Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways DOI Creative Commons
Zhi Zhu, A. J. Robert McGray, Weijian Jiang

et al.

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Oct. 11, 2022

Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness OV as monotherapy remains limited, and thus investigators have been exploring various combinations other anti-cancer agents demonstrated improved As cancer cells evolved alter signaling pathways enhanced cell proliferation, progression metastasis, these cellular molecular changes offer promising targets rational therapy design. In this regard, molecules in relevant or/and immune cells, such EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, epigenetic, or histone deacetylases, cGAS-STING) are currently under investigation potential synergize modulate milieu tumor microenvironment (TME), thereby improving sustaining immunity. many small molecule modulators developed shown strong potential, here we review findings related both OV-mediated immunotherapy utility immuno-oncology. Then, focus on discussion rationales strategies combining selected targeting TME enhance Finally, provide perspectives viewpoints application novel experimental systems technologies that can propel exciting branch medicine into bright future.

Language: Английский

Advances in covalent drug discovery DOI Open Access
Lydia Boike, Nathaniel J. Henning, Daniel K. Nomura

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(12), P. 881 - 898

Published: Aug. 25, 2022

Language: Английский

Citations

485
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials DOI Creative Commons
Xin Xie, Tingting Yu, Xiang Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

Citations

166
Therapeutic developments in pancreatic cancer DOI
Zilun Hu, Eileen M. O’Reilly

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 21(1), P. 7 - 24

Published: Oct. 5, 2023

Language: Английский

Citations

143
Adagrasib: First Approval DOI

Sohita Dhillon

Drugs, Journal Year: 2023, Volume and Issue: 83(3), P. 275 - 285

Published: Feb. 1, 2023

Language: Английский

Citations

90
Endometriosis and adenomyosis: shared pathophysiology DOI Creative Commons
Serdar E. Bulun, Şule Yıldız, Mazhar Adli

et al.

Fertility and Sterility, Journal Year: 2023, Volume and Issue: 119(5), P. 746 - 750

Published: March 15, 2023

Language: Английский

Citations

85
Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme DOI Creative Commons
Alona Sosinsky,

John C. Ambrose,

William Cross

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(1), P. 279 - 289

Published: Jan. 1, 2024

Abstract The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities precision cancer care within UK National Healthcare System (NHS). Genomics England, alongside NHS analyzed WGS data from 13,880 solid tumors spanning 33 types, integrating genomic real-world treatment and outcome data, a secure Research Environment. Incidence somatic mutations in genes recommended standard-of-care testing varied across types. For instance, glioblastoma multiforme, small variants were present 94% cases copy number aberrations at least one gene 58% cases, while sarcoma demonstrated highest occurrence actionable structural (13%). Homologous recombination deficiency identified 40% high-grade serous ovarian 30% linked pathogenic germline variants, highlighting value combined analysis. linkage longitudinal life course clinical allowed assessment outcomes stratified according pangenomic markers. Our findings demonstrate utility linking enable survival analysis identify that affect prognosis advance our understanding how genomics impacts patient outcomes.

Language: Английский

Citations

83
Expanding PROTACtable genome universe of E3 ligases DOI Creative Commons
Yuan Liu, Jingwen Yang, Tianlu Wang

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 16, 2023

Abstract Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce by the ubiquitin-proteasome system (UPS) offer new opportunities to engage targets remain challenging be inhibited conventional small molecules. One fundamental element in process is E3 ligase. However, less than 2% amongst hundreds of ligases human genome have been engaged current studies TPD field, calling for recruiting additional ones further enhance therapeutic potential TPD. To accelerate development PROTACs utilizing under-explored ligases, we systematically characterize from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, PPI interface analyzing 30 large-scale data sets. Our analysis uncovers several as promising extant PROTACs. In total, combining confidence score, pattern, PPI, identified 76 PROTAC-interacting candidates. We develop a user-friendly flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers rapidly identify with activities against specifically desired targets, facilitating these therapies cancer beyond.

Language: Английский

Citations

76
Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer DOI Open Access
E O'Sullivan, Anna Keogh,

Brian E. Henderson

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(6), P. 1635 - 1635

Published: March 7, 2023

Activating mutations in KRAS are highly prevalent solid tumours and frequently found 35% of lung, 45% colorectal, up to 90% pancreatic cancers. Mutated is a prognostic factor for disease-free survival (DFS) overall (OS) NSCLC associated with more aggressive clinical phenotype, highlighting the need KRAS-targeted therapy. Once considered undruggable due its smooth shallow surface, breakthrough showed that activated G12C-mutated isozyme can be directly inhibited via newly identified switch II pocket. This discovery led development new class selective small-molecule inhibitors against G12C isoform. Sotorasib adagrasib approved locally advanced or metastatic patients who have received at least one prior systemic Currently, there twelve being tested trials, either as single agent combination. In this study, mutation prevalence, subtypes, rates occurrence treatment-resistant invasive mucinous adenocarcinomas (IMAs), novel drug delivery options reviewed. Additionally, current status inhibitors, multiple resistance mechanisms limit efficacy, their use combination treatment strategies multitargeted approaches discussed.

Language: Английский

Citations

47
Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications DOI Creative Commons
Mateusz Kciuk, Manzar Alam, Nemat Ali

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(13), P. 5246 - 5246

Published: July 6, 2023

Cellular signaling pathways involved in the maintenance of equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited prevention treatment cancer. Epigallocatechin-3-gallate (EGCG) is most abundant phenolic compound found green tea. It has been shown to regulate multiple crucial cellular pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, others. Deregulation abovementioned pathophysiology demonstrated EGCG may exert anti-proliferative, anti-inflammatory, apoptosis-inducing effects or induce epigenetic changes. Furthermore, preclinical clinical studies suggest used numerous disorders, This review aims summarize existing knowledge regarding biological properties EGCG, especially context cancer prophylaxis.

Language: Английский

Citations

46
Targeting cancer with small-molecule pan-KRAS degraders DOI
Johannes Popow, William Farnaby, Andreas Gollner

et al.

Science, Journal Year: 2024, Volume and Issue: 385(6715), P. 1338 - 1347

Published: Sept. 19, 2024

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule potently degrades 13 out 17 most alleles. Compared inhibition, degradation results more profound sustained pathway modulation across broad range mutant cell lines, killing cancer cells while sparing models without genetic aberrations. Pharmacological was tolerated led to tumor regression vivo. Together, these findings unveil new path toward addressing KRAS-driven cancers degraders.

Language: Английский

Citations

38