Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation (original) (raw)
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Targeting cell signaling pathways for drug discovery: An old lock needs a new key
Journal of Cellular Biochemistry, 2007
In this age of targeted therapy, the failure of most current drug-discovery efforts to yield safe, effective, and inexpensive drugs has generated widespread concern. Successful drug development has been stymied by a general focus on target selection rather than clinical safety and efficacy. The very process of validating the targets themselves is inefficient and in many cases leads to drugs having poor efficacy and undesirable side effects. Indeed, some rationally designed drugs (e.g., inhibitors of receptor tyrosine kinases, tumor necrosis factor (TNF), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), bcr-abl, and proteasomes) are ineffective against cancers and other inflammatory conditions and produce serious side effects. Since any given cancer carries mutations in an estimated 300 genes, this raises an important question about how effective these targeted therapies can ever be against cancer. Thus, it has become necessary to rethink drug development strategies. This review analyzes the shortcomings of rationally designed target-specific drugs against cancer cell signaling pathways and evaluates the available options for future drug development.
Oncotarget, 2014
The discovery of inhibitors for oncogenic signalling pathways remains a key focus in modern oncology, based on personalized and targeted therapeutics. Computational drug repurposing via the analysis of FDA-approved drug network is becoming a very effective approach to identify therapeutic opportunities in cancer and other human diseases. Given that gene expression signatures can be associated with specific oncogenic mutations, we tested whether a "reverse" oncogene-specific signature might assist in the computational repositioning of inhibitors of oncogenic pathways. As a proof of principle, we focused on oncogenic PI3K-dependent signalling, a molecular pathway frequently driving cancer progression as well as raising resistance to anticancer-targeted therapies. We show that implementation of "reverse" oncogenic PI3K-dependent transcriptional signatures combined with interrogation of drug networks identified inhibitors of PI3K-dependent signalling among FDA-approved compounds. This led to repositioning of Niclosamide (Niclo) and Pyrvinium Pamoate (PP), two anthelmintic drugs, as inhibitors of oncogenic PI3K-dependent signalling. Niclo inhibited phosphorylation of P70S6K, while PP inhibited phosphorylation of AKT and P70S6K, which are downstream targets of PI3K. Anthelmintics inhibited oncogenic PI3K-dependent gene expression and showed a cytostatic effect in vitro and in mouse mammary gland. Lastly, PP inhibited the growth of breast cancer cells harbouring PI3K mutations. Our data indicate that drug repositioning by network analysis of oncogene-specific transcriptional signatures is an efficient strategy for identifying oncogenic pathway inhibitors among FDA-approved compounds. We
1999
The focus of drug development has moved from cytotoxic compounds identified by screening to therapies that act at specific molecular targets. Although some of these agents may cause visible tumor reduction and may be adequately evaluated by standard oncology drug development methods, other novel therapies may not be amenable to our current practices. Consequently, our concepts of drug development must evolve and address various questions. How should we approach the preclinical development of these agents? Which laboratory experiments are critical prior to studying these new agents in the clinic? What phase I design strategies are appropriate? Agents that target specific molecules may not cause toxicity at effective doses and, therefore, phase I concepts such as maximum tolerated dose (MTD) may not be relevant. What phase II designs suit these agents? Drugs that have a cytostatic effect may be overlooked if tumor response is required as a selection criteria. Phase II studies may not be necessary if the relevant end point is survival, which cannot be fully addressed without a large randomized phase III trial. What can we learn from other areas of medicine? Many nononcology drugs target specific end points and are developed in a pattern quite different from the formula used in oncology. Should we be adopting their methods of drug development? At the 10th National Cancer Institute-European Organization for Research and Treatment of Cancer Symposium on New Drugs in Cancer Therapy, a workshop discussed these issues. In this commentary, we summarize some of the presentations. Although many new agents are entering or are already in clinical trials, it is imperative that we continue this dialogue with scientists, clinical researchers, cooperative groups, and industry and regulatory authorities because there is not yet an international consensus on how to approach the challenges that lie ahead.
2019
Kinase-dependent signaling networks are frequently dysregulated in cancer, driving disease progression. While kinase inhibition has become an important therapeutic approach many cancers resist drug treatment. Therefore, we need both reliable biomarkers that predict drug responses and new targets to overcome drug resistance. Determining the kinase(s) that control cancer progression in individual cancers can pose a significant challenge. Genomics has identified important, yet limited numbers of kinase driver mutations. Transcriptomics can quantify aberrant gene expression, but it cannot measure the protein phosphorylation that regulates kinase-dependent signaling network activity. Proteomics measures protein expression and phosphorylation and, therefore, quantifies aberrant signaling network activity directly. We developed a kinome-centric pharmacoproteomics platform to study signaling pathways that determine cancer drug response. Using hepatocellular carcinoma (HCC) as our model, we determined kinome activity with kinobead/LC-MS profiling, and screened 299 kinase inhibitors for growth inhibition. Integrating kinome activity with drug responses, we obtained a comprehensive database of predictive biomarkers, and kinase targets that promote drug sensitivity and resistance. Our dataset specified pathway-based biomarkers for the clinical HCC drugs sorafenib, regorafenib and lenvatinib, and we found these biomarkers enriched in human HCC specimens. Strikingly, our database also revealed signaling pathways that promote HCC cell epithelialmesenchymal transition (EMT) and drug resistance, and that NUAK1 and NUAK2 regulate these pathways. Inhibition of these kinases reversed the EMT and sensitized HCC cells to kinase inhibition. These results .
Synergistic combinations of signaling pathway inhibitors: Mechanisms for improved cancer therapy
Drug Resistance Updates, 2009
Cancer cells contain multiple signal transduction pathways whose activities are frequently elevated due to their transformation, and that are often activated following exposure to established cytotoxic therapies including ionizing radiation and chemical DNA damaging agents. Many pathways activated in response to transformation or toxic stresses promote cell growth and invasion and counteract the processes of cell death. As a result of these findings many drugs, predominantly protein and lipid kinase inhibitors, of varying specificities, have been developed to block signaling by cell survival pathways in the hope of killing tumor cells and sensitizing them to toxic therapies. Unfortunately, due to the plasticity of signaling processes within a tumor cell, inhibition of any one growth factor receptor or signaling pathway frequently has only modest long term effects on cancer cell viability, tumor growth, and patient survival. As a result of this realization, a greater emphasis has begun to be placed on rational combinations of drugs that simultaneously inhibit multiple inter-linked signal transduction/survival pathways. This, it is hoped, will limit the ability of tumor cells to adapt and survive because the activity within multiple parallel survival signaling pathways has been reduced. This review will discuss some of the approaches that have been taken to combine signal transduction modulatory agents to achieve enhanced tumor cell killing.
Drug Targets for Cancer Treatment: An Overview
Medicinal Chemistry, 2015
Cancer is one of the major cause of death worldwide. Malignant cells display metabolic changes, when compared to normal cells, because of both genetic and epigenetic alterations. Number of drugs being used for the cancer treatment follows different mechanisms of action. Therapeutic strategies include targeting of drugs at specific genes or proteins/enzymes found in cancer cells or the internal tissue environment which contributes to growth and survival of these cells. Targeted therapy is often used along with chemotherapy and other treatments to restrict the growth and spread of cancer cells. During the past few decades, targeted therapy has emerged as a promising approach for the development of selective anticancer agents. There is a class of targeted therapy drugs called angiogenesis inhibitors which focus on blocking the development of new blood vessels in tumor tissues. In addition, anticancer drugs also include DNA intercalators, DNA synthesis inhibitors, transcription regulators, enzyme inhibitors etc. This review focuses on major classes of anticancer drug targets and their therapeutic importance.
First Symposium of Novel Molecular Targets for Cancer Therapy
The Oncologist, 2001
This symposium was convened in Buenos Aires, Argentina (October 5-6, 2000) to foster dissemination of new knowledge in the field of new drug development, with an emphasis on innovative cancer therapies. The organizers, Adrian M. Senderowicz and Antonio Giordano, assembled a team of experts in a wide spectrum of related fields: signal transduction, angiogenesis, invasion and metastases, gene therapy, apoptosis, immune modulation, and cell cycle control. The meeting was held under the auspices of three U.S. institutions: the National Cancer Institute (NCI), the National Institute for Dental and Craniofacial Research (NIDCR), and the Sbarro Institute for Cancer Research and Molecular Medicine. This meeting provided a unique opportunity for about 500 local clinicians, researchers, and medical students to interact with distinguished investigators from the U.S. and Europe. The fact that five out of 19 speakers had obtained their degrees in Argentina further stimulated the interest of the audience and strongly motivated many medical students to participate in the meeting. The topics were organized in broad areas, such as modulation of signal transduction pathways, angiogenesis, invasion and metastases, gene therapy, apoptosis, and immunotherapy. Clinical applications of these novel therapies for specific tumor types were discussed on the last day of the symposium. Dr. Senderowicz (NIDCR, National Institutes of Health [NIH]) opened the symposium with the statement that after many years of development in cancer treatments, patients with advanced solid tumors still have a very poor prognosis. He also emphasized that the lack of significant advances in the treatment of solid tumors in the last few decades was due to the lack of basic knowledge of carcinogenesis; this is reflected in the limited number of targets for cancer therapy developed in the last century (i.e., tubulin, DNA, protein synthesis). He then outlined new approaches/targets that academia and industry are testing in the clinic. Furthermore, he described how the new research tools and technologies, including DNA microarray and proteomics, may impact the diagnosis, prognosis and treatment of cancer therapy. Dr. Silvio Gutkind (NIDCR, NIH) presented a comprehensive review of signal transduction pathways, with special emphasis on mitogen-activated protein kinase family and the nuclear factor kB. An in-depth description of receptor-activated interaction with ras and src oncogenes, and the multiple phosphorylation cascades modulating c-jun expression quickly followed a historical perspective, starting with the observations of P. Rous in 1911 on chicken tumorigenesis. An interesting finding highlighted by Dr. Gutkind was the fact that the Kaposi's sarcoma Herpesvirus encodes a G proteincoupled receptor with cell-transforming capabilities. This receptor, when activated, upregulates the transcription of vascular endothelial growth factor (VEGF), a growth factor that is thought to play an important role in the pathogenesis of this highly angiogenic tumor. Dr. Dirk Mendel (Sugen Inc.; South San Francisco, CA) showed preclinical and early clinical data on two tyrosinekinase inhibitors (TKI), SU 5416, and the antiangiogenic drug SU 6668. SU 5416, a drug that was shown to inhibit