Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers DOI Open Access
Lindsey Carlsen, Kelsey E. Huntington, Wafik S. El‐Deiry

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(4), P. 1028 - 1028

Published: Feb. 17, 2022

Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after metastasizes. Frontline treatments for such as chemotherapy and radiation often produce dose-limiting toxicities in patients acquired resistance cells. Additional targeted are needed improve patient outcomes quality life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules engage train immune system kill Preclinical clinical investigations immunotherapy including checkpoint blockade, adoptive cell therapy, monoclonal oncolytic anti-cancer vaccines, modulators have been promising, but demonstrate limitations proficient mismatch repair enzymes. In review, we discuss preclinical studies investigating predictive biomarkers response these treatments. We also consider open questions optimal combination maximize efficacy, minimize toxicity, prevent approaches sensitize repair-proficient immunotherapy.

Language: Английский

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity DOI

Jude Canon,

Karen Rex,

Anne Y. Saiki

et al.

Nature, Journal Year: 2019, Volume and Issue: 575(7781), P. 217 - 223

Published: Oct. 30, 2019

Language: Английский

Citations

1803
Comprehensive review of targeted therapy for colorectal cancer DOI Creative Commons
Yuanhong Xie, Yingxuan Chen, Jing‐Yuan Fang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: March 20, 2020

Abstract Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in world was responsible for nearly 881,000 cancer-related deaths 2018. Surgery chemotherapy have long been first choices patients. However, prognosis of CRC has never satisfying, especially patients with metastatic lesions. Targeted therapy a new optional approach that successfully prolonged overall survival Following successes anti-EGFR (epidermal growth factor receptor) agent cetuximab anti-angiogenesis bevacizumab, agents blocking different critical pathways as well immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide currently updating recommended targeted drugs on basis increasing number high-quality clinical trials. This review provides overview existing CRC-targeted their underlying mechanisms, discussion limitations future trends.

Language: Английский

Citations

1313
Kinase-targeted cancer therapies: progress, challenges and future directions DOI Creative Commons
Khushwant S. Bhullar,

Naiara Orrego Lagarón,

Eileen McGowan

et al.

Molecular Cancer, Journal Year: 2018, Volume and Issue: 17(1)

Published: Feb. 15, 2018

The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these are associated with cancer initiation and progression. recent development small-molecule kinase inhibitors for the treatment diverse types has proven successful in clinical therapy. Significantly, second most targeted drug targets, after G-protein-coupled receptors. Since first inhibitor, early 1980s, 37 have received FDA approval malignancies such as breast lung cancer. Furthermore, about 150 kinase-targeted drugs phase trials, many kinase-specific preclinical stage development. Nevertheless, factors confound efficacy molecules. Specific tumor genetics, microenvironment, resistance, pharmacogenomics determine how useful compound will be given This review provides an overview discovery relation oncology highlights challenges future potential therapies.

Language: Английский

Citations

1054
Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors DOI
Anju Singh, Sreedhar Venkannagari, Kyu Hee Oh

et al.

ACS Chemical Biology, Journal Year: 2016, Volume and Issue: 11(11), P. 3214 - 3225

Published: Aug. 23, 2016

Loss of function mutations in Kelch-like ECH Associated Protein 1 (KEAP1), or gain-of-function nuclear factor erythroid 2-related 2 (NRF2), are common non-small cell lung cancer (NSCLC) and associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughput screen using diverse set ∼400 000 small molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the National Center Advancing Translational Sciences. We identified ML385 as probe molecule that binds to inhibits its downstream target gene expression. Specifically, Neh1, Cap 'N' Collar Basic Leucine Zipper (CNC-bZIP) domain NRF2, interferes binding V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homologue G (MAFG)-NRF2 protein complex regulatory DNA sequences. In clonogenic assays, when used combination platinum-based drugs, doxorubicin taxol, substantially enhances cytotoxicity NSCLC cells, compared single agents. shows specificity selectivity cells KEAP1 mutation, leading gain function. preclinical models function, carboplatin showed significant antitumor activity. demonstrate discovery validation specific inhibitor conclude targeting may represent promising strategy treatment advanced NSCLC.

Language: Английский

Citations

466
Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer DOI Open Access
Sorbarikor Piawah, Alan P. Venook

Cancer, Journal Year: 2019, Volume and Issue: 125(23), P. 4139 - 4147

Published: Aug. 21, 2019

Despite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding pathways implicated evolution proliferation cancer cells has led to development targeted therapies, that is, agents with action directed at these pathways/features. This approach is more specific within which pathways, such as epidermal growth factor receptor (EGFR), overactive; this contrast relatively indiscriminate mechanism by cytotoxic chemotherapy tends affect rapidly dividing cells, regardless their role. Although factors unique given patient, location primary tumor (sidedness) or presence mutations confer resistance, may limit utility agents, therapies now part treatment paradigm for survival outcomes have significantly improved. review provides an overview role therapy metastases well discussion issues patient selection, focus on inhibitors angiogenesis, EGFR‐targeted therapy, BRAF mutation–targeted other novel strategies, including immunotherapy.

Language: Английский

Citations

407
Cellular and molecular mechanisms of kidney fibrosis DOI
Sonja Djudjaj, Peter Boor

Molecular Aspects of Medicine, Journal Year: 2018, Volume and Issue: 65, P. 16 - 36

Published: June 22, 2018

Language: Английский

Citations

377
Cutaneous adverse effects of targeted therapies DOI
James B. Macdonald,

Brooke Macdonald,

Loren E. Golitz

et al.

Journal of the American Academy of Dermatology, Journal Year: 2015, Volume and Issue: 72(2), P. 203 - 218

Published: Jan. 12, 2015

Language: Английский

Citations

223
CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation DOI
Kenji Kashima,

Hiroki Kawauchi,

Hiromi Tanimura

et al.

Molecular Cancer Therapeutics, Journal Year: 2020, Volume and Issue: 19(11), P. 2288 - 2297

Published: Sept. 18, 2020

Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric TKIs (e.g., EAI-045) that potentially overcome L858R/T790M/C797S identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having potential to EGFR-Del19/T790M/C797S. showed potent antitumor activities tumor with EGFR-Del19/T790M/C797S in vitro and vivo addition EGFR-Del19/T790M/C797S, characterization assays more selectively inhibits various types mutants L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, L858R) over wild type. Furthermore, crystal structure analysis suggested a noncovalent ATP-competitive for utilizes multiple interactions EGFR's αC-helix-in conformation achieve inhibitory activity mutant selectivity. Therefore, conclude therapy patients, especially cases

Language: Английский

Citations

145
The gold complex auranofin: new perspectives for cancer therapy DOI Creative Commons

Farah H. Abdalbari,

Carlos M. Telleria

Discover Oncology, Journal Year: 2021, Volume and Issue: 12(1)

Published: Oct. 20, 2021

Abstract Advanced stages of cancer are highly associated with short overall survival in patients due to the lack long-term treatment options following standard form care. New for therapy needed improve without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that currently enrolled clinical trials potential repurposing cancer. mainly targets anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects cell from oxidative stress and death cytoplasm mitochondria. TrxR over-expressed many cancers as an adaptive mechanism proliferation, rendering it attractive target therapy, auranofin therapeutic Inhibiting dysregulates intracellular redox state causing increased reactive oxygen species levels, stimulates cellular demise. An alternate action mimic proteasomal inhibition blocking ubiquitin–proteasome (UPS), critically important cells prevent when compared non-cancer cells, because its role on cycle regulation, protein degradation, gene expression, DNA repair. This article provides new perspectives mechanisms used alone, combination diverse other compounds, or platinating agents and/or immune checkpoint inhibitors combat while assessing feasibility setting.

Language: Английский

Citations

108
Current Targeted Therapy for Metastatic Colorectal Cancer DOI Open Access
Tomokazu Ohishi, Mika K. Kaneko, Yukihiro Yoshida

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1702 - 1702

Published: Jan. 15, 2023

Colorectal cancer (CRC) is the third most common type of and second leading cause deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as main therapeutic strategies until early 2000s, when targeted drugs, like cetuximab bevacizumab, developed. The use drugs in clinical practice has significantly increased patients’ overall survival. To date, emergence several types opened new possibilities revealed prospects mCRC treatment. Therapeutic are continually being updated to select suitable based on results trials that currently underway. This review discusses up-to date molecular evidence therapy summarizes Food Drug Administration-approved including trials. We also explain their mechanisms action how these affect choice a therapy.

Language: Английский

Citations

66