Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and has gained considerable global attention. Epidermal growth factor receptor (EGFR) plays a key role in NSCLC treatment. NSCLC with wild-type EGFR (WT-EGFR) is not responsive to EGFR tyrosine kinase inhibitors (TKIs), and chemotherapy, such as cisplatin (cDDP), continues to be utilized as a primary clinical treatment. However, the therapeutic efficacy of cDDP remains limited. Therefore, there exists an urgent need for the development of novel therapeutic strategies. Cudratricusxanthone A (CTXA) as a natural bioactive xanthone exhibits potential antitumor activity, but the mechanism has been unknown. In this study, we aimed to evaluate the potential antitumor effect and mechanism of CTXA against NSCLC with WT-EGFR by cell experiments, molecular dynamics simulation and surface plasmon resonance (SPR) technology. Our results showed that CTXA inhibited cell proliferation in NSCLC cells by suppressing the EGFR/Erk/AKT pathway. Additionally, CTXA exhibited antitumor effects by inhibiting the migration of A549 cells, causing G1 phase arrest, and inducing cell apoptosis. Further investigation revealed that these effects were mediated by the binding of CTXA to EGFR, with a K_D value of 6.302 × 10^- 5 M. This interaction may lead to the suppression of EGFR phosphorylation and its downstream signaling. Moreover, the synergistic inhibition of CTXA in combination with cDDP was also found to be mediated by the suppression of the EGFR pathway and its downstream signaling. We demonstrated that CTXA exhibited antitumor activity and enhanced chemosensitivity to cDDP against NSCLC via the EGFR signaling. Our findings indicate that the utilization of CTXA alone or in combination with cDDP represents a potential novel candidate against NSCLC harboring WT-EGFR.

01 Mar 2023·The bone & joint journal

CT required to perform robotic-assisted total hip arthroplasty can identify previously undiagnosed osteoporosis and guide femoral fixation strategy

Article

Author: Binkley, Neil ; Illgen, Richard ; Sandhu, Kevin P. ; Pickhardt, Perry J. ; Bernatz, James T. ; Anderson, Paul A. ; Bukowski, Brett R.

Aims:

Osteoporosis can determine surgical strategy for total hip arthroplasty (THA), and perioperative fracture risk. The aims of this study were to use hip CT to measure femoral bone mineral density (BMD) using CT X-ray absorptiometry (CTXA), determine if systematic evaluation of preoperative femoral BMD with CTXA would improve identification of osteopenia and osteoporosis compared with available preoperative dual-energy X-ray absorptiometry (DXA) analysis, and determine if improved recognition of low BMD would affect the use of cemented stem fixation.

Methods:

Retrospective chart review of a single-surgeon database identified 78 patients with CTXA performed prior to robotic-assisted THA (raTHA) (Group 1). Group 1 was age- and sex-matched to 78 raTHAs that had a preoperative hip CT but did not have CTXA analysis (Group 2). Clinical demographics, femoral fixation method, CTXA, and DXA data were recorded. Demographic data were similar for both groups.

Results:

Preoperative femoral BMD was available for 100% of Group 1 patients (CTXA) and 43.6% of Group 2 patients (DXA). CTXA analysis for all Group 1 patients preoperatively identified 13 osteopenic and eight osteoporotic patients for whom there were no available preoperative DXA data. Cemented stem fixation was used with higher frequency in Group 1 versus Group 2 (28.2% vs 14.3%, respectively; p = 0.030), and in all cases where osteoporosis was diagnosed, irrespective of technique (DXA or CTXA).

Conclusion:

Preoperative hip CT scans which are routinely obtained prior to raTHA can determine bone health, and thus guide femoral fixation strategy. Systematic preoperative evaluation with CTXA resulted in increased recognition of osteopenia and osteoporosis, and contributed to increased use of cemented femoral fixation compared with routine clinical care; in this small study, however, it did not impact short-term periprosthetic fracture risk.Cite this article: Bone Joint J 2023;105-B(3):254–260.

27 Jul 2021·ACS nanoQ1 · MATERIALS SCIENCE

Tuning the Diameter, Stability, and Membrane Affinity of Peptide Pores by DNA-Programmed Self-Assembly

Q1 · MATERIALS SCIENCE

Article

Author: Yang, Jerry ; Bertani, Frederick ; Sukyte, Viktorija ; Rodriguez Gonzalo, Sandra ; Ducrey, Julie ; List, Jonathan ; Mayer, Simon F. ; Vargas, Reyner D. ; Pascual Fernandez, Laura ; Mayer, Michael ; Dupasquier, Jessica ; Fennouri, Aziz

Protein pores recently enabled a breakthrough in bioanalytics by making it possible to sequence individual DNA and RNA strands during their translocation through the lumen of the pore. Despite this success and the overall promise of nanopore-based single-molecule analytics, protein pores have not yet reached their full potential for the analysis and characterization of globular biomolecules such as natively folded proteins. One reason is that the diameters of available protein pores are too small for accommodating the translocation of most folded globular proteins through their lumen. The work presented here provides a step toward overcoming this limitation by programmed self-assembly of α-helical pore-forming peptides with covalently attached single-stranded DNA (ssDNA). Specifically, hybridization of the peptide ceratotoxin A (CtxA) with N-terminally attached ssDNA to a complementary DNA template strand with 4, 8, or 12 hybridization sites made it possible to trigger the assembly of pores with various diameters ranging from approximately 0.5 to 4 nm. Hybridization of additional DNA strands to these assemblies achieved extended functionality in a modular fashion without the need for modifying the amino acid sequence of the peptides. For instance, functionalization of these semisynthetic biological nanopores with DNA-cholesterol anchors increased their affinity to lipid membranes compared to pores formed by native CtxA, while charged transmembrane segments prolonged their open-state lifetime. Assembly of these hybrid DNA-peptides by a template increased their cytotoxic activity and made it possible to kill cancer cells at 20-fold lower total peptide concentrations than nontemplated CtxA.

News (Medical) associated with CTXA-8

17 Jan 2024

·pipelinereview.com

VRG Therapeutics announces successful in vivo efficacy results of their CAR-T project targeting glioblastoma

BUDAPEST, Hungary I January 16, 2024 I VRG Therapeutics Plc. announces successful in vivo efficacy results of their CAR-T project with patented chlorotoxin analogue targeting glioblastoma, encouraging further development. VRG Therapeutics (VRG Tx), a biotechnology R&D company focused on miniprotein pharmaceuticals and cellular & gene therapy (CGT) products has announced that their proprietary chlorotoxin (CTX) analogue, CTXA8, applied as a targeting molecule in chimeric antigen receptor T (CAR-T) cells, shows efficacy in an in vivo heterotopic glioblastoma murine model. CTXA8 has been developed leveraging VRG Tx’s AI-powered miniprotein platform. The promising preclinical results give a solid background to speed up the allogenic gamma-delta CAR-T (γδCAR-T) program. The company is committed to proceed with the project towards clinical development and is looking for a co-development partner with expertise in CAR-T preclinical and clinical development. CAR-T therapy targeting brain tumors: CAR-T cells are modified white blood cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen that holds the potential of identification and elimination of cancer cells. The extraordinary therapeutic effect experienced with CAR-T cell therapies targeting hematological malignancies have drawn interest in developing similar products for solid tumors, including brain tumors. High overexpression of MMP2 protein on tumor cells is a recently utilized new target in CAR-T therapy in glioblastoma. The expected increased safety and efficacy of CTXA8-based CAR-T therapy can be explained by the enhanced affinity and selectivity of CTXA8 versus original CTX towards MMP2 overexpressing tumors, such as glioblastoma. VRG Tx’s animal in vivo proof of concept (PoC) study: VRG Tx established a heterotopic xenograft mice model to demonstrate the effectiveness and safety of its CTXA8-targeting CAR-T cell therapy that is designed to treat patients with glioblastoma multiforme (a common type of brain tumor). The mouse model closely mirrors the clinical trial that is currently ongoing with CAR-T cells targeting the original CTX (NCT04214392, City of Hope Medical Center). CTXA8-CAR-T cells showed effective tumor growth inhibition compared to non-specific T cell controls at three different dose levels. The highest dose of administered CTXA8-CAR-T resulted in over 60% inhibition of tumor growth including two individuals with complete tumor remission. The animals did not show any signs of toxicity or body weight loss during the study indicating promising safety features. VRG Tx’s allogenic CAR-T therapy targeting brain tumors: VRG Tx is currently looking for a co-development partner experienced in allogenic CAR-T development, to step into preclinical phase with its proprietary CTXA8 analogue applied in allogenic cell therapy applications. Based on the same MoA, in vitro results of VRG Tx’s CTXA8- γδCAR-T cells show efficacy and high durability against glioblastoma multiforme cells. About VRG Tx’s Miniprotein platform utilizing ISEP and WISDOM technologies: VRG Tx’s proprietary miniprotein technology leverages artificial intelligence (AI) and pioneers in protein engineering to create CGT and peptide-based applications. The Wetlab-verified In Silico Design of Miniproteins (WISDOM) and Individual Sequence Enrichment Pattern (ISEP) technologies build on the evolutionary conserved structures of natural peptides and applies both in silico and in vitro high throughput screenings. Combining AI-powered interaction modelling with NGS-based advanced analytics, VRG Tx designs novel therapeutic candidates with unprecedented selectivity and affinity in an extremely fast discovery process. Miniproteins combine the benefits of small molecules and biologics. About VRG Tx: VRG Therapeutics is an original biopharmaceutical research and development company located in Budapest, Hungary. VRG Tx’s vision is to leverage its unique miniprotein ISEP and WISDOM technologies to create cure for diseases through targets and mechanisms of action that are beyond the reach of conventional biopharma approaches. For more information, please visit www.vrgtherapeutics.com . SOURCE: VRG Therapeutics

Cell TherapyImmunotherapyClinical Study

100 Deals associated with CTXA-8

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Preclinical	Hungary	VRG Therapeutics	10 Oct 2024
Glioblastoma	Preclinical	Hungary	VRG Therapeutics	17 Jan 2024

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