Molecular Profiling in Drug Development: Paving a Way Forward

2020 ◽  
pp. e309-e318
Author(s):  
Suzanne F. Jones ◽  
Andrew J. McKenzie
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Molecular Mechanisms ◽  
Target Identification ◽  
Tumor Biology ◽  
Chemotherapeutic Agents ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Screening Techniques ◽  
Molecular Oncology

As researchers learn more about tumor biology and the molecular mechanisms involved in tumorigenesis, metastasis, and tumor evolution, clinical trials are growing more complex and patient selection for clinical trials is becoming more specific. Rather than exploit certain phenotypic characteristics of tumor cells (e.g., rapid cell division and uncontrolled cell growth), pharmaceuticals targeting the genotypic causes of tumorigenesis are emerging. The sequencing of the human genome, advances in chemical techniques, and increased efficiency in drug target identification have changed the way drugs are developed. Now, more precise drugs targeting specific mutations within individual genes are being used to treat narrow patient populations harboring these specific driver mutations, often with greater efficacy and lower toxicity than traditional chemotherapeutic agents. This precision in drug development relies not only on the ability to design exquisitely specific pharmaceuticals but also to identify (with the same level of precision) the patients who are most likely to respond to those therapies. Robust screening techniques and adequate molecular oncology education are required to match the appropriate patient to precision therapies, and these same screening techniques provide the data necessary to advance to the next generation of drug development.

Drug development in IBD: from novel target identification to early clinical trials

Gut ◽  
2016 ◽  
Vol 65 (8) ◽  
pp. 1233-1239 ◽  
Author(s):  
Silvio Danese ◽  
Claudio Fiocchi ◽  
Julián Panés
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Target Identification ◽  
Novel Target

Drug Development in the Era of Personalized Oncology: From Population-Based Trials to Enrichment and Prescreening Strategies

2012 ◽  
pp. 168-172
Author(s):  
Rodrigo Dienstmann ◽  
Jordi Rodon ◽  
Josep Tabernero
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Large Scale ◽  
Human Genetics ◽  
Tumor Biology ◽  
Drug Approval ◽  
Population Based ◽  
Tumor Subtypes ◽  
Recent Success ◽  
Personalized Oncology

Overview: Recent advances in tumor biology and human genetics along with the development of drugs for specific targets hold promise for an era of personalized oncology treatment. Routine use of modern technologies, such as large-scale genome sequencing, will help to unravel the specific biology of each tumor. Adding a rigorous genomic view could determine key genetic events, critical dependencies, and stratification of patients in early clinical trials. Integrating biomarker development into the early testing of novel agents might provide clinically relevant therapeutic opportunities for patients with advanced-stage cancer and also accelerate the drug-approval process. After recent success stories of therapies targeting driver molecular aberrations in genetically defined tumor subtypes, innovative clinical trials based on a strong biologic hypothesis are expected to bring further excitement to the field. In this article, we describe a new trend in biomarker-driven early drug development using enrichment and prescreening strategies. Technical and logistical obstacles that may hinder progress of this approach will be discussed, along with ethical and economic concerns.

scholarly journals Chemoprotective and chemosensitizing effects of apigenin on cancer therapy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zahra Nozhat ◽  
Shabnam Heydarzadeh ◽  
Zahra Memariani ◽  
Amirhossein Ahmadi
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Side Effects ◽  
Combination Therapy ◽  
Molecular Mechanisms ◽  
Cancer Therapeutics ◽  
Therapeutic Index ◽  
Chemotherapeutic Agents ◽  
Potential Candidate ◽  
Anti Cancer

Abstract Background Therapeutic resistance to radiation and chemotherapy is one of the major obstacles in cancer treatment. Although synthetic radiosensitizers are pragmatic solution to enhance tumor sensitivity, they pose concerns of toxicity and non-specificity. In the last decades, scientists scrutinized novel plant-derived radiosensitizers and chemosensitizers, such as flavones, owing to their substantial physiological effects like low toxicity and non-mutagenic properties on the human cells. The combination therapy with apigenin is potential candidate in cancer therapeutics. This review explicates the combinatorial strategies involving apigenin to overcome drug resistance and boost the anti-cancer properties. Methods We selected full-text English papers on international databases like PubMed, Web of Science, Google Scholar, Scopus, and ScienceDirect from 1972 up to 2020. The keywords included in the search were: Apigenin, Chemoprotective, Chemosensitizing, Side Effects, and Molecular Mechanisms. Results In this review, we focused on combination therapy, particularly with apigenin augmenting the anti-cancer effects of chemo drugs on tumor cells, reduce their side effects, subdue drug resistance, and protect healthy cells. The reviewed research data implies that these co-therapies exhibited a synergistic effect on various cancer cells, where apigenin sensitized the chemo drug through different pathways including a significant reduction in overexpressed genes, AKT phosphorylation, NFκB, inhibition of Nrf2, overexpression of caspases, up-regulation of p53 and MAPK, compared to the monotherapies. Meanwhile, contrary to the chemo drugs alone, combined treatments significantly induced apoptosis in the treated cells. Conclusion Briefly, our analysis proposed that the combination therapies with apigenin could suppress the unwanted toxicity of chemotherapeutic agents. It is believed that these expedient results may pave the path for the development of drugs with a high therapeutic index. Nevertheless, human clinical trials are a prerequisite to consider the potential use of apigenin in the prevention and treatment of various cancers. Conclusively, the clinical trials to comprehend the role of apigenin as a chemoprotective agent are still in infancy. Graphical Abstract

Artificial Intelligence Effecting a Paradigm Shift in Drug Development

2020 ◽  
pp. 247263032095693
Author(s):  
Masturah Bte Mohd Abdul Rashid
Keyword(s):  
Artificial Intelligence ◽  
Clinical Trials ◽  
Drug Development ◽  
Paradigm Shift ◽  
Drug Repositioning ◽  
Target Identification ◽  
Success Rates ◽  
Drug Target Identification ◽  
The Cost ◽  
Novel Drug

The inverse relationship between the cost of drug development and the successful integration of drugs into the market has resulted in the need for innovative solutions to overcome this burgeoning problem. This problem could be attributed to several factors, including the premature termination of clinical trials, regulatory factors, or decisions made in the earlier drug development processes. The introduction of artificial intelligence (AI) to accelerate and assist drug development has resulted in cheaper and more efficient processes, ultimately improving the success rates of clinical trials. This review aims to showcase and compare the different applications of AI technology that aid automation and improve success in drug development, particularly in novel drug target identification and design, drug repositioning, biomarker identification, and effective patient stratification, through exploration of different disease landscapes. In addition, it will also highlight how these technologies are translated into the clinic. This paradigm shift will lead to even greater advancements in the integration of AI in automating processes within drug development and discovery, enabling the probability and reality of attaining future precision and personalized medicine.

Next-Generation Sequencing: A Discovery Tool for Blood Disorders

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-10-SCI-10
Author(s):  
Elaine R. Mardis ◽  
Li Ding ◽  
Peter Westervelt ◽  
John S. Welch ◽  
Jeffery M. Klco ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Massively Parallel Sequencing ◽  
Tumor Biology ◽  
Cancer Genome ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Whole Genome ◽  
Next Generation ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Abstract SCI-10 The advent and evolution of next-generation massively parallel sequencing (MPS) has radically altered our approaches to studying the cancer genome and transcriptome. By using unbiased and comprehensive MPS in the context of clinically annotated samples from leukemia cases, rapid progress has resulted in our understanding of the mutational spectrum of hematopoietic malignancies, the heterogeneity of disease presentation, and the impact of chemotherapy on the cancer genome, among others. The complexity of the transcriptome, while daunting from an analytical standpoint, further reveals the nuances of gene expression changes in leukemia that often cannot be predicted simply by studying the genome. By applying the digital nature of MPS to explore tumor heterogeneity and tumor evolution, we have shown that de novo acute myeloid leukemia (AML) presents either as a mono- or multiclonal disease, and that the relapse presentation in the same patient is an evolved genetic derivation of the de novopresentation, often with novel driver mutations that have been acquired during the course of chemotherapy (1). New data from whole genome sequencing of hematopoietic stem cells in healthy volunteers indicates that somatic mutations largely are acquired during aging and occur randomly, carrying forward in the transformed cell. This baseline is important for the further comparison of AML subtypes, and provides a context for understanding tumor biology. Last, by studying 200 AML cases using whole-genome and exome sequencing, RNA-seq, miRNA-seq and array-based methylation, we have begun an integrated characterization of AML in an effort to inform tumor biology. These studies and the accompanying technologies set the stage for precision treatment of each AML patient according to the additional information provided by the person's integrated “omic” profile. Disclosures: No relevant conflicts of interest to declare.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells

2019 ◽  
Vol 14 (5) ◽  
pp. 405-420 ◽  
Author(s):  
Eduardo Alvarado-Ortiz ◽  
Miguel Á. Sarabia-Sánchez ◽  
Alejandro García-Carrancá
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Tumor Biology ◽  
Molecular Tools ◽  
Recent Past ◽  
Functional Roles ◽  
Cellular Population ◽  
Cellular Markers ◽  
A Minor

Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Saleh A. Almatroodi ◽  
Mansoor Ali Syed ◽  
Arshad Husain Rahmani
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Active Compound ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Cell Signalling ◽  
Chemopreventive Agents ◽  
Signalling Molecules ◽  
Cancer Management ◽  
Induced Apoptosis

Background:: Curcumin, an active compound of turmeric spice is one of the most-studies natural compounds and have been widely recognized as chemopreventive agents. Several molecular mechanisms have been proven, curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as inhibition of carcinogenesis process. Objective:: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. Methods:: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed central and Google scholar for the implication of curcumin in cancer management along with special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com and www.freshpatents.com. Result:: Recent studies based on cancer cells have proven that curcumin have potential effects against cancer cells, prevent the growth of cancer and act as cancer therapeutic agents. Besides, curcumin exerted anticancer effects through inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. Conclusion:: Accumulating evidences suggest that curcumin has potentiality to inhibit cancer growth, induced apoptosis and modulate various cell signalling pathways molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy and safe dose in the management of various cancers.

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