GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets DOI Creative Commons
Paul A. Insel, Krishna Sriram,

Shu Z. Wiley

et al.

Frontiers in Pharmacology, Journal Year: 2018, Volume and Issue: 9

Published: May 22, 2018

G protein-coupled receptors (GPCRs), the largest family of targets for approved drugs, are rarely targeted cancer treatment, except certain endocrine and hormone-responsive tumors. Limited knowledge regarding GPCR expression in cells likely has contributed to this lack use GPCR-targeted drugs as therapeutics. We thus undertook GPCRomic studies define endoGPCRs (which respond endogenous hormones, neurotransmitters, metabolites) multiple types cells. Using TaqMan qPCR arrays quantify mRNA ~340 such GPCRs, we found that human chronic lymphocytic leukemia (CLL) cells/stromal associated with CLL, breast cell lines, colon pancreatic ductal adenocarcinoma (PDAC) cells, fibroblasts (CAFs), PDAC tumors express 50 >100 including many orphan GPCRs known physiologic agonists). prior data exist or function most highly expressed these Independent results from databases confirm GPCRs. propose (for example, GPRC5A GPR68 CAFs) may contribute malignant phenotype, serve biomarkers and/or be novel therapeutic treatment cancer.

Language: Английский

Exploiting senescence for the treatment of cancer DOI Open Access
Liqin Wang, Lina Lankhorst, René Bernards

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(6), P. 340 - 355

Published: March 3, 2022

Language: Английский

Citations

518
Evolving therapeutic landscape of advanced hepatocellular carcinoma DOI
Chen Yang, Hailin Zhang,

Linmeng Zhang

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2022, Volume and Issue: 20(4), P. 203 - 222

Published: Nov. 11, 2022

Language: Английский

Citations

442
Effective drug combinations in breast, colon and pancreatic cancer cells DOI Creative Commons
Patricia Jaaks, Elizabeth A. Coker,

Daniël J. Vis

et al.

Nature, Journal Year: 2022, Volume and Issue: 603(7899), P. 166 - 173

Published: Feb. 23, 2022

Abstract Combinations of anti-cancer drugs can overcome resistance and provide new treatments 1,2 . The number possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active the tissues molecular contexts in which they are most effective accelerate development combination treatments. Here we evaluate potency efficacy 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal pancreatic cancer cell lines. We show that synergy between is rare highly context-dependent, targeted agents likely synergistic. incorporate multi-omic features biomarkers specify synergistic their contexts, including basal-like breast cancer, microsatellite-stable or KRAS -mutant colon cancer. Our results irinotecan CHEK1 inhibition have effects – TP53 double-mutant cells, leading apoptosis suppression tumour xenograft growth. This study identifies distinct subpopulations resource guide rational efforts develop combinatorial

Language: Английский

Citations

302
Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen DOI Creative Commons
Michael P. Menden, Dennis Wang, Mike J. Mason

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: June 17, 2019

Abstract The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number possible combinations vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large combination dataset, consisting 11,576 experiments from 910 across 85 molecularly characterized cell lines, and results a DREAM Challenge evaluate computational strategies for predicting synergistic pairs biomarkers. 160 teams participated provide comprehensive methodological development benchmarking. Winning methods incorporate prior knowledge drug-target interactions. Synergy predicted an accuracy matching biological replicates >60% 20% are poorly by all methods. Genomic rationale synergy predictions identified, including ADAM17 inhibitor antagonism when combined PIK3CB/D inhibition contrasting other PI3K-pathway inhibitors in PIK3CA mutant cells.

Language: Английский

Citations

301
Breaking the selectivity-uptake trade-off of photoimmunoconjugates with nanoliposomal irinotecan for synergistic multi-tier cancer targeting DOI Creative Commons
Barry J. Liang, Michael Pigula, Yan Baglo

et al.

Journal of Nanobiotechnology, Journal Year: 2020, Volume and Issue: 18(1)

Published: Jan. 2, 2020

Abstract Background Photoimmunotherapy involves targeted delivery of photosensitizers via an antibody conjugate (i.e., photoimmunoconjugate, PIC) followed by light activation for selective tumor killing. The trade-off between PIC selectivity and uptake is a major drawback limiting the efficacy photoimmunotherapy. Despite ample evidence showing that photoimmunotherapy most effective when combined with chemotherapy, design nanocarriers to co-deliver PICs chemotherapy drugs remains unmet need. To overcome these challenges, we developed novel photoimmunoconjugate-nanoliposome (PIC-Nal) comprising three clinically used agents: anti-epidermal growth factor receptor (anti-EGFR) monoclonal cetuximab (Cet), benzoporphyrin derivative (BPD) photosensitizer, irinotecan (IRI) chemotherapy. Results BPD were first tethered Cet at molar ratio 6:1 using carbodiimide chemistry form PICs. Conjugation onto nanoliposome (Nal–IRI) was facilitated copper-free click chemistry, which resulted in monodispersed PIC–Nal–IRI average size 158.8 ± 15.6 nm. highly against EGFR-overexpressing epithelial ovarian cancer cells 2- 6-fold less accumulation low EGFR expressing cells. Successful coupling Nal–IRI enhanced up 30% OVCAR-5 Furthermore, synergistically reduced viability unique three-way mechanism downregulation, mitochondrial depolarization, DNA damage). Conclusion It increasingly evident therapies will involve combination treatments target multiple non-overlapping pathways while minimizing side effects. Nanotechnology photochemistry provides opportunity simultaneously deliver activate all regions cell—plasma membrane, cytoplasm, nucleus. offers promising strategy selectivity-uptake trade-off, improve efficacy, enable multi-tier targeting. Controllable drug compartmentalization, easy surface modification, high clinical relevance collectively make extremely valuable merits further investigations living animals.

Language: Английский

Citations

259
The Genetic/Non-genetic Duality of Drug ‘Resistance’ in Cancer DOI
Ravi Salgia, Prakash Kulkarni

Trends in cancer, Journal Year: 2018, Volume and Issue: 4(2), P. 110 - 118

Published: Feb. 1, 2018

Language: Английский

Citations

241
Maximising the potential of AKT inhibitors as anti-cancer treatments DOI Creative Commons
Jessica Brown, Udai Banerji

Pharmacology & Therapeutics, Journal Year: 2016, Volume and Issue: 172, P. 101 - 115

Published: Dec. 3, 2016

PI3K/AKT signalling is commonly disrupted in human cancers, with AKT being a central component of the pathway, influencing multiple processes that are directly involved tumourigenesis. Targeting therefore highly attractive anti-cancer strategy inhibitors now various stages clinical development. In this review, we summarise role and regulation normal cellular physiology. We highlight mechanisms by which can be hyperactivated cancers discuss past, present future strategies for inhibition oncology.

Language: Английский

Citations

209
Metallodrugs in cancer nanomedicine DOI
Quim Peña, Alec Wang, Orysia Zaremba

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(7), P. 2544 - 2582

Published: Jan. 1, 2022

Metal complexes are extensively used for cancer therapy. The multiple variables available tuning (metal, ligand, and metal-ligand interaction) offer unique opportunities drug design, have led to a vast portfolio of metallodrugs that can display higher diversity functions mechanisms action with respect pure organic structures. Clinically approved metallodrugs, such as cisplatin, carboplatin oxaliplatin, treat many types play prominent roles in combination regimens, including immunotherapy. However, generally suffer from poor pharmacokinetics, low levels target site accumulation, metal-mediated off-target reactivity development resistance, which all limit their efficacy clinical translation. Nanomedicine has arisen powerful tool help overcome these shortcomings. Several nanoformulations already significantly improved the reduced toxicity (chemo-)therapeutic drugs, some promising metallodrug-containing nanomedicines currently trials. In this critical review, we analyse challenges assess advantages limitations metallodrug delivery, both nanocarrier metal-nano interaction perspective. We describe latest most relevant nanomedicine formulations developed metal complexes, discuss how rational coordination chemistry technology assist promoting translation metallodrugs.

Language: Английский

Citations

144
Gene expression based inference of cancer drug sensitivity DOI Creative Commons

Smriti Chawla,

Anja Rockstroh, Melanie Lehman

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 27, 2022

Abstract Inter and intra-tumoral heterogeneity are major stumbling blocks in the treatment of cancer responsible for imparting differential drug responses patients. Recently, availability high-throughput screening datasets has paved way machine learning based personalized therapy recommendations using molecular profiles specimens. In this study, we introduce Precily, a predictive modeling approach to infer response cancers gene expression data. context, demonstrate benefits considering pathway activity estimates tandem with descriptors as features. We apply Precily on single-cell bulk RNA sequencing data associated hundreds cell lines. then assess predictability outcomes our in-house prostate line xenografts exposed conditions. Further, applicability patient from The Cancer Genome Atlas an independent clinical study describing journey three melanoma Our findings highlight importance chemo-transcriptomics approaches selection.

Language: Английский

Citations

81
Targeted nanomedicine in cisplatin-based cancer therapeutics DOI Creative Commons
Yu Han,

Panyue Wen,

Junjie Li

et al.

Journal of Controlled Release, Journal Year: 2022, Volume and Issue: 345, P. 709 - 720

Published: March 31, 2022

Language: Английский

Citations

74