On October 21, 2021 Researchers from the University of Dundee and Promega Corporation reported that they have shown how a "three-headed hydra" significantly improves efficacy in targeted protein degradation (Press release, Promega, OCT 21, 2021, View Source [SID1234591720]). This discovery opens new possibilities in a field that is revolutionizing drug discovery for cancer and other targets. The research is published today in Nature Chemical Biology.

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Targeted Protein Degradation

Targeted protein degradation is an area of chemical biology that is revolutionizing drug discovery. It involves co-opting the cell’s natural disposal systems to also remove disease-causing proteins. This system is applicable to diverse therapeutic areas including oncology, inflammation, dermatology, immunology, and respiratory diseases.

Degrading a target protein offers several advantages over traditional inhibitors. This type of drug may show a greater response even at lower doses, and it is more precise with potentially reduced side effects and disease resistance. The first compounds in this class, termed Proteolysis-targeting chimeras (PROTACs), are being trialed as candidate medicines against various cancers and progressing through clinical trials.

PROTACs are conventionally small molecules designed with two heads, called bivalent or heterobifunctional compounds. However, new research carried out by Dundee’s Centre for Targeted Protein Degradation (CeTPD) in collaboration with biotechnology company Promega broke away from this conventional design and showed that degraders can be significantly improved by making them trivalent, i.e. consisting of three heads.

Novel Trivalent PROTACs

The best trivalent PROTAC designed by the researchers proved to be remarkably more potent than their bivalent predecessor compounds, showing in cellular studies stronger anti-cancer activity at a much lower dose and improved pharmacological responses over a wider dose range.

"Three heads can be better than two in PROTACs," says Dr. Alessio Ciulli, Director of the Center for Targeted Protein Degradation. "We hypothesized that we could improve degraders by latching onto the target protein more productively. To do this, we designed trivalent PROTACs by adding an additional protein-binding ligand, in effect creating a three-headed monster that destroys cancer-causing proteins more effectively."

The Dundee/Promega team demonstrated that the new PROTAC works due to the combined effect of two important features of protein and small molecule molecular recognition – avidity and cooperativity. Avidity refers to the combined strength of multiple interactions between two molecules. Cooperativity is a phenomenon shown by molecules with multiple binding sites in which the affinity of the remaining binding sites is increased after a ligand binds to one of them.

The researchers conclude that the trivalent PROTAC concept offers a new strategy that is shown to improve on many aspects of degrader drug action and could in future be applied to a wider range of protein targets, including those thought to be undruggable. If this is shown to be the case, it raises the possibility of scientists being able to develop drugs more easily for diseases for which there are currently no effective treatments, greatly expanding the number of available therapeutics.

"We took a significant risk with this project, but its success has opened new doors for the design of highly potent degraders, as well as other multi-specific compounds," says Dr. Danette Daniels, Senior Research Scientist and Group Leader at Promega Corporation.

Learn More

For more information, read the paper published today in Nature Chemical Biology.

To learn more about Targeted Protein Degradation at Promega, visit www.promega.com/NatureTPD

On October 21, 2021 RefleXion Medical, a therapeutic oncology company pioneering biology-guided radiotherapy* (BgRT) as a new modality for treating all stages of cancer, reported multiple clinical abstracts evaluating the potential use and utility of its novel technology were accepted for presentation during the American Society for Radiation Oncology (ASTRO) 2021 Annual Meeting, Oct. 24-27, in Chicago (Press release, RefleXion Medical, OCT 21, 2021, View Source [SID1234591717]). The company will showcase technology from the RefleXion X1 machine in its booth, #1309.

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"Particularly gratifying among our multiple abstracts are oral presentations demonstrating physical validation of biological guidance for delivering radiotherapy to an FDG-avid target and exploring whether novel prostate surface membrane antigen radiotracers hold promise for one day enabling BgRT in prostate cancer," said Shervin ‘Sean’ Shirvani, M.D., M.P.H., chief medical officer at RefleXion. "Also, our earliest clinical adopters are presenting work detailing commissioning of the very first commercial X1 machine, which has delivered hundreds of fractions of conventional radiotherapy, a critical step toward bringing BgRT to the clinic."

The following presentations taking place during ASTRO 2021 evaluate RefleXion’s X1 technology:

Sunday, Oct 24: Radiation and Cancer Physics

1:55 PM 1002 "Feasibility of using FDG in the Stereotactic Ablative Setting for Tracked Dose Delivery with BgRT: Results from a Prospective Study of Serial Inter-Fraction PET/CTs." (Oral Abstract, Room 178 a/b)
4:45 PM 2248 Poster Q&A 02 – Session 02 – "Dosimetric comparison of single-isocenter and multiple-isocenter techniques for two-lesion lung SBRT using the RefleXion high-speed ring-gantry system." (Room W375)
Monday, Oct 25, 11:20 AM: Radiation and Cancer Physics

40 "Physical validation of biology-guided radiotherapy for delivering a tracked dose distribution to a moving PET-avid target." (Oral Abstract, Room 184 a/b/c/d)
Tuesday, Oct 26:

1:30 PM 98 Radiation and Cancer Physics "Evaluation of PSMA-PET biology-guided radiotherapy sequential boost to the dominant intraprostatic lesion in low-volume advanced prostate cancer." (Oral Abstract, Room W185 a/b/c/d)
3:30 PM Poster Q&A 08 – Session 08 – Lung Cancer/Thoracic Malignancies and Palliative Care. (Outside Room 375)
2883 "Disease Burden on FDG-PET Predicts Outcomes for Advanced Non-Small Cell Cancer Patients Treated with First-Line Immunotherapy."
2884 "Characterization of the Entire Metastatic Spectrum for Non-Small Cell Lung Cancer in the Immunotherapy Era."
Wednesday, Oct. 27, 10:30 AM: Poster Q&A 09 – Session 09 – Physics Treatment Techniques and Patient Safety (Outside Room 375)

3067 "First Beam Commissioning Report of a Novel Medical Linear Accelerator Designed for Biologically Guided Radiotherapy."
3069 "Physical Confirmation of Biology-guided Radiotherapy Directed at Static Targets with Varying Shapes and Background Contrast Environments."
3074 "Comparison of a First-in-class LINAC-integrated PET System and a Diagnostic PET/CT Scanner."
3075 "Initial Evaluation of Biology-guided Radiotherapy (BgRT) Plans Generated Using PET Acquired on the First Installation of Reflexion X1 System."
3115 "The kVCT System Commissioning of a Novel Medical Linear Accelerator Designed for Biology-guided Radiotherapy."
3138 "Utilizing Biology-guided Radiotherapy for Coronary Artery Avoidance During Free-breathing External Beam Radiation Delivery."

On October 21, 2021 Biognosys, a leading inventor and developer of mass spectrometry-based proteomics solutions, reported they will be presenting major scientific and technological advances on their proprietary proteomics research services, software, and kits at the American Society for Mass Spectrometry (ASMS) Annual Conference from October 31st to November 4th in Philadelphia (USA) (Press release, Biognosys, OCT 21, 2021, View Source [SID1234591715]).

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Biognosys will present a record number of 3 oral presentations, 10 scientific posters, 2 poster collaborations, 1 workshop panel, and 2 Spectronaut breakfast seminars. In addition, their team of scientific experts will be present at booth #224 to answer questions and demo software. Further demo sessions will be offered at the Bruker Daltonics booth #719.

Collectively, this presence demonstrates Biognosys’ significant contributions to transforming life science and clinical research with next-generation proteomics, particularly in the areas of plasma proteomics, immunopeptidomics, and proteomics data analysis.

Lukas Reiter, PhD, Chief Technology Officer of Biognosys:
"Our major contribution to the ASMS scientific program is a testimony of Biognosys’ relentless commitment to innovation in mass spectrometry-based proteomics and progress in life science and clinical research."

Discovering biomarkers in cancer with next-generation plasma proteomics

The plasma proteome is an underexplored source of insights on the health state of an individual. Biognosys will present results from a deep human plasma profiling study on a cohort of 180 lung, breast, colorectal, pancreatic, and prostate cancer patients, using an early version of their next-generation Plasma Biomarker Discovery workflow, launching in November. The workflow is optimized for use on Thermo Fisher Scientific Exploris 480 and FAIMS Pro instruments. Out of the entire plasma proteome, they quantified over 2,700 proteins and identified a protein panel with a significant positive predictive value for individual cancer stages.

Andreas Huhmer, Senior Director Life Sciences Research OMICS Marketing at Thermo Fisher Scientific:
"Biognosys has a proven track record for maximizing all innovative features of the Thermo Scientific Orbitrap mass spectrometers in state-of-the-art proteome analysis. Their new Plasma Biomarker Discovery workflow is a good example of this. The unprecedented depth and quantitative precision they can achieve, coupled with the inherently unbiased nature of mass spectrometry-based analysis, has the potential to take plasma biomarker discovery to the next level."

Gaining insights on the immune system to support personalized drug development

Immunopeptides play an essential role in the immune system and can be analyzed to support the development of personalized treatments. Mass spectrometry is currently the only technology that can reliably measure and identify immunopeptide profiles of biological samples on a large scale. Biognosys will present their immunopeptidomics workflow, optimized to provide deep and comprehensive biological insights on the immune system in large-scale clinical studies.

Turning data to insights with Spectronaut, SpectroMine, and SpectroDive

Biognosys provides leading software products for proteomics data analysis. In a series of talks, their team will detail how they leverage the latest developments in Machine Learning and Deep Learning to allow deeper insights into the proteome. Biognosys is also excited to host two breakfast seminars with three guest speakers sharing their latest results from using Spectronaut in their research projects. In addition, a sneak-peak into the next planned release will be disclosed.

Gary Kruppa, Vice President, Proteomics at Bruker Daltonics:
"Biognosys’ software tools are among the top solutions for the analysis of proteomics data generated with Bruker instruments. Particularly the latest Spectronaut version yields spectacular performance improvements for dia-PASEF data. We invite all Bruker users to experience Spectronaut’s capabilities and enjoy the exceptional support Biognosys provides."

Visit biognosys.com/asms2021 for a complete overview of Biognosys’ presence at ASMS.

On October 21, 2021 Personalis, Inc. (Nasdaq: PSNL), a leader in advanced genomics for cancer, reported it will release its third quarter 2021 financial results before the market opens on Thursday, November 4, 2021 (Press release, Personalis, OCT 21, 2021, View Source [SID1234591713]). In conjunction with the release, the company will host a conference call and webcast that day at 5:30 a.m. Pacific Time / 8:30 a.m. Eastern Time to discuss its financial results and recent highlights.

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Interested parties may access the live call via telephone by dialing (866) 220-8061 for domestic callers or (470) 495-9168 for international callers, using conference ID: 7896264. The live webinar of the call may be accessed by visiting the Events section of the company’s website at investors.personalis.com. A replay of the webinar will be available shortly after the conclusion of the call and will be archived on the company’s website.

On October 21, 2021 Agilent Technologies Inc. (NYSE: A) reported it has received CE-IVD mark approval for the PD-L1 IHC 28-8 pharmDx to guide options for the first-line treatment of adult patients with HER2-negative advanced or metastatic gastric, gastroesophageal junction, or esophageal cancers (Press release, Agilent, OCT 21, 2021, View Source [SID1234591711]).

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"The added indication of PD-L1 IHC 28-8 pharmDx will give physicians in Europe important information to inform first-line treatment decisions for patients with these common and potentially deadly cancers"

Gastric (stomach) cancer is the fifth most common cancer and the fourth leading cause of cancer death worldwide, with over 1,000,000 new cases and approximately 770,000 deaths in 2020.1 Esophageal cancer is the seventh most common cancer and the sixth leading cause of death from cancer worldwide, with approximately 600,000 new cases and over 540,000 deaths in 2020. 1 Together with cancers of the gastroesophageal junction, they constitute an important – and growing – global health concern.

PD-L1 is a critical biomarker for response to anti-PD-1 therapies, including the immunotherapeutic agent OPDIVO (nivolumab). When used in conjunction with the PD-L1 IHC 28-8 pharmDx as a companion test, treatment with Opdivo in combination with chemotherapy provides the first and only PD-1-directed treatment to demonstrate superior overall survival (OS) and progression-free survival (PFS) when compared to chemotherapy alone in patients with advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) ≥ 5.

"The added indication of PD-L1 IHC 28-8 pharmDx will give physicians in Europe important information to inform first-line treatment decisions for patients with these common and potentially deadly cancers," said Sam Raha, president of the Agilent’s Diagnostics and Genomics Group. "Agilent values opportunities such as this to partner with pharmaceutical companies in the development of clinically relevant IHC-based or NGS-based diagnostics that enhance confidence in targeted cancer therapy."

This approval builds on Agilent’s previous successes in expanding the applicability of PD-L1 IHC tests and marks the latest milestone in their ongoing commitment to drug/diagnostic co-development.