the cancer cells in patients' tumors -- with combination treatment versus six that did not. They discovered the two groups of pretreatment tumors could be reliably distinguished by a set of genes with 135 of the genes turned up and 5 turned down. The majority of the 135 genes were associated with enhanced cell growth, suggesting the tumors that responded to the dual therapy were particularly aggressive. The researchers were also able to examine how the gene expression pro in the responsive cancers before and after treatment. They found that in tumors displaying MPR, dual therapy not only reversed the activity of this 140-gene set, it also increased the activation of genes associated with cellular pathways involved in immunity and tissue repair. The activity of the 140 genes which correlated with treatment response is particularly promising as clinicians could use the signature to identify people who would gain the maximum benefit from immunotherapy. The researchers plan to test whether tumors with this aggressive gene signature have a better response to the combination therapy in a larger patient study.

Researchers have discovered that it is not just molecular density, but also pattern and structural rigidity, that control super-selective binding interactions between nanomaterials and protein surfaces. The breakthrough could help optimize existing approaches to virus prevention and cancer detection. EPFL researchers have discovered that it is not just molecular density, but also pattern and structural rigidity, that control super-selective binding interactions between nanomaterials and protein surfaces. The breakthrough could help optimize existing approaches to virus prevention and cancer detection. So much of biology comes down to the biophysical process of binding: making a strong connection between one or more groups of atoms -- known as ligands -- to their corresponding receptor molecule on a surface. A binding event is the first fundamental process that allows a virus to infect a host, or chemotherapy to fight cancer. But binding interactions -- at least, our understanding of them -- have a 'Goldilocks problem': too few ligands on one molecule makes it impossible for it to stably bind with the correct target, while too many can result in undesirable side-effects. "When binding is triggered by a threshold density of target receptors, we call this "super-selective" binding, which is key to preventing random interactions that could dysregulate biological function," explains Maartje Bastings, head of the Programmable Biomaterials Laboratory (PBL) in the School of Engineering. "Since nature typically doesn't overcomplicate things, we wanted to know the minimum number of binding interactions that would still allow for super-selective binding to occur. We were also interested to know whether the pattern the ligand molecules are arranged in makes a difference in selectivity. As it turns out, it does!" Bastings and four of her PhD students have recently published a study in the Journal of the American Chemical Society that identifies the optimal ligand number for super-selective binding: six. But they also found, to their excitement, that the arrangement of these ligands -- in a line, circle, or triangle, for example -- also significantly impacted binding efficacy. They have dubbed the phenomenon "multivalent pattern recognition" or MPR. "MPR opens up a whole new set of hypotheses around how molecular communication in biological and immunological processes might work. For example, the SARS-CoV-2 virus has a pattern of spike proteins that it uses to bind to cell surfaces, and these patterns could be really critical when it comes to selectivity." From coronaviruses to cancer Because its double helix structure is so precise and well understood, DNA is the perfect model molecule for the PBL's research. For this study, the team designed a rigid disk made entirely out of DNA, where the position and number of all ligand molecules could be precisely controlled. After engineering a series of ligand-receptor architectures to explore how density, geometry, and nano-spacing influenced binding super-selectivity, the team realized that rigidity was a key factor. "The more flexible, the less precise," Bastings summarizes. "Our aim was to carve out design principles in as minimalist a way as possible, so that every ligand molecule participates in the binding interaction. What we now have is a really nice toolbox to further exploit super-selective binding interactions in biological systems." The applications for such a "toolbox" are far-reaching, but Bastings sees three immediately valuable uses. "Like it or not," she says, "the SARS-CoV-2 virus is currently a first thought when it comes to virological applications. With the insights from our study, one could imagine developing a super-selective particle with ligand patterns designed to bind with the virus to prevent infection, or to block a cell site so that the virus cannot infect it." Diagnostics and therapeutics such as chemotherapy could also benefit from super-selectivity, which could allow for more reliable binding with cancer cells, for which certain receptor molecules are known to have a higher density. In this case, healthy cells would remain undetected, drastically reducing side effects. Finally, such selectivity engineering could offer key insights into complex interactions within the immune system. "Because we can now play precisely with patterns of what happens at binding sites, we can, in a sense, potentially 'communicate' with the immune system," Bastings says.

PITTSBURGH, Feb. 01, 2021 (GLOBE NEWSWIRE) -- Cognition Therapeutics, Inc., a clinical stage neuroscience company developing drugs that treat neurodegenerative disorders by regulating cellular damage response pathways, today announced that a peer-reviewed manuscript, entitled, “Sigma-2-Receptor Antagonists Rescue Neuronal Dysfunction Induced by Parkinson’s Patient Brain-Derived α-Synuclein,” has been published online in the Journal of Neuroscience Research (). In this publication, Cognition scientists identify the sigma-2 (σ-2) receptor as integral in the pathology of Parkinson’s disease. In Parkinson’s disease, cumulative damage from a variety of stressors results in structural changes in the α-synuclein protein. Aggregates of α-synuclein are strongly correlated with disease pathology in Parkinson’s and related “synucleinopathies” such as dementia with Lewy bodies and multiple system atrophy. In these diseases, α-synuclein oligomers have been shown to disrupt several important cellular functions including autophagy and intracellular trafficking. When these processes are impaired, aggregated α-synuclein and other altered proteins build up in neurons, causing further damage and eventual cell death. Cognition scientists conducted extensive screening to identify compounds that rescue neurons from α-synuclein oligomer-induced deficits, specifically in autophagy and trafficking processes. The compounds that had the most profound effects were discovered to be σ-2 receptor antagonists. This is consistent with findings reported in the literature describing σ-2 receptor components, TMEM97 and PGRMC1, as regulators of these pathways, but it is the first time that σ-2 antagonists have been demonstrated to have effects against α-synuclein oligomers. “These data support the hypothesis that σ-2 receptor antagonists could represent a unique therapeutic approach to treating some of the underlying disease pathology in Parkinson’s disease and potentially other related diseases like dementia with Lewy bodies,” explained Susan Catalano, Ph.D., Cognition’s founder and chief science officer. “We have plans to explore one or more compounds from our library of σ-2 receptor antagonists in models of Parkinson’s disease to better understand the role of σ-2 receptors in synucleinopathies.” About Cognition Therapeutics, Inc.Cognition Therapeutics, Inc. has discovered and is developing a pipeline of novel, disease modifying, oral drug candidates to treat a broad array of neurodegenerative and neuro-ophthalmic disorders. Our pipeline compounds uniquely target the σ-2 receptor, a key regulator of the cellular damage response. CT1812, our lead product candidate, is being assessed in a comprehensive clinical program for Alzheimer’s disease, including a 540-person Phase 2 study in collaboration with ACTC and supported by a competitive grant from the National Institute on Aging. Additional information about Cognition and its product candidates may be found online at . Cautionary Statement Regarding Forward Looking Statements This press release contains forward-looking statement, including those concerning the development and commercialization of Cognition Therapeutics’ product candidates and pipeline, their potential benefits and the Company’s expectations regarding its prospects. Forward-looking statements are subject to risks, assumptions and uncertainties that could cause actual future results to differ materially from such statements. These statements are based on information that is available as of date of this press release, and except as required by law, we undertake no obligation to update any such statements. This press release contains references to CT1812, an investigational product. Use of CT1812 has not been approved by the FDA.