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Sadeghi Shaker M, Rokni M, Kavosi H, Enayati S, Madreseh E, Mahmoudi M, Farhadi E, Vodjgani M. Salirasib Inhibits the Expression of Genes Involved in Fibrosis in Fibroblasts of Systemic Sclerosis Patients. Immun Inflamm Dis 2024; 12:e70063. [PMID: 39601641 PMCID: PMC11600624 DOI: 10.1002/iid3.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 09/01/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Fibrosis is a principal sign of systemic sclerosis (SSc) which can affect several organs including the lung, heart, and dermis. Dermal fibroblasts of SSc patients are characterized by persistent and activated Ras and ERK1/2 signaling which stimulates extreme collagen and extracellular matrix synthesis. Salirasib is a Ras inhibitor that competitively prevents the adherence of GTP-bound Ras to the plasma membrane, that inhibits Ras signaling. This study intended to clarify whether salirasib can influence fibrotic mediators in SSc fibroblasts. MATERIALS AND METHODS Dermal fibroblasts from 10 SSc patients were treated with salirasib in the presence of TGF-β1, and mRNA levels of H-Ras and genes related to fibrosis, such as COL1A1, COL1A2, CTGF, TGF-β1, fibronectin, ACTA2, and MMP1 was measured by real-time PCR. The α-SMA protein expression was analyzed by immunofluorescence staining. RESULTS In dermal fibroblasts of SSc patients, salirasib treatment, markedly downregulated the H-Ras gene expression. In addition, the protein expression of α-SMA and gene expression of ACTA2 were inhibited upon salirasib treatment. Salirasib also significantly reduced the expression of COL1A1, and COL1A2 genes and augmented the gene expression of MMP1. The mRNA levels of other genes related to fibrosis such as FN1, CTGF, and TGF-β1 were significantly decreased upon salirasib treatment. CONCLUSION Considering salirasib significantly reduced the expression of genes related to the fibrosis process and α-SMA gene and protein expression, and given significant upregulation of MMP1 by salirasib, it can be considered as a new curative strategy for fibrotic diseases like SSc.
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Affiliation(s)
- Mina Sadeghi Shaker
- Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
| | - Mohsen Rokni
- Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Department of ImmunologyUniversity of social Welfare and Rehabilitation SciencesTehranIran
| | - Hoda Kavosi
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Research Center for Chronic Inflammatory DiseasesTehran University of Medical SciencesTehranIran
| | - Samaneh Enayati
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
| | - Elham Madreseh
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Department of Epidemiology and Biostatistics, School of Public HealthTehran University of Medical SciencesTehranIran
| | - Mahdi Mahmoudi
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Research Center for Chronic Inflammatory DiseasesTehran University of Medical SciencesTehranIran
| | - Elham Farhadi
- Rheumatology Research CenterTehran University of Medical SciencesTehranIran
- Research Center for Chronic Inflammatory DiseasesTehran University of Medical SciencesTehranIran
| | - Mohammad Vodjgani
- Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
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Mondal K, Posa MK, Shenoy RP, Roychoudhury S. KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways. Cells 2024; 13:1221. [PMID: 39056802 PMCID: PMC11274496 DOI: 10.3390/cells13141221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/28/2024] [Accepted: 05/11/2024] [Indexed: 07/28/2024] Open
Abstract
The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates the hallmark features of cancer and interacts with other cancer-causing driver mutations. However, there remains a lack of precise information on their cooccurrence with mutated variants of KRAS and any correlations between KRAS and other driver mutations. To enquire about this issue, we delved into cBioPortal, TCGA, UALCAN, and Uniport studies. We aimed to unravel the complexity of KRAS and its relationships with other driver mutations. We noticed that G12D and G12V are the prevalent mutated variants of KRAS and coexist with the TP53 mutation in PAAD and CRAD, while G12C and G12V coexist with LUAD. We also noticed similar observations in the case of PIK3CA and APC mutations in CRAD. At the transcript level, a positive correlation exists between KRAS and PIK3CA and between APC and KRAS in CRAD. The existence of the co-mutation of KRAS and other driver mutations could influence the signaling pathway in the neoplastic transformation. Moreover, it has immense prognostic and predictive implications, which could help in better therapeutic management to treat cancer.
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Affiliation(s)
- Koushik Mondal
- Division of Basic & Translational Research, Saroj Gupta Cancer Centre & Research Institute, MG Road, Kolkata 700063, West Bengal, India
- Department of Cancer Immunology, SwasthyaNiketan Integrated Healthcare & Research Foundation, Koramangala, Bengaluru 560034, Karnataka, India
| | - Mahesh Kumar Posa
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur 302017, Rajasthan, India;
| | - Revathi P. Shenoy
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India;
| | - Susanta Roychoudhury
- Division of Basic & Translational Research, Saroj Gupta Cancer Centre & Research Institute, MG Road, Kolkata 700063, West Bengal, India
- CSIR-Indian Institute of Chemical Biology, 4 Raja S.C.Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
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Targeting KRAS mutant cancers by preventing signaling transduction in the MAPK pathway. Eur J Med Chem 2020; 211:113006. [PMID: 33228976 DOI: 10.1016/j.ejmech.2020.113006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 01/06/2023]
Abstract
KRAS genes are the most commonly mutated oncogenes in cancer. Unfortunately, effective therapeutic strategies for targeting KRAS mutant cancers have proven to be difficult to obtain. A key reason for this setback is due to the lack of success direct KRAS mutant inhibitors have received. Researchers have turned their efforts away from targeting the KRAS nucleotide-binding site directly and towards targeting other areas of the MAPK signaling pathway to block KRAS function. Researchers found that inhibiting enzymes and protein-protein interactions involved in the MAPK signaling pathway inhibit the activation of KRAS mutant therefore can lead to a potential therapeutic for KRAS mutated cancers. Throughout the past two decades, various indirect inhibitors have been designed and tested. EGFR and MEK inhibitors have presented with less success; however, significant advances have been made when targeting the plasma membrane localization process and the allosteric site of KRAS mutant. Farnesyltransferase and allosteric inhibitors have both advanced to human clinical trials. This comprehensive review presents the most recent developments of direct and indirect KRAS mutant inhibitors. This review summarizes published data on the inhibitory and anti-cancer activity of compounds that target KRAS activation as well as highlights the most promising strategies for targeting KRAS mutant cancers.
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Galectin-8 binds to the Farnesylated C-terminus of K-Ras4B and Modifies Ras/ERK Signaling and Migration in Pancreatic and Lung Carcinoma Cells. Cancers (Basel) 2019; 12:cancers12010030. [PMID: 31861875 PMCID: PMC7017085 DOI: 10.3390/cancers12010030] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 12/23/2022] Open
Abstract
K-Ras is the most prominent driver of oncogenesis and no effective K-Ras inhibitors have been established despite decades of intensive research. Identifying new K-Ras-binding proteins and their interaction domains offers the opportunity for defining new approaches in tackling oncogenic K-Ras. We have identified Galectin-8 as a novel, direct binding protein for K-Ras4B by mass spectrometry analyses and protein interaction studies. Galectin-8 is a tandem-repeat Galectin and it is widely expressed in lung and pancreatic carcinoma cells. siRNA-mediated depletion of Galectin-8 resulted in increased K-Ras4B content and ERK1/2 activity in lung and pancreatic carcinoma cells. Moreover, cell migration and cell proliferation were inhibited by the depletion of Galectin-8. The K-Ras4B–Galectin-8 interaction is indispensably associated with the farnesylation of K-Ras4B. The lysine-rich polybasic domain (PBD), a region that is unique for K-Ras4B as compared to H- and N-Ras, stabilizes the interaction and accounts for the specificity. Binding assays with the deletion mutants of Galectin-8, comprising either of the two carbohydrate recognition domains (CRD), revealed that K-Ras4B only interacts with the N-CRD, but not with the C-CRD. Structural modeling uncovers a potential binding pocket for the hydrophobic farnesyl chain of K-Ras4B and a cluster of negatively charged amino acids for interaction with the positively charged lysine residues in the N-CRD. Our results demonstrate that Galectin-8 is a new binding partner for K-Ras4B and it interacts via the N-CRD with the farnesylated PBD of K-Ras, thereby modulating the K-Ras effector pathways as well as cell proliferation and migration.
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Saliani M, Jalal R, Ahmadian MR. From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers. Cancer Biol Med 2019; 16:435-461. [PMID: 31565476 PMCID: PMC6743616 DOI: 10.20892/j.issn.2095-3941.2018.0530] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/10/2019] [Indexed: 12/12/2022] Open
Abstract
Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancer-related genes. Several therapeutic strategies targeting oncogenic KRAS (KRAS onc ) signaling pathways have been suggested, including the inhibition of synthetic lethal interactions, direct inhibition of KRAS onc itself, blockade of downstream KRAS onc effectors, prevention of post-translational KRAS onc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways, targeted RNA replacement, and oncogene-induced senescence. Despite intensive and continuous efforts, KRAS onc remains an elusive target for cancer therapy. To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date. An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.
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Affiliation(s)
- Mahsa Saliani
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Razieh Jalal
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
- Department of Research Cell and Molecular Biology, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Mohammad Reza Ahmadian
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf 40225, Germany
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6
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Lakkakula BVKS, Farran B, Lakkakula S, Peela S, Yarla NS, Bramhachari PV, Kamal MA, Saddala MS, Nagaraju GP. Small molecule tyrosine kinase inhibitors and pancreatic cancer-Trials and troubles. Semin Cancer Biol 2019; 56:149-167. [PMID: 30314681 DOI: 10.1016/j.semcancer.2018.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/18/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.
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Affiliation(s)
| | - Batoul Farran
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA
| | - Saikrishna Lakkakula
- Department of Zoology, Visvodaya Government Degree College, Venkatagiri, AP-524132, India
| | - Sujatha Peela
- Department of Biotechnology, Dr.B.R.Ambedkar University, Srikakulam, Andhra Pradesh, India
| | - Nagendra Sastry Yarla
- Dr. LV Prasad Diagnostics and Research Laboratory, Khairtabad, Hyderabad, AP- 500004, India
| | | | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia; Novel Global Community Educational Foundation, Australia
| | | | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA.
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Stout MC, Campbell PM. RASpecting the oncogene: New pathways to therapeutic advances. Biochem Pharmacol 2018; 158:217-228. [PMID: 30352234 DOI: 10.1016/j.bcp.2018.10.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 10/19/2018] [Indexed: 12/13/2022]
Abstract
RAS is the most commonly mutated driver of tumorigenesis, seen in about 30% of all cancer cases. There is a subset of tumors termed RAS-driven cancers in which RAS mutation or overactivation is evident, including as much as 95% in pancreatic and 50% in colon cancer. RAS is a family of small membrane bound GTPases that act as a signaling node to control both normal and cancer biology. Since the discovery of RAS' overall prominence in many tumor types and specifically in RAS-dependent cancers, it has been an obvious therapeutic target for drug development. However, RAS has proved a very elusive target, and after a few prominent RAS targeted drugs failed in clinical trials after decades of research, RAS was termed "undruggable" and research in this field was greatly hampered. An increase in knowledge about basic RAS biology has led to a resurgence in the generation of novel therapeutics targeting RAS signaling utilizing various and distinct approaches. These new drugs target RAS activation directly, block downstream signaling effectors and inhibit proper post-translational processing and trafficking/recycling of RAS. This review will cover how these new drugs were developed and how they have fared in preclinical and early phase clinical trials.
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Affiliation(s)
- Matthew C Stout
- Department of Pharmacology and Physiology, College of Medicine, Drexel University, USA; Cancer Biology Program and The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, USA
| | - Paul M Campbell
- Cancer Biology Program and The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, USA.
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8
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Furuse J, Kurata T, Okano N, Fujisaka Y, Naruge D, Shimizu T, Kitamura H, Iwasa T, Nagashima F, Nakagawa K. An early clinical trial of Salirasib, an oral RAS inhibitor, in Japanese patients with relapsed/refractory solid tumors. Cancer Chemother Pharmacol 2018; 82:511-519. [PMID: 29992354 PMCID: PMC6105164 DOI: 10.1007/s00280-018-3618-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 06/04/2018] [Indexed: 12/23/2022]
Abstract
Purpose Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. Methods Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. Results A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1–13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79–373). Conclusion Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. Clinical trial registration JAPIC Clinical Trials Information; JapicCTI-121751. Electronic supplementary material The online version of this article (10.1007/s00280-018-3618-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Junji Furuse
- Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
| | - Takayasu Kurata
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Yasuhito Fujisaka
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Daisuke Naruge
- Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Toshio Shimizu
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Hiroshi Kitamura
- Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Tsutomu Iwasa
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Fumio Nagashima
- Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
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Sugita S, Enokida H, Yoshino H, Miyamoto K, Yonemori M, Sakaguchi T, Osako Y, Nakagawa M. HRAS as a potential therapeutic target of salirasib RAS inhibitor in bladder cancer. Int J Oncol 2018; 53:725-736. [PMID: 29901113 DOI: 10.3892/ijo.2018.4435] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 05/10/2018] [Indexed: 11/06/2022] Open
Abstract
The active form of the small GTPase RAS binds to downstream effectors to promote cell growth and proliferation. RAS signal enhancement contributes to tumorigenesis, invasion, and metastasis in various different cancers. HRAS proto-oncogene GTPase (HRAS), one of the RAS isoforms, was the first human oncogene for which mutations were reported in T24 bladder cancer (BC) cells in 1982, and HRAS mutation or upregulation has been reported in several cancers. According to data from The Cancer Genome Atlas, HRAS expression was significantly upregulated in clinical BC samples compared to healthy samples (P=0.0024). HRAS expression was also significantly upregulated in BC with HRAS mutation compared to patients without HRAS mutation (P<0.0001). The tumor suppressive effect of salirasib, a RAS inhibitor, has been reported in several cancer types, but only at relatively high concentrations. As such, RAS inhibitors have not been used for clinical applications. The aim of the current study was to investigate the therapeutic potential of targeting HRAS using salirasib and small interfering RNA (siRNA) and to characterize the mechanism by which HRAS functions using recently developed quantitative in vitro proteome-assisted multiple reaction monitoring for protein absolute quantification (iMPAQT), in BC cells. iMPAQT allows measurement of the absolute abundance of any human protein with the high quantitative accuracy. Salirasib and siRNA targeting of HRAS inhibited cell proliferation, migration and invasion in HRAS wild type and HRAS-mutated cell lines. Proteomic analyses revealed that several metabolic pathways, including the oxidative phosphorylation pathway and glycolysis, were significantly downregulated in salirasib-treated BC cells. However, the expression levels of hexokinase 2, phosphoglycerate kinase 1, pyruvate kinase, muscle (PKM)1, PKM2 and lactate dehydrogenase A, which are downstream of RAS and target genes of hypoxia inducible factor-1α, were not notably downregulated, which may explain the high concentration of salirasib required to inhibit cell viability. These findings provide insight into the mechanisms of salirasib, and suggest the need for novel therapeutic strategies to treat cancers such as BC.
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Affiliation(s)
- Satoshi Sugita
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
| | - Hideki Enokida
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
| | - Hirofumi Yoshino
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
| | - Kazutaka Miyamoto
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
| | - Masaya Yonemori
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
| | - Takashi Sakaguchi
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
| | - Yoichi Osako
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
| | - Masayuki Nakagawa
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima 890-8520, Japan
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Altshuler A, Verbuk M, Bhattacharya S, Abramovich I, Haklai R, Hanna JH, Kloog Y, Gottlieb E, Shalom-Feuerstein R. RAS Regulates the Transition from Naive to Primed Pluripotent Stem Cells. Stem Cell Reports 2018; 10:1088-1101. [PMID: 29456180 PMCID: PMC5918191 DOI: 10.1016/j.stemcr.2018.01.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 01/07/2018] [Accepted: 01/08/2018] [Indexed: 12/13/2022] Open
Abstract
The transition from naive to primed state of pluripotent stem cells is hallmarked by epithelial-mesenchymal transition, metabolic switch from oxidative phosphorylation to aerobic glycolysis, and changes in the epigenetic landscape. Since these changes are also seen as putative hallmarks of neoplastic cell transformation, we hypothesized that oncogenic pathways may be involved in this process. We report that the activity of RAS is repressed in the naive state of mouse embryonic stem cells (ESCs) and that all three RAS isoforms are significantly activated upon early differentiation induced by LIF withdrawal, embryoid body formation, or transition to the primed state. Forced expression of active RAS and RAS inhibition have shown that RAS regulates glycolysis, CADHERIN expression, and the expression of repressive epigenetic marks in pluripotent stem cells. Altogether, this study indicates that RAS is located at a key junction of early ESC differentiation controlling key processes in priming of naive cells.
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Affiliation(s)
- Anna Altshuler
- Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Mila Verbuk
- Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Swarnabh Bhattacharya
- Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Ifat Abramovich
- Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Roni Haklai
- Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel
| | - Jacob H Hanna
- The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Yoel Kloog
- Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel
| | - Eyal Gottlieb
- Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel
| | - Ruby Shalom-Feuerstein
- Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
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Choi M, Bien H, Mofunanya A, Powers S. Challenges in Ras therapeutics in pancreatic cancer. Semin Cancer Biol 2017; 54:101-108. [PMID: 29170065 DOI: 10.1016/j.semcancer.2017.11.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/17/2017] [Accepted: 11/19/2017] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer is considered among the most aggressive and the least curable of all human malignancies. It is usually characterized by multiple aberrations in tumor suppressor genes and oncogenes, most notably activating mutations in KRAS. This review examines the various attempts that have been made to inhibit Kras and its downstream signaling pathways in pancreatic cancer with an emphasis on challenges related to clinical trials. Attempts include preventing the localization of Ras protein to the plasma membrane, inhibiting downstream oncogenic signaling by targeting Kras effectors such as MEK1/2, Erk1/2 or Akt singly or in combination, and directly inhibiting Kras protein. Most clinical trials have focused on inhibiting downstream effector pathways and clinical benefit has been limited due to compensatory mechanisms and toxicity associated with small therapeutic windows. Additionally, genetic screens have been conducted to identify gene or genes that could provide therapeutic vulnerabilities in mutant KRAS cells and provide a way to target mutant Kras protein only. We also discuss how potentially transforming clinical trials have failed in the past and what new strategies are on-going in clinical trials for pancreas cancer. For long-term success in targeting Kras, future efforts should focus on combinatorial strategies to more effectively block Kras pathways at multiple points, and improve translational application of pre-clinical data to the clinic.
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Affiliation(s)
- Minsig Choi
- Division of Hematology/Oncology, Stony Brook University, Stony Brook, NY, United States.
| | - Harold Bien
- Division of Hematology/Oncology, Stony Brook University, Stony Brook, NY, United States
| | - Adaobi Mofunanya
- Department of Pathology, Stony Brook University, Stony Brook, NY, United States
| | - Scott Powers
- Department of Pathology, Stony Brook University, Stony Brook, NY, United States
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12
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Furuse J, Nagashima F. Emerging protein kinase inhibitors for treating pancreatic cancer. Expert Opin Emerg Drugs 2017; 22:77-86. [PMID: 28253828 DOI: 10.1080/14728214.2017.1293648] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Pancreatic cancer, the incidence and mortality of which are increasing around the world, has the most dismal prognosis among the commonly encountered cancers. Systemic chemotherapy plays an important role in the treatment of patients with pancreatic cancer, and development of more effective chemotherapies is being sought. Areas covered: This review article provides a summary about protein kinase inhibitors that have been investigated for the treatment of pancreatic cancer, not only existing agents targeting RAS, EGFR, VEGFR, MEK, etc., but also various compounds targeting, including the MAPK, PI3 K/Akt/mTOR, and JAK/STAT signaling pathways, trials of which are currently ongoing. To date, none has shown sufficient efficacy as to merit becoming established as a standard treatment agent for pancreatic cancer. Expert opinion: As the toxicities of protein kinase inhibitors usually differ from those of cytotoxic agents, it could be of value to use these agents in combination with gemcitabine plus nab-paclitaxel. It may be reasonable to identify a suitable disease and/or predictive markers for new compounds in proof of concept trials. It is an urgent need to conduct phase III trials, on the basis of the results obtained, in subpopulations with biomarkers to predict the efficacy of these drugs.
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Affiliation(s)
- Junji Furuse
- a Department of Medical Oncology , Kyorin University, Faculty of Medicine , Tokyo , Japan
| | - Fumio Nagashima
- a Department of Medical Oncology , Kyorin University, Faculty of Medicine , Tokyo , Japan
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Vijayvergia N, Cohen SJ. Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer? J Gastrointest Oncol 2016; 7:727-737. [PMID: 27747087 PMCID: PMC5056260 DOI: 10.21037/jgo.2016.08.01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 06/14/2016] [Indexed: 12/12/2022] Open
Abstract
Pancreatic adenocarcinoma is the fourth leading cause of cancer related death in the United States. Most patients are diagnosed at a late stage and despite recent advances in chemotherapeutic approaches, outcomes are poor. With the introduction of combination chemotherapy, novel biomarkers are clearly needed to identify subsets of patients likely to benefit from these therapies. Advances in our understanding of the molecular drivers of pancreatic cancer offer the hope of personalized therapy that may benefit our patients. In this review, we summarize the current knowledge about the biology of pancreatic cancer and its implication for treatment. We discuss recent advances in targeted therapies and the role of potential biomarkers in predicting response to established therapies. We also review novel therapeutic approaches that may be able to fulfill the promise of personalized therapy for pancreatic cancer.
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Affiliation(s)
- Namrata Vijayvergia
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Steven J Cohen
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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14
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The association between let-7, RAS and HIF-1α in Ewing Sarcoma tumor growth. Oncotarget 2016; 6:33834-48. [PMID: 26393682 PMCID: PMC4741806 DOI: 10.18632/oncotarget.5616] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 08/23/2015] [Indexed: 11/25/2022] Open
Abstract
Ewing Sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. microRNAs (miRNAs) are involved in cancer as tumor suppressors or oncogenes. We studied the involvement of miRNAs located on chromosomes 11q and 22q that participate in the most common translocation in ES. Of these, we focused on 3 that belong to the let-7 family. We studied the expression levels of let-7a, and let-7b and detected a significant correlation between low expression of let-7b and increased risk of relapse. let-7 is known to be a negative regulator of the RAS oncogene. Indeed, we detected an inverse association between the expression of let-7 and RAS protein levels and its downstream target p-ERK, following transfection of let-7 mimics and inhibitors. Furthermore, we identified let-7 as a negative regulator of HIF-1α and EWS-FLI-1. Moreover, we were able to show that HIF-1α directly binds to the EWS-FLI-1 promoter. Salirasib treatment in-vitro resulted in the reduction of cell viability, migration ability, and in the decrease of cells in S-phase. A significant reduction in tumor burden and in the expression levels of both HIF-1α and EWS-FLI-1 proteins were observed in mice after treatment. Our results support the hypothesis that let-7 is a tumor suppressor that negatively regulates RAS, also in ES, and that HIF-1α may contribute to the aggressive metastatic behavior of ES. Moreover, the reduction in the tumor burden in a mouse model of ES following Salirasib treatment, suggests therapeutic potential for this RAS inhibitor in ES.
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Liu J, Ji S, Liang C, Qin Y, Jin K, Liang D, Xu W, Shi S, Zhang B, Liu L, Liu C, Xu J, Ni Q, Yu X. Critical role of oncogenic KRAS in pancreatic cancer (Review). Mol Med Rep 2016; 13:4943-4949. [PMID: 27121414 DOI: 10.3892/mmr.2016.5196] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 04/14/2016] [Indexed: 11/06/2022] Open
Abstract
Pancreatic cancer is a human malignancy with one of the highest mortality rates and little progress has been achieved in its treatment in recent decades. Further improvement to the understanding of the biological and molecular mechanisms underlying the initiation and development of pancreatic ductal adenocarcinoma (PDAC) is required. Previous studies using genetically engineered mouse models have demonstrated that oncogenic GTPase KRas (KRAS) mutation is involved in the formation of pancreatic intraepithelial neoplasia and promotes the progression of PDAC. However, attempts to target KRAS directly by pharmacological inhibition have been unsuccessful. This has resulted in increased efforts to identify pharmacological targets and nodes associated with the mutated KRAS. The present review discusses the recent progress and prospects of KRAS signaling in pancreatic cancer.
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Affiliation(s)
- Jiang Liu
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Chen Liang
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Yi Qin
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Dingkon Liang
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Wenyan Xu
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Si Shi
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Bo Zhang
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Liang Liu
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Chen Liu
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Jin Xu
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China
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16
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Quah SY, Tan MS, Teh YH, Stanslas J. Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs. Pharmacol Ther 2016; 162:35-57. [PMID: 27016467 DOI: 10.1016/j.pharmthera.2016.03.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Oncogenic rat sarcoma (Ras) is linked to the most fatal cancers such as those of the pancreas, colon, and lung. Decades of research to discover an efficacious drug that can block oncogenic Ras signaling have yielded disappointing results; thus, Ras was considered "undruggable" until recently. Inhibitors that directly target Ras by binding to previously undiscovered pockets have been recently identified. Some of these molecules are either isolated from natural products or derived from natural compounds. In this review, we described the potential of these compounds and other inhibitors of Ras signaling in drugging Ras. We highlighted the modes of action of these compounds in suppressing signaling pathways activated by oncogenic Ras, such as mitogen-activated protein kinase (MAPK) signaling and the phosphoinositide-3-kinase (PI3K) pathways. The anti-Ras strategy of these compounds can be categorized into four main types: inhibition of Ras-effector interaction, interference of Ras membrane association, prevention of Ras-guanosine triphosphate (GTP) formation, and downregulation of Ras proteins. Another promising strategy that must be validated experimentally is enhancement of the intrinsic Ras-guanosine triphosphatase (GTPase) activity by small chemical entities. Among the inhibitors of Ras signaling that were reported thus far, salirasib and TLN-4601 have been tested for their clinical efficacy. Although both compounds passed phase I trials, they failed in their respective phase II trials. Therefore, new compounds of natural origin with relevant clinical activity against Ras-driven malignancies are urgently needed. Apart from salirasib and TLN-4601, some other compounds with a proven inhibitory effect on Ras signaling include derivatives of salirasib, sulindac, polyamine, andrographolide, lipstatin, levoglucosenone, rasfonin, and quercetin.
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Affiliation(s)
- Shun Ying Quah
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia
| | - Michelle Siying Tan
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia
| | - Yuan Han Teh
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia
| | - Johnson Stanslas
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia; Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
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17
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Akinleye A, Iragavarapu C, Furqan M, Cang S, Liu D. Novel agents for advanced pancreatic cancer. Oncotarget 2015; 6:39521-37. [PMID: 26369833 PMCID: PMC4741843 DOI: 10.18632/oncotarget.3999] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 05/20/2015] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is relatively insensitive to conventional chemotherapy. Therefore, novel agents targeting dysregulated pathways (MAPK/ERK, EGFR, TGF-β, HEDGEHOG, NOTCH, IGF, PARP, PI3K/AKT, RAS, and Src) are being explored in clinical trials as monotherapy or in combination with cytotoxic chemotherapy. This review summarizes the most recent advances with the targeted therapies in the treatment of patients with advanced pancreatic cancer.
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Affiliation(s)
- Akintunde Akinleye
- Division of Hematology/Oncology, Department of Medicine, New York Medical College, Valhalla, New York, United States
| | - Chaitanya Iragavarapu
- Division of Hematology/Oncology, Department of Medicine, New York Medical College, Valhalla, New York, United States
| | - Muhammad Furqan
- Division of Hematology/Oncology, Department of Medicine, University of Iowa, Iowa City, Iowa, United States
| | - Shundong Cang
- Department of Oncology, Henan Province People's Hospital, Zhengzhou University, Zhengzhou, China
| | - Delong Liu
- Department of Oncology, Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
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18
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Menachem A, Bodner O, Pastor J, Raz A, Kloog Y. Inhibition of malignant thyroid carcinoma cell proliferation by Ras and galectin-3 inhibitors. Cell Death Discov 2015; 1:15047. [PMID: 27551476 PMCID: PMC4979473 DOI: 10.1038/cddiscovery.2015.47] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 09/02/2015] [Accepted: 09/08/2015] [Indexed: 12/13/2022] Open
Abstract
Anaplastic Thyroid carcinoma is an extremely aggressive solid tumor that resists most treatments and is almost always fatal. Galectin-3 (Gal-3) is an important marker for thyroid carcinomas and a scaffold of the K-Ras protein. S-trans, transfarnesylthiosalicylic acid (FTS; Salirasib) is a Ras inhibitor that inhibits the active forms of Ras proteins. Modified citrus pectin (MCP) is a water-soluble citrus-fruit-derived polysaccharide fiber that specifically inhibits Gal-3. The aim of this study was to develop a novel drug combination designed to treat aggressive anaplastic thyroid carcinoma. Combined treatment with FTS and MCP inhibited anaplastic thyroid cells proliferation in vitro by inducing cell cycle arrest and increasing apoptosis rate. Immunoblot analysis revealed a significant decrease in Pan-Ras, K-Ras, Ras-GTP, p-ERK, p53, and Gal-3 expression levels and significant increase in p21 expression levels. In nude mice, treatment with FTS and MCP inhibited tumor growth. Levels of Gal-3, K-Ras-GTP, and p-ERK were significantly decreased. To conclude, our results suggest K-Ras and Gal-3 as potential targets in anaplastic thyroid tumors and herald a novel treatment for highly aggressive anaplastic thyroid carcinoma.
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Affiliation(s)
- A Menachem
- Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv, Israel
| | - O Bodner
- Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv, Israel
| | - J Pastor
- Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv, Israel
| | - A Raz
- The Departments of Oncology and Pathology, School of Medicine, The Karmanos Cancer Institute, Wayne State University , Detroit, MI, USA
| | - Y Kloog
- Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv, Israel
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19
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Takai E, Yachida S. Genomic alterations in pancreatic cancer and their relevance to therapy. World J Gastrointest Oncol 2015; 7:250-258. [PMID: 26483879 PMCID: PMC4606179 DOI: 10.4251/wjgo.v7.i10.250] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 07/28/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.
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20
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Abstract
RAS mutations are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors and around a fifth of common myeloid malignancies, but they have evaded therapeutic interventions, despite being the focus of intense research over the last three decades. Recent discoveries lend new understanding about the structure, function, and signaling of RAS and have opened new avenues for development of much needed new therapies. We discuss the various approaches under investigation to target mutant RAS proteins. The recent development of direct RAS inhibitors specific to KRAS G12C mutations represents a landmark discovery that promises to change the perception about RAS's druggability. Multiple clinical trials targeting synthetically lethal partners and/or downstream signaling partners of RAS are underway. Novel inhibitors targeting various arms of RAS processing and signaling have yielded encouraging results in the laboratory, but refinement of the drug-like properties of these molecules is required before they will be ready for the clinic.
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Affiliation(s)
- Harshabad Singh
- Harshabad Singh and Bruce A. Chabner, Massachusetts General Hospital Cancer Center; Harshabad Singh, Dana-Farber Cancer Institute; and Dan L. Longo, Brigham and Women's Hospital, Boston, MA
| | - Dan L Longo
- Harshabad Singh and Bruce A. Chabner, Massachusetts General Hospital Cancer Center; Harshabad Singh, Dana-Farber Cancer Institute; and Dan L. Longo, Brigham and Women's Hospital, Boston, MA
| | - Bruce A Chabner
- Harshabad Singh and Bruce A. Chabner, Massachusetts General Hospital Cancer Center; Harshabad Singh, Dana-Farber Cancer Institute; and Dan L. Longo, Brigham and Women's Hospital, Boston, MA.
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21
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Schmukler E, Wolfson E, Haklai R, Elad-Sfadia G, Kloog Y, Pinkas-Kramarski R. Chloroquine synergizes with FTS to enhance cell growth inhibition and cell death. Oncotarget 2014; 5:173-84. [PMID: 24368422 PMCID: PMC3960199 DOI: 10.18632/oncotarget.1500] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
The Ras family of small GTPases transmits extracellular signals that regulate cell growth, differentiation, motility and death. Ras signaling is constitutively active in a large number of human cancers. Ras can also regulate autophagy by affecting several signaling pathways including the mTOR pathway. Autophagy is a process that regulates the balance between protein synthesis and protein degradation. It is important for normal growth control, but may be defective in diseases. Previously, we have shown that Ras inhibition by FTS induces autophagy, which partially protects cancer cells and may limit the use of FTS as an anti-cancer drug. Since FTS is a non toxic drug we hypothesized that FTS and chloroquine (an autophagy inhibitor) will synergize in cell growth inhibition and cell death. Thus, in the present study, we explored the mechanism of each individual drug and their combined action. Our results demonstrate that in HCT-116 and in Panc-1 cells, FTS induces autophagy, which can be inhibited by chloroquine. Furthermore, the combined treatment synergistically decreased the number of viable cells. Interestingly, the combined treatment enhanced apoptotic cell death as indicated by increased sub-G1 cell population, increased Hoechst staining, activation of caspase 3, decrease in survivin expression and release of cytochrome c. Thus, chloroquine treatment may promote FTS-mediated inhibition of tumor cell growth and may stimulate apoptotic cell death.
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Affiliation(s)
- Eran Schmukler
- Department of Neurobiology. Tel-Aviv University, Ramat-Aviv, Israel
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22
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Abstract
New drugs targeting the mitogen-activated protein kinase (MAPK) pathway have generated striking clinical response in melanoma therapy. From the discovery of BRAF mutation in melanoma in 2002, to the approval of first BRAF inhibitor vemurafenib for melanoma treatment by the US Food and Drug Administration in 2011, therapies targeting the MAPK pathway have been proven effective in less than a decade. The success of vemurafenib stimulated more intensive investigation of the molecular mechanisms of melanoma pathogenesis and development of new treatment strategies targeting specific molecules in MAPK pathway. Although selective BRAF inhibitors and MEK inhibitors demonstrated improved overall survival of metastatic melanoma patients, limited duration or development of resistance to BRAF inhibitors have been reported. Patients with metastatic melanoma still face very poor prognosis and lack of clarified therapies. Studies and multiple clinical trials on more potent and selective small molecule inhibitory compounds to further improve the clinical effects and overcome drug resistance are underway. In this review, we analyzed the therapeutic potentials of each member of the MAPK signaling pathway, summarized important MAPK-inhibiting drugs, and discussed the promising combination treatment targeting multiple targets in melanoma therapy, which may overcome the drawbacks of current drugs treatment.
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Affiliation(s)
- Yabin Cheng
- Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada
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23
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Abstract
Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.
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Zhang Y, Huang Y, Li S. Polymeric micelles: nanocarriers for cancer-targeted drug delivery. AAPS PharmSciTech 2014; 15:862-71. [PMID: 24700296 DOI: 10.1208/s12249-014-0113-z] [Citation(s) in RCA: 218] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 03/13/2014] [Indexed: 11/30/2022] Open
Abstract
Polymeric micelles represent an effective delivery system for poorly water-soluble anticancer drugs. With small size (10-100 nm) and hydrophilic shell of PEG, polymeric micelles exhibit prolonged circulation time in the blood and enhanced tumor accumulation. In this review, the importance of rational design was highlighted by summarizing the recent progress on the development of micellar formulations. Emphasis is placed on the new strategies to enhance the drug/carrier interaction for improved drug-loading capacity. In addition, the micelle-forming drug-polymer conjugates are also discussed which have both drug-loading function and antitumor activity.
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25
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Vasan N, Boyer JL, Herbst RS. A RAS renaissance: emerging targeted therapies for KRAS-mutated non-small cell lung cancer. Clin Cancer Res 2014; 20:3921-30. [PMID: 24893629 DOI: 10.1158/1078-0432.ccr-13-1762] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Of the numerous oncogenes implicated in human cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. Since the discovery of RAS in the 1960s, numerous studies have elucidated the mechanism of activity, regulation, and intracellular trafficking of the RAS gene products, and of its regulatory pathways. These pathways yielded druggable targets, such as farnesyltransferase, during the 1980s to 1990s. Unfortunately, early clinical trials investigating farnesyltransferase inhibitors yielded disappointing results, and subsequent interest by pharmaceutical companies in targeting RAS waned. However, recent advances including the identification of novel regulatory enzymes (e.g., Rce1, Icmt, Pdeδ), siRNA-based synthetic lethality screens, and fragment-based small-molecule screens, have resulted in a "Ras renaissance," signified by new Ras and Ras pathway-targeted therapies that have led to new clinical trials of patients with Ras-driven cancers. This review gives an overview of KRas signaling pathways with an emphasis on novel targets and targeted therapies, using non-small cell lung cancer as a case example.
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Affiliation(s)
- Neil Vasan
- Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Julie L Boyer
- The Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College, New York, New York; and
| | - Roy S Herbst
- Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut
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Rasfonin, a novel 2-pyrone derivative, induces ras-mutated Panc-1 pancreatic tumor cell death in nude mice. Cell Death Dis 2014; 5:e1241. [PMID: 24853419 PMCID: PMC4047882 DOI: 10.1038/cddis.2014.213] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 03/31/2014] [Accepted: 03/31/2014] [Indexed: 12/27/2022]
Abstract
Rasfonin is a novel 2-pyrone derivative reported to induce apoptosis in ras-dependent cells. In this study, its effects on ras-mutated pancreatic cancer cells were investigated in vitro and in vivo. Two human pancreatic cancer cell lines Panc-1 (mutated K-ras) and BxPC-3 (wild-type K-ras) were selected to test the effects of rasfonin on cell proliferation, clone formation, migration and invasion in vitro. Immunoblotting was used to detect the expressions of EGFR-Ras-Raf-MEK-ERK signaling pathway proteins. Ras activity was measured using a pull-down ELISA kit and guanine exchange factor (GEF)/GTPase-activating proteins (GAP) activity was measured by [(3)H]-GDP radiometric ligand binding. For an in vivo study, CD1 nude mice bearing Panc-1 cells were treated with rasfonin or Salirasib (FTS). We found that rasfonin suppressed proliferation more strongly in Panc-1 cells (IC50=5.5 μM) than BxPC-3 cells (IC50=10 μM) in vitro. Clone formation, migration and invasion by Panc-1 cells were also reduced by rasfonin. Rasfonin had little effect on the farnesylation of Ras, but it strongly downregulated Ras activity and consequently phosphorylation of c-Raf/MEK/ERK. Further experiments indicated that rasfonin reduced Son of sevenless (Sos1) expression but did not alter GEF and GAP activities. The in vivo experiments also revealed that rasfonin (30 mg/kg) delayed the growth of xenograft tumors originating from Panc-1 cells. Tumor weight was ultimately decreased after 20 days of treatment of rasfonin. Rasfonin is a robust inhibitor of pancreatic cancers with the K-ras mutation. The reduction of Sos1 expression and the consequently depressed Ras-MAPK activity could be important in its anticancer activity.
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27
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Blum R, Kloog Y. Metabolism addiction in pancreatic cancer. Cell Death Dis 2014; 5:e1065. [PMID: 24556680 PMCID: PMC3944253 DOI: 10.1038/cddis.2014.38] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 01/06/2014] [Accepted: 01/08/2014] [Indexed: 12/16/2022]
Abstract
Pancreatic ductal adenocarcinoma, an aggressively invasive, treatment-resistant malignancy and the fourth leading cause of cancer deaths in the United States, is usually detectable only when already inevitably fatal. Despite advances in genetic screening, mapping and molecular characterization, its pathology remains largely elusive. Renewed research interest in longstanding doctrines of tumor metabolism has led to the emergence of aberrant signaling pathways as critical factors modulating central metabolic networks that fuel pancreatic tumors. Such pathways, including those of Ras signaling, glutamine-regulatory enzymes, lipid metabolism and autophagy, are directly affected by genetic mutations and extreme tumor microenvironments that typify pancreatic tumor cells. Elucidation of these metabolic networks can be expected to yield more potent therapies against this deadly disease.
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Affiliation(s)
- R Blum
- Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY, USA
| | - Y Kloog
- Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel
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28
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Collins MA, Pasca di Magliano M. Kras as a key oncogene and therapeutic target in pancreatic cancer. Front Physiol 2014; 4:407. [PMID: 24478710 PMCID: PMC3896882 DOI: 10.3389/fphys.2013.00407] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 12/24/2013] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Advances in our understanding of the biology of this disease provide new potential opportunities for treatment. Pancreatic cancer is preceded by precursor lesions, the most common of which are known as Pancreatic Intraepithelial Neoplasia (PanIN). PanIN lesions, which are the focus of this review, have a high incidence of Kras mutations, and Kras mutations are a hallmark of the late-stage disease. We now know from genetically engineered mouse models that oncogenic Kras is not only driving the formation of pancreatic cancer precursor lesions, but it is also required for their progression, and for the maintenance of invasive and metastatic disease. Thus, an enormous effort is being placed in generating Kras inhibitors for clinical use. Additionally, alternative approaches, including understanding the role of Kras effector pathways at different stages of the disease progression, are being devised to target Kras effector pathways therapeutically. In particular, efforts have focused on the MAPK pathway and the PI3K pathway, for which inhibitors are widely available. Finally, recent studies have highlighted the need for oncogenic Kras to establish feedback mechanisms that maintain its levels of activity; the latter might constitute alternative ways to target Kras in pancreatic cancer. Here, we will review recent basic research and discuss potential therapeutic applications.
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Affiliation(s)
- Meredith A Collins
- Program in Cellular and Molecular Biology, University of Michigan Ann Arbor, MI, USA
| | - Marina Pasca di Magliano
- Program in Cellular and Molecular Biology, University of Michigan Ann Arbor, MI, USA ; Department of Surgery, University of Michigan Ann Arbor, MI, USA ; Department of Cell and Developmental Biology, University of Michigan Ann Arbor, MI, USA
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Schokoroy S, Juster D, Kloog Y, Pinkas-Kramarski R. Disrupting the oncogenic synergism between nucleolin and Ras results in cell growth inhibition and cell death. PLoS One 2013; 8:e75269. [PMID: 24086490 PMCID: PMC3782480 DOI: 10.1371/journal.pone.0075269] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 08/14/2013] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The ErbB receptors, Ras proteins and nucleolin are major contributors to malignant transformation. The pleiotropic protein nucleolin can bind to both Ras protein and ErbB receptors. Previously, we have demonstrated a crosstalk between Ras, nucleolin and the ErbB1 receptor. Activated Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 levels. The three oncogenes synergistically facilitate anchorage independent growth and tumor growth in nude mice. METHODOLOGY/PRINCIPAL FINDINGS In the present study we used several cancer cell lines. The effect of Ras and nucleolin inhibition was determined using cell growth, cell death and cell motility assays. Protein expression was determined by immunohistochemistry. We found that inhibition of Ras and nucleolin reduces tumor cell growth, enhances cell death and inhibits anchorage independent growth. Our results reveal that the combined treatment affects Ras and nucleolin levels and localization. Our study also indicates that Salirasib (FTS, Ras inhibitor) reduces cell motility, which is not affected by the nucleolin inhibitor. CONCLUSIONS/SIGNIFICANCE These results suggest that targeting both nucleolin and Ras may represent an additional avenue for inhibiting cancers driven by these oncogenes.
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Affiliation(s)
- Sari Schokoroy
- Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel
| | - Dolly Juster
- Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel
| | - Yoel Kloog
- Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel
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Schmukler E, Grinboim E, Schokoroy S, Amir A, Wolfson E, Kloog Y, Pinkas-Kramarski R. Ras inhibition enhances autophagy, which partially protects cells from death. Oncotarget 2013; 4:145-55. [PMID: 23370967 PMCID: PMC3702214 DOI: 10.18632/oncotarget.703] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Autophagy, a process of regulated turnover of cellular constituents, is essential for normal growth control but may be defective under pathological conditions. The Ras/PI3K/mTOR signaling pathway negatively regulates autophagy. Ras signaling has been documented in a large number of human cancers. In this in-vitro study we examined the effect of the Ras inhibitor Salirasib (S-trans, trans-farnesylthiosalicylic acid; FTS) on autophagy induction and cell viability. We show that Ras inhibition by FTS induced autophagy in several cell lines, including mouse embryonic fibroblasts and the human cancer cell lines HeLa, HCT-116 and DLD-1. The autophagy induced by FTS seems to inhibit the cell death induced by FTS, since in the absence of autophagy the death of FTS-treated cells was enhanced. Therefore, inhibition of autophagy may promote the inhibition of tumor cell growth and the cell death mediated by FTS.
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Affiliation(s)
- Eran Schmukler
- Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel
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31
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Abstract
The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS, Salirasib®) interferes with Ras membrane interactions that are crucial for Ras-dependent signaling and cellular transformation. FTS had been successfully evaluated in clinical trials of cancer patients. Interestingly, its effect is mediated by targeting Ras chaperones that serve as key coordinators for Ras proper folding and delivery, thus offering a novel target for cancer therapy. The development of new FTS analogs has revealed that the specific modifications to the FTS carboxyl group by esterification and amidation yielded compounds with improved growth inhibitory activity. When FTS was combined with additional therapeutic agents its activity toward Ras was significantly augmented. FTS should be tested not only in cancer but also for genetic diseases associated with abnormal Ras signaling, as well as for various inflammatory and autoimmune disturbances, where Ras plays a major role. We conclude that FTS has a great potential both as a safe anticancer drug and as a promising immune modulator agent.
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Affiliation(s)
- Yoel Kloog
- Department of Neurobiology, Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv, Israel.
| | - Galit Elad-Sfadia
- Department of Neurobiology, Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv, Israel
| | - Roni Haklai
- Department of Neurobiology, Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv, Israel
| | - Adam Mor
- Department of Medicine, New York University School of Medicine, New York, New York, USA; Department of Pathology, New York University School of Medicine, New York, New York, USA
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Abstract
Pancreatic cancer continues to be a challenging disease to treat because of its aggressive nature, advanced stage at the time of diagnosis, and limited treatment options that are available. Traditional cytotoxic chemotherapy provides modest benefit to patients with pancreatic adenocarcinoma. Recently, a FOLFIRINOX regimen revealed improved response in overall and progression-free survival over single-agent gemcitabine in metastatic pancreatic cancer, but there is still much needed advancement in the systemic treatment of pancreatic cancer. There is a growing interest in the development of novel agents, while our understanding of molecular pathogenesis of pancreatic adenocarcinoma continues to expand. With identification of various molecular pathways in pancreatic cancer tumorigenesis, potential targets for drug development have been pursued with the use of monoclonal antibodies and small-molecule inhibitors. Although preclinical studies with multiple targeted therapies demonstrated encouraging results in pancreatic cancer, only erlotinib, an epidermal growth factor receptor inhibitor, showed a marginal survival benefit in a phase III clinical trial, when combined with gemcitabine. As further signaling pathways and their importance in pancreatic cancer tumorigenesis are better understood, further clinical trials will need to be designed to study these targeted agents as single agents, in combination with other novel agents or in combination with cytotoxic chemotherapy. In this review, we present the current knowledge on targeted therapy in pancreatic adenocarcinoma and its application in clinical practice.
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Calvert RJ, Gupta M, Maciag A, Shiao YH, Anderson LM. K-ras 4A and 4B mRNA levels correlate with superoxide in lung adenocarcinoma cells, while at the protein level, only mutant K-ras 4A protein correlates with superoxide. Lung Cancer 2013; 80:263-9. [PMID: 23474128 PMCID: PMC3992873 DOI: 10.1016/j.lungcan.2013.01.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 01/18/2013] [Accepted: 01/26/2013] [Indexed: 10/27/2022]
Abstract
The K-ras gene is frequently mutated in lung and other cancers. K-ras protein includes two splice variants, K-ras 4A and 4B. While K-ras 4B is more widely expressed, recent evidence implicates K-ras 4A in lung tumorigenesis. We found that K-ras 4A protein has a wide range of expression in a large panel of human lung adenocarcinoma cell lines. In cell lines with mutant K-ras, but not those with wildtype K-ras, the K-ras 4A protein had a strong positive correlation with levels of cellular superoxide. We investigated whether K-ras 4A protein was involved in superoxide production, or alternatively was modulated by elevated superoxide. Experiments with small interfering RNA targeting K-ras 4A did not confirm its role in superoxide generation. However, decreasing cellular superoxide with the scavenger Tiron tended to reduce levels of K-ras 4A protein. K-ras 4A and 4B mRNA were also quantified in a number of NSCLC cell lines. 4A mRNA correlated with 4A protein only in K-ras-mutant cells. K-ras 4A mRNA also correlated with superoxide, but with no difference between cell lines with mutant or wildtype K-ras. K-ras 4B mRNA correlated with 4A mRNA and with superoxide, in both K-ras mutant and wildtype cells. The results are consistent with superoxide directly or indirectly up-regulating expression of all K-ras genes, and also increasing the stability of K-ras 4A mutant protein selectively.
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Affiliation(s)
- Richard J Calvert
- U.S. Food and Drug Administration, MOD-1 Laboratory, 8301 Muirkirk Road, Laurel, MD 20708, USA.
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Zhang X, Lu J, Huang Y, Zhao W, Li J, Gao X, Venkataramanan R, Sun M, Stolz DD, Zhang L, Li S. PEG-farnesylthiosalicylate conjugate as a nanomicellar carrier for delivery of paclitaxel. Bioconjug Chem 2013; 24:464-72. [PMID: 23425093 PMCID: PMC3623935 DOI: 10.1021/bc300608h] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a potent and especially nontoxic Ras antagonist. It inhibits both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. In this work, an FTS conjugate with poly(ethylene glycol) (PEG) through a labile ester linkage, PEG5K-FTS2(L), was developed. PEG5K-FTS2 conjugate readily forms micelles in aqueous solutions with a critical micelle concentration of 0.68 μM, and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these particles. Both drug-free and PTX-loaded micelles were spherical in shape with a uniform size of 20-30 nm. The release of PTX from PTX-loaded PEG5K-FTS2 micelles was significantly slower than that from Taxol formulation. In vitro cytotoxicity studies with several tumor cell lines showed that PEG5K-FTS2(L) was comparable to FTS in antitumor activity. Western immunoblotting showed that total Ras levels were downregulated in several cancer cell lines treated with FTS or PEG5K-FTS2(L). The micellar formulation of PTX exhibited more in vitro cytotoxic activity against several tumor cell lines compared with free PTX, suggesting a possible synergistic effect between the carrier and the codelivered drug. The antitumor activity of the PTX loaded PEG5K-FTS2(L) micelles in a syngeneic murine breast cancer model was found to be significantly higher than that of Taxol, which may be attributed to their preferential tumor accumulation and a possible synergistic effect between PEG5K-FTS2 carrier and loaded PTX.
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Affiliation(s)
- Xiaolan Zhang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Jianqin Lu
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Yixian Huang
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Wenchen Zhao
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Jiang Li
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Xiang Gao
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Raman Venkataramanan
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Min Sun
- Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
| | - Donna D. Stolz
- Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
| | - Lin Zhang
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
| | - Song Li
- Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
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Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RKS, Bear MF. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 2013; 77:243-50. [PMID: 23352161 PMCID: PMC3597444 DOI: 10.1016/j.neuron.2012.01.034] [Citation(s) in RCA: 181] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2012] [Indexed: 12/13/2022]
Abstract
Many neuropsychiatric symptoms of fragile X syndrome (FXS) are believed to be a consequence of altered regulation of protein synthesis at synapses. We discovered that lovastatin, a drug that is widely prescribed for the treatment of high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent one of the robust functional consequences of increased protein synthesis in FXS, epileptogenesis. These data suggest that lovastatin is potentially disease modifying and could be a viable prophylactic treatment for epileptogenesis in FXS.
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Affiliation(s)
- Emily K Osterweil
- Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Mologni L, Brussolo S, Ceccon M, Gambacorti-Passerini C. Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells. PLoS One 2012; 7:e51449. [PMID: 23227266 PMCID: PMC3515485 DOI: 10.1371/journal.pone.0051449] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 10/31/2012] [Indexed: 11/24/2022] Open
Abstract
Activation of Wnt signalling due to inability to degrade β-catenin is found in >85% of colorectal cancers. Approximately half of colon cancers express a constitutively active KRAS protein. A significant fraction of patients show both abnormalities. We previously reported that simultaneous down-regulation of both β-catenin and KRAS was necessary to induce significant cell death and tumor growth inhibition of colorectal cancer cells. Although attractive, an RNAi-based therapeutic approach is still far from being employed in the clinical setting. Therefore, we sought to recapitulate our previous findings by the use of small-molecule inhibitors of β-catenin and KRAS. We show here that the β-catenin inhibitors PKF115-584 and pyrvinium pamoate block β-catenin-dependent transcriptional activity and synergize with the KRAS inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) in colon cancer cells driven by Wnt and KRAS oncogenic signals, but not in cells carrying BRAF mutations. The combined use of these compounds was superior to the use of any drug alone in inducing cell growth arrest, cell death, MYC and survivin down-modulation, and inhibition of anchorage-independent growth. Expression analysis of selected cancer-relevant genes revealed down-regulation of CD44 as a common response to the combined treatments. These data provide a proof of principle for a combination therapeutic strategy in colorectal cancer.
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Affiliation(s)
- Luca Mologni
- Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
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37
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Gerrits L, Overheul GJ, Derks RC, Wieringa B, Hendriks WJ, Wansink DG. Gene duplication and conversion events shaped three homologous, differentially expressed myosin regulatory light chain (MLC2) genes. Eur J Cell Biol 2012; 91:629-39. [DOI: 10.1016/j.ejcb.2012.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 01/30/2012] [Accepted: 02/03/2012] [Indexed: 10/28/2022] Open
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Aizman E, Mor A, Levy A, George J, Kloog Y. Ras inhibition by FTS attenuates brain tumor growth in mice by direct antitumor activity and enhanced reactivity of cytotoxic lymphocytes. Oncotarget 2012; 3:144-57. [PMID: 22323550 PMCID: PMC3326645 DOI: 10.18632/oncotarget.420] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
One of the concerns in targeted drug therapy is that the inhibition of receptors and signaling molecules in tumor cells may also affect similar components in the tumor microenvironment or in the immune system, with undefined consequences for inhibition of tumor growth. Thus, in addition to its antitumor activity in mice and humans, the Ras inhibitor salirasib (S-farnesylthiosalicylic acid, FTS) also exhibits anti-inflammatory activity. Here we show three antitumor effects of FTS in immune-competent mice with subcutaneous or intracranial tumors. First, FTS exhibited antitumor activity in immune-competent, intracranial tumor-bearing mice and increased their survival relative to tumor-bearing immune-compromised mice. Second, FTS induced an increase in regulatory T cells in mouse splenocytes, but the inhibitory effects of FTS on tumor growth were not affected by these Foxp3+ T lymphocytes. Third, FTS increased antitumor T-cell reactivity by downregulating Foxp3. This caused TGF-β-dependent sensitization of the tumor to the immune system.
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Affiliation(s)
- Elizabeta Aizman
- Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv
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Abstract
Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field-breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many-sometimes-related, although also distinct-biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field.
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Affiliation(s)
- Hensin Tsao
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
- The Wellman Center for Photomedicine, Boston, Massachusetts 02114, USA
| | - Lynda Chin
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Levi A. Garraway
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
| | - David E. Fisher
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Laheru D, Shah P, Rajeshkumar NV, McAllister F, Taylor G, Goldsweig H, Le DT, Donehower R, Jimeno A, Linden S, Zhao M, Song D, Rudek MA, Hidalgo M. Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer. Invest New Drugs 2012; 30:2391-9. [PMID: 22547163 DOI: 10.1007/s10637-012-9818-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 04/03/2012] [Indexed: 12/14/2022]
Abstract
PURPOSE S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). PATIENTS AND METHODS In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. RESULTS Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. CONCLUSION The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.
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Affiliation(s)
- Daniel Laheru
- Department of Medical Oncology, Skip Viragh Center for Pancreatic Cancer Research and Patient Care, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting- Blaustein Cancer Research Building, Room 4M09, Baltimore, MD 21231, USA.
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Goldberg L, Israeli R, Kloog Y. FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice. Cell Death Dis 2012; 3:e284. [PMID: 22419113 PMCID: PMC3317504 DOI: 10.1038/cddis.2012.24] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The Ras inhibitor S-trans-trans farnesylthiosalicylic acid (FTS)
inhibits active Ras, which controls cell proliferation, differentiation,
survival, and metabolism. FTS also inhibits HIF1α expression in
cancer cells, leading to an energy crisis. The synthetic glucose analog
2-deoxy-D-glucose (2-DG), which inhibits glycolysis, is selectively directed to
tumor cells that exhibit increased glucose consumption. The 2-DG enters tumor
cells, where it competes with glucose for glycolytic enzymes. In cancer models,
as well as in human phase 1 trials, 2-DG inhibits tumor growth without toxicity.
We postulated that under normoxic conditions, tumor cells treated with FTS would
be more sensitive than normal cells to 2-DG. We show here that combined
treatment with FTS and 2-DG inhibited cancer cell proliferation additively, yet
induced apoptotic cell death synergistically both in vitro and in
vivo. The induced apoptosis was inferred from QVD-OPH inhibition, an
increase in cleaved caspase 3, and loss of survivin. FTS and 2-DG when combined,
but not separately, also induced an increase in fibrosis of the tumor tissue,
chronic inflammation, and tumor shrinkage. Overall, these results suggest a
possible new treatment of pancreatic tumors by the combined administration of
FTS and 2-DG, which together induce pancreatic tumor cell death and tumor
shrinkage under non-toxic conditions.
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Affiliation(s)
- L Goldberg
- Department of Neurobiology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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Abstract
The RAS oncogenes (HRAS, NRAS and KRAS) comprise the most frequently mutated class of oncogenes in human cancers (33%), thus stimulating intensive effort in developing anti-Ras inhibitors for cancer treatment. Despite intensive effort, to date, no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer. Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery.
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Ji Z, Flaherty KT, Tsao H. Targeting the RAS pathway in melanoma. Trends Mol Med 2012; 18:27-35. [PMID: 21962474 PMCID: PMC3759017 DOI: 10.1016/j.molmed.2011.08.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 07/26/2011] [Accepted: 08/08/2011] [Indexed: 02/02/2023]
Abstract
Metastatic melanoma is a highly lethal type of skin cancer and is often refractory to all traditional chemotherapeutic agents. Key insights into the genetic makeup of melanoma tumors have led to the development of promising targeted agents. An activated RAS pathway, anchored by oncogenic BRAF, appears to be the central motor driving melanoma proliferation. Although recent clinical trials have brought enormous hope to patients with melanoma, adverse effects and novel escape mechanisms of these inhibitors have already emerged. Definition of the limits of the first successful targeted therapies will provide the basis for further advances in management of disseminated melanoma. In this review, the current state of targeted therapy for melanoma is discussed, including the potent BRAF(V600E) inhibitor vemurafenib.
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Affiliation(s)
- Zhenyu Ji
- Wellman Center for Photomedicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
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Hypoxia signature of splice forms of tryptophanyl-tRNA synthetase marks pancreatic cancer cells with distinct metastatic abilities. Pancreas 2011; 40:1043-56. [PMID: 21926542 DOI: 10.1097/mpa.0b013e318222e635] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES Pancreatic cancer is one of most deadly because of its aggressive growth and high metastatic ability that correlates with intratumoral hypoxia. Earlier diagnosis and prognosis marker of pancreatic cancer is not yet available. In colorectal cancer, protein biosynthesis enzyme, tryptophanyl-tRNA synthetase (TrpRS), is up-regulated in good-prognosis tumors and down-regulated in metastatic poor-prognosis tumors. Tryptophanyl-tRNA synthetase status in pancreatic cancer is unknown. To correlate metastatic ability with hypoxia and TrpRS as a possible prognostic marker, we examined mRNA and protein expression in 2 human pancreatic cancer cell lines with different metastatic abilities and TrpRS levels using our site-specific monoclonal antibodies directed to conformation-dependent epitopes on pancreatic TrpRS. METHODS Pancreatic MIAPaCa-2, Panc-1, cervical HeLa, and prostate cancer PC-3 cells were cultivated under normoxia or in hypoxic chamber. Expression of full-length TrpRS, antiangiogenic TrpRS, cyclin B1, hypoxia-inducible factor 1α, and Glut-1 was determined with reverse transcriptase-polymerase chain reaction, immunoblotting, and immunocytochemistry. RESULTS We demonstrate that hypoxia regulates differentially TrpRS splice forms. Pronounced down-regulation of full-length TrpRS by hypoxia is concomitant with higher metastatic ability. CONCLUSIONS Tryptophanyl-tRNA synthetase down-regulation by hypoxia may be a factor responsible for low TrpRS in tumors with high metastatic ability. Tryptophanyl-tRNA synthetase recognizability is important for pancreatic cancer prognosis and as a new target for metastasis treatment.
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Inhibition of contact sensitivity by farnesylthiosalicylic acid-amide, a potential Rap1 inhibitor. J Invest Dermatol 2011; 131:2040-8. [PMID: 21716322 DOI: 10.1038/jid.2011.152] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We hypothesized that Ras proximate 1 (Rap1) functions as an additional target for farnesylthiosalicylic acid (FTS) or its derivatives, and that the inhibition of Rap1 in lymphocytes by these agents may represent a method for treating inflammatory disorders. Indeed, we found that FTS-amide (FTS-A) was able to inhibit the elicitation phase of delayed cutaneous hypersensitivity in vivo. This effect was associated with the inhibition of Rap1 more than with the inhibition of Harvey rat sarcoma viral oncogene (Ras). Moreover, FTS-A inhibited Rap1 and contact sensitivity far better than FTS. We suggest that FTS-A may serve as a possible therapeutic tool in contact sensitivity in particular and T-cell-mediated inflammation in general.
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Biran A, Brownstein M, Haklai R, Kloog Y. Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy. Int J Cancer 2011; 128:691-701. [PMID: 20473860 DOI: 10.1002/ijc.25367] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), constitute a novel class of anticancer agents that cause an increase in acetylated histones and thus restore the expression of dormant tumor-suppressor and other genes related to cell differentiation, cell-cycle arrest or apoptosis of tumor cells. The Ras inhibitor farnesylthiosalicylic acid (FTS, salirasib) attenuates cancer cell proliferation in vitro and in vivo and, under certain circumstances, induces cell death. FTS by itself does not induce differentiation or complete growth arrest. The abovementioned activity of VPA as a differentiation agent suggested that it might be worth investigating its possible therapeutic potential in synergistic combination with FTS. Here, we examined whether the combined application of VPA and FTS could synergistically inhibit the proliferation of cancer cells that express oncogenic K-Ras (A549 nonsmall-cell lung carcinoma cells), DLD1 (colon carcinoma cells) or chronically active wild-type K-Ras and constitutively active B-Raf (ARO, thyroid carcinoma cells). The results showed that combined treatment with VPA and FTS synergistically reduces proliferation in all of these cancer cell lines by downregulating Ras and blocking the expression of Survivin and Aurora A. These alterations, which were most pronounced following the combined treatment, led to a mitotic crisis, as reflected by mislocalization of the chromosomal passenger complex. Our findings thus demonstrate that combination therapy with VPA and FTS might offer a promising therapeutic approach to the treatment of epithelial tumors.
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Affiliation(s)
- Anat Biran
- Department of Neurobiology, George S Wise Faculty of Life Science, Tel Aviv University, Tel-Aviv, Israel
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Bustinza-Linares E, Kurzrock R, Tsimberidou AM. Salirasib in the treatment of pancreatic cancer. Future Oncol 2010; 6:885-91. [PMID: 20528225 DOI: 10.2217/fon.10.71] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The Ras family of genes is involved in the cellular regulation of proliferation, differentiation, cell adhesion and apoptosis. The K-ras gene is mutated in over 90% of pancreatic cancer cases. Salirasib (S-trans,trans-farnesylthiosalycilic acid [FTS]) is a synthetic small molecule that acts as a potent Ras inhibitor. It is a farnesylcysteine mimetic that selectively disrupts the association of active RAS proteins with the plasma membrane. Animal studies demonstrated that salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of salirasib combined with standard doses of gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. The salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer.
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Affiliation(s)
- Ernesto Bustinza-Linares
- Department of Investigational Cancer Therapeutics, The Phase I Clinical Trials Program, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Levy R, Grafi-Cohen M, Kraiem Z, Kloog Y. Galectin-3 promotes chronic activation of K-Ras and differentiation block in malignant thyroid carcinomas. Mol Cancer Ther 2010; 9:2208-19. [PMID: 20682656 DOI: 10.1158/1535-7163.mct-10-0262] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Anaplastic thyroid carcinomas are deadly tumors that are highly invasive, particularly into the bones. Although oncogenic Ras can transform thyroid cells into a severely malignant phenotype, thyroid carcinomas do not usually harbor ras gene mutations. Therefore, it is not known whether chronically active Ras contributes to thyroid carcinoma cell proliferation, although galectin-3 (Gal-3), which is strongly expressed in thyroid carcinomas but not in benign tumors or normal glands, is known to act as a K-Ras chaperone that stabilizes and drives K-Ras.GTP nanoclustering and signal robustness. Here, we examined the possibility that thyroid carcinomas expressing high levels of Gal-3 exhibit chronically active K-Ras. Using cell lines representing three types of malignant thyroid tumors--papillary, follicular, and anaplastic--we investigated the possible correlation between Gal-3 expression and active Ras content, and then examined the therapeutic potential of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib) for thyroid carcinoma. Thyroid carcinoma cells strongly expressing Gal-3 showed high levels of K-Ras.GTP expression, and K-Ras.GTP transmitted strong signals to extracellular signal-regulated kinase. FTS disrupted interactions between Gal-3 and K.Ras, strongly reduced K-Ras.GTP and phospho-extracellular signal-regulated kinase expression, and enhanced the expression of the cell cycle inhibitor p21 as well as of the thyroid transcription factor 1, which is involved in thyroid cell differentiation. FTS also inhibited anaplastic thyroid carcinoma cell proliferation in vitro and tumor growth in nude mice. We conclude that wild-type K-Ras.GTP in association with Gal-3 contributes to thyroid carcinoma malignancy and that Ras inhibition might be a useful treatment strategy against these deadly tumors.
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Affiliation(s)
- Ran Levy
- Department of Neurobiology, Tel Aviv University, 69978 Tel-Aviv, Israel
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Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling. Oncogene 2009; 29:380-91. [PMID: 19838215 PMCID: PMC2809798 DOI: 10.1038/onc.2009.336] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The Rheb1 and Rheb2 small GTPases and their effector mTOR are aberrantly activated in human cancer and are attractive targets for anti-cancer drug discovery. Rheb is targeted to endomembranes via its C-terminal CAAX (C = cysteine, A = aliphatic, X = terminal amino acid) motif, a substrate for posttranslational modification by a farnesyl isoprenoid. Following farnesylation, Rheb undergoes two additional CAAX-signaled processing steps, Rce1-catalyzed cleavage of the AAX residues and Icmt-mediated carboxylmethylation of the farnesylated cysteine. However, whether these post-prenylation processing steps are required for Rheb signaling through mTOR is not known. We found that Rheb1 and Rheb2 localize primarily to the endoplasmic reticulum and Golgi apparatus. We determined that Icmt and Rce1 processing is required for Rheb localization, but is dispensable for Rheb-induced activation of the mTOR substrate p70 S6 kinase (S6K). Finally, we evaluated whether farnesylthiosalicylic acid (FTS) blocks Rheb localization and function. Surprisingly, FTS prevented S6K activation induced by a constitutively active mTOR mutant, indicating that FTS inhibits mTOR at a level downstream of Rheb. We conclude that inhibitors of Icmt and Rce1 will not block Rheb function, but FTS could be a promising treatment for Rheb- and mTOR-dependent cancers.
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Schneider-Merck T, Borbath I, Charette N, De Saeger C, Abarca J, Leclercq I, Horsmans Y, Stärkel P. The Ras inhibitor farnesylthiosalicyclic acid (FTS) prevents nodule formation and development of preneoplastic foci of altered hepatocytes in rats. Eur J Cancer 2009; 45:2050-60. [DOI: 10.1016/j.ejca.2009.04.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2008] [Accepted: 04/06/2009] [Indexed: 10/20/2022]
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