scholarly journals Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Daolin Tang ◽  
Guido Kroemer ◽  
Rui Kang
Keyword(s):  
Cancer Progression ◽  
Drug Binding ◽  
Precision Oncology ◽  
Secondary Resistance ◽  
New Era ◽  
Loop Region ◽  
Downstream Effectors ◽  
Covalent Inhibitors ◽  
Expression Processing ◽  
Upstream Regulators

AbstractAcross a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.

scholarly journals Current status of ctDNA in precision oncology for hepatocellular carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yan Li ◽  
Yuanyuan Zheng ◽  
Liwei Wu ◽  
Jingjing Li ◽  
Jie Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Diagnostic Technique ◽  
Response Assessment ◽  
Selection Response ◽  
Circulating Tumor Dna ◽  
Current Status ◽  
Precision Oncology ◽  
Tumor Biopsy ◽  
Non Invasive

AbstractThe conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.

scholarly journals Precision oncology: A new era of cancer clinical trials

2017 ◽  
Vol 387 ◽  
pp. 121-126 ◽  
Author(s):  
Lindsay A. Renfro ◽  
Ming-Wen An ◽  
Sumithra J. Mandrekar
Keyword(s):  
Clinical Trials ◽  
Cancer Clinical Trials ◽  
Precision Oncology ◽  
New Era

scholarly journals Targeting CD82/KAI1 for Precision Therapeutics in Surmounting Metastatic Potential in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4486
Author(s):  
Maximillian Viera ◽  
George Wai Cheong Yip ◽  
Han-Ming Shen ◽  
Gyeong Hun Baeg ◽  
Boon Huat Bay
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Therapeutic Approach ◽  
Traditional Approach ◽  
Unmet Need ◽  
Great Promise ◽  
Metastasis Suppressor ◽  
Precision Oncology ◽  
Breast Cancer Patients

Metastasis is the main cause of mortality in breast cancer patients. There is an unmet need to develop therapies that can impede metastatic spread. Precision oncology has shown great promise for the treatment of cancers, as the therapeutic approach is tailored to a specific group of patients who are likely to benefit from the treatment, rather than the traditional approach of “one size fits all”. CD82, also known as KAI1, a glycoprotein belonging to the tetraspanin family and an established metastasis suppressor, could potentially be exploited to hinder metastases in breast cancer. This review explores the prospect of targeting CD82 as an innovative therapeutic approach in precision medicine for breast cancer patients, with the goal of preventing cancer progression and metastasis. Such an approach would entail the selection of a subset of breast cancer patients with low levels of CD82, and instituting an appropriate treatment scheme tailored towards restoring the levels of CD82 in this group of patients. Proposed precision treatment regimens include current modalities of treating breast cancer, in combination with either clinically approved drugs that could restore the levels of CD82, CD82 peptide mimics or non-coding RNA-based therapeutics.

scholarly journals Artificial intelligence-aided clinical annotation of a large multi-cancer genomic dataset

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kenneth L. Kehl ◽  
Wenxin Xu ◽  
Alexander Gusev ◽  
Ziad Bakouny ◽  
Toni K. Choueiri ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Language Processing ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Precision Oncology ◽  
Free Survival ◽  
Clinical Endpoints ◽  
Mutation Burden ◽  
Clinical Annotation ◽  
Cancer Types

AbstractTo accelerate cancer research that correlates biomarkers with clinical endpoints, methods are needed to ascertain outcomes from electronic health records at scale. Here, we train deep natural language processing (NLP) models to extract outcomes for participants with any of 7 solid tumors in a precision oncology study. Outcomes are extracted from 305,151 imaging reports for 13,130 patients and 233,517 oncologist notes for 13,511 patients, including patients with 6 additional cancer types. NLP models recapitulate outcome annotation from these documents, including the presence of cancer, progression/worsening, response/improvement, and metastases, with excellent discrimination (AUROC > 0.90). Models generalize to cancers excluded from training and yield outcomes correlated with survival. Among patients receiving checkpoint inhibitors, we confirm that high tumor mutation burden is associated with superior progression-free survival ascertained using NLP. Here, we show that deep NLP can accelerate annotation of molecular cancer datasets with clinically meaningful endpoints to facilitate discovery.

scholarly journals Comprehensive Characterization of Androgen-Responsive lncRNAs Mediated Regulatory Network in Hormone-Related Cancers

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Dan Wang ◽  
Mingyue Li ◽  
Jing Li ◽  
Xuechao Wan ◽  
Yan Huang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Regulatory Network ◽  
Bioinformatics Analysis ◽  
Mapk Signaling ◽  
Ppi Network ◽  
Network Analyses ◽  
Comprehensive Characterization ◽  
Upstream Regulators

The AR signaling pathway plays an important role in initiation and progression of many hormone-related cancers including prostate, bladder, kidney, lung, and breast cancer. However, the potential roles of androgen-responsive long noncoding RNAs (lncRNAs) in hormone-related cancers remained unclear. In the present study, we identified 469 novel androgen-responsive lncRNAs using microarray data. After validating the accuracy of the array data, we constructed a transcriptional network which contained more than 30 transcriptional factors using ChIP-seq data to explore upstream regulators of androgen-responsive lncRNAs. Next, we conducted bioinformatics analysis to identify lncRNA-miRNA-mRNA regulatory network. To explore the potential roles of androgen-responsive lncRNAs in hormone-related cancers, we performed coexpression network and PPI network analyses using TCGA data. GO and KEGG analyses showed these lncRNAs were mainly involved in regulating signal transduction, transcription, development, cell adhesion, immune response, cell differentiation, and MAPK signaling pathway. We also highlight the prognostic value of HPN-AS1, TPTEP1, and LINC00623 in cancer outcomes. Our results suggest that androgen-responsive lncRNAs played important roles in regulating hormone-related cancer progression and could be novel molecular biomarkers.

scholarly journals CRISPR-mediated modification of DNA methylation pattern in the new era of cancer therapy

Epigenomics ◽  
2020 ◽  
Vol 12 (20) ◽  
pp. 1845-1859
Author(s):  
Faezeh Maroufi ◽  
Amirhosein Maali ◽  
Meghdad Abdollahpour-Alitappeh ◽  
Mohammad Hossein Ahmadi ◽  
Mehdi Azad
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cancer Progression ◽  
Methylation Pattern ◽  
Epigenetic Therapy ◽  
Special Importance ◽  
New Era ◽  
Major Mechanism ◽  
Aberrant Dna Methylation ◽  
Normal Status

In the last 2 decades, a wide variety of studies have been conducted on epigenetics and its role in various cancers. A major mechanism of epigenetic regulation is DNA methylation, including aberrant DNA methylation variations such as hypermethylation and hypomethylation in the promoters of critical genes, which are commonly detected in tumors and mark the early stages of cancer development. Therefore, epigenetic therapy has been of special importance in the last decade for cancer treatment. In epigenetic therapy, all efforts are made to modulate gene expression to the normal status. Importantly, recent studies have shown that epigenetic therapy is focusing on the new gene editing technology, CRISPR-Cas9. This tool was found to be able to effectively modulate gene expression and alter almost any sequence in the genome of cells, resulting in events such as a change in acetylation, methylation, or histone modifications. Of note, the CRISPR-Cas9 system can be used for the treatment of cancers caused by epigenetic alterations. The CRISPR-Cas9 system has greater advantages than other available methods, including potent activity, easy design and high velocity as well as the ability to target any DNA or RNA site. In this review, we described epigenetic modulators, which can be used in the CRISPR-Cas9 system, as well as their functions in gene expression alterations that lead to cancer initiation and progression. In addition, we surveyed various species of CRISPR-dead Cas9 (dCas9) systems, a mutant version of Cas9 with no endonuclease activity. Such systems are applicable in epigenetic therapy for gene expression modulation through chemical group editing on nucleosomes and chromatin remodeling, which finally return the cell to the normal status and prevent cancer progression.

Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2093-2098 ◽  
Author(s):  
Su Chu ◽  
Helen Xu ◽  
Neil P. Shah ◽  
David S. Snyder ◽  
Stephen J. Forman ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Drug Binding ◽  
Myelogenous Leukemia ◽  
In Vitro Mutagenesis ◽  
Mrna Levels ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
Abl Kinase ◽  
Cd34 Cells

AbstractThe BCR-ABL kinase inhibitor imatinib mesylate induces complete cytogenetic response (CCR) in a high proportion of chronic myelogenous leukemia (CML) patients. However, patients in CCR usually demonstrate evidence of residual BCR-ABL–positive progenitors. The mechanisms underlying persistence of small numbers of malignant progenitors in imatinib-sensitive patients are unclear. BCR-ABL kinase domain mutations affecting drug binding can lead to secondary resistance to imatinib. We show here that kinase mutations could be detected in CD34+ cells isolated from CML patients in CCR on imatinib. Most mutations seen have not been reported in previous clinical studies. Interestingly, several of the involved amino acid positions have been implicated in an in vitro mutagenesis screen. These BCR-ABL mutations were associated with varying levels of imatinib resistance. Two of 5 patients in whom mutations were detected on initial evaluation have relapsed. In addition, 4 patients in whom mutations were not initially detected, but with rising BCR-ABL mRNA levels on quantitative polymerase chain reaction (Q-PCR) analysis, had mutations detected on follow-up evaluation. We conclude that BCR-ABL kinase mutations can be detected in CD34+ cells from CML patients in CCR on imatinib, may contribute to persistence of small populations of malignant progenitors, and could be a potential source of relapse.

scholarly journals The Interplay between ROS and Ras GTPases: Physiological and Pathological Implications

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Elisa Ferro ◽  
Luca Goitre ◽  
Saverio Francesco Retta ◽  
Lorenza Trabalzini
Keyword(s):  
Bound State ◽  
Small Gtpases ◽  
Signaling Networks ◽  
Biological Macromolecules ◽  
Cellular Processes ◽  
Ras Gtpases ◽  
Downstream Effectors ◽  
Redox Agents ◽  
Upstream Regulators ◽  
Cell Signaling Pathways

The members of the RasGTPase superfamily are involved in various signaling networks responsible for fundamental cellular processes. Their activity is determined by their guanine nucleotide-bound state. Recent evidence indicates that some of these proteins may be regulated by redox agents. Reactive oxygen species (ROSs) and reactive nitrogen species (RNSs) have been historically considered pathological agents which can react with and damage many biological macromolecules including DNA, proteins, and lipids. However, a growing number of reports have suggested that the intracellular production of ROS is tightly regulated and that these redox agents serve as signaling molecules being involved in a variety of cell signaling pathways. Numerous observations have suggested that some Ras GTPases appear to regulate ROS production and that oxidants function as effector molecules for the small GTPases, thus contributing to their overall biological function. Thus, redox agents may act both as upstream regulators and as downstream effectors of Ras GTPases. Here we discuss current understanding concerning mechanisms and physiopathological implications of the interplay between GTPases and redox agents.

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