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1
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Kita K, Burdowski A. Recent clinical trials and optical control as a potential strategy to develop microtubule-targeting drugs in colorectal cancer management. World J Gastroenterol 2024; 30:1780-1790. [PMID: 38659489 PMCID: PMC11036503 DOI: 10.3748/wjg.v30.i13.1780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/08/2024] [Accepted: 03/19/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) has remained the second and the third leading cause of cancer-related death worldwide and in the United States, respectively. Although significant improvement in overall survival has been achieved, death in adult populations under the age of 55 appears to have increased in the past decades. Although new classes of therapeutic strategies such as immunotherapy have emerged, their application is very limited in CRC so far. Microtubule (MT) inhibitors such as taxanes, are not generally successful in CRC. There may be some way to make MT inhibitors work effectively in CRC. One potential advantage that we can take to treat CRC may be the combination of optical techniques coupled to an endoscope or other fiber optics-based devices. A combination of optical devices and photo-activatable drugs may allow us to locally target advanced CRC cells with highly potent MT-targeting drugs. In this Editorial review, we would like to discuss the potential of optogenetic approaches in CRC management.
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Affiliation(s)
- Katsuhiro Kita
- Department of Biology, St. Francis College, Brooklyn, NY 11201, United States
| | - Allen Burdowski
- Department of Biology, St. Francis College, Brooklyn, NY 11201, United States
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Yuan J, Guo Y. Targeted Therapy for Anaplastic Thyroid Carcinoma: Advances and Management. Cancers (Basel) 2022; 15:cancers15010179. [PMID: 36612173 PMCID: PMC9818071 DOI: 10.3390/cancers15010179] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/17/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Anaplastic thyroid carcinoma (ATC) is a rare and highly fatal cancer with the worst prognosis of all thyroid carcinoma (TC) histological subtypes and no standard treatment. In recent years, the explosion of investigations on ATC-targeted agents has provided a new treatment strategy for this malignant condition, and a review of these studies is warranted. We conducted a comprehensive literature search for ATC-targeted drug studies and compiled a summary of their efficacy and adverse effects (AEs) to provide new insights. Multiple clinical trials have demonstrated the efficacy and safety of dabrafenib in combination with trametinib for the treatment of ATC, but vemurafenib and NTRK inhibitors showed limited clinical responses. We found that the previously valued therapeutic effect of lenvatinib may be unsatisfactory; combining tyrosine kinase (TK) inhibitors (TKIs) with other agents results in a higher rate of clinical benefit. In addition, specific medications, including RET inhibitors, mTOR inhibitors, CDK4/6 inhibitors, and Combretastatin A4-phosphate (CA4P), offer tremendous therapeutic potential. The AEs reported for all agents are relatively numerous but largely manageable clinically. More clinical trials are expected to further confirm the effectiveness and safety of these targeted drugs for ATC.
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Affiliation(s)
- Jiaqian Yuan
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yong Guo
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310001, China
- Correspondence:
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3
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Barbosa G, Gelves LGV, Costa CMX, Franco LS, de Lima JAL, Aparecida-Silva C, Teixeira JD, Mermelstein CDS, Barreiro EJ, Lima LM. Discovery of Putative Dual Inhibitor of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs. Pharmaceuticals (Basel) 2022; 15:913. [PMID: 35893736 PMCID: PMC9394307 DOI: 10.3390/ph15080913] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 01/25/2023] Open
Abstract
Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and 2 on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC50 values ranging from 0.030 μM to 7.53 μM (MTT at 72 h) and 0.096 μM to 8.768 μM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog 10 (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound 2 (LASSBio-1586) and the methylated homolog 3 (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog 10 was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 (10) as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives.
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Affiliation(s)
- Gisele Barbosa
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Luis Gabriel Valdivieso Gelves
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Caroline Marques Xavier Costa
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Lucas Silva Franco
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - João Alberto Lins de Lima
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Cristiane Aparecida-Silva
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - John Douglas Teixeira
- Laboratório de Diferenciação Muscular e Citoesqueleto, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (J.D.T.); (C.d.S.M.)
| | - Claudia dos Santos Mermelstein
- Laboratório de Diferenciação Muscular e Citoesqueleto, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (J.D.T.); (C.d.S.M.)
| | - Eliezer J. Barreiro
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Lidia Moreira Lima
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (G.B.); (L.G.V.G.); (C.M.X.C.); (L.S.F.); (J.A.L.d.L.); (C.A.-S.); (E.J.B.)
- Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
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Sojka DR, Hasterok S, Vydra N, Toma-Jonik A, Wieczorek A, Gogler-Pigłowska A, Scieglinska D. Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A. Cells 2021; 10:1418. [PMID: 34200371 PMCID: PMC8229576 DOI: 10.3390/cells10061418] [Citation(s) in RCA: 13] [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: 05/12/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/14/2022] Open
Abstract
Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) as cytoprotective factors can counteract the deleterious effects of various stressful stimuli. In this study, we examined whether the anticancer effects of MA can be counteracted by the mechanism related to HSPs belonging to the HSPA (HSP70) family. We found that MA caused cell type-specific alterations in the levels of HSPAs. These changes included concomitant upregulation of the stress-inducible (HSPA1 and HSPA6) and downregulation of the non-stress-inducible (HSPA2) paralogs. However, neither HSPA1 nor HSPA2 were necessary to provide protection against MA in lung cancer cells. Conversely, the simultaneous repression of several HSPA paralogs using pan-HSPA inhibitors (VER-155008 or JG-98) sensitized cancer cells to MA. We also observed that genetic ablation of the heat shock factor 1 (HSF1) transcription factor, a main transactivator of HSPAs expression, sensitized MCF7 cells to MA treatment. Our study reveals that inhibition of HSF1-mediated heat shock response (HSR) can improve the anticancer effect of MA. These observations suggest that targeting the HSR- or HSPA-mediated adaptive mechanisms may be a promising strategy for further preclinical developments.
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Affiliation(s)
- Damian Robert Sojka
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102 Gliwice, Poland; (D.R.S.); (S.H.); (N.V.); (A.T.-J.); (A.G.-P.)
| | - Sylwia Hasterok
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102 Gliwice, Poland; (D.R.S.); (S.H.); (N.V.); (A.T.-J.); (A.G.-P.)
| | - Natalia Vydra
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102 Gliwice, Poland; (D.R.S.); (S.H.); (N.V.); (A.T.-J.); (A.G.-P.)
| | - Agnieszka Toma-Jonik
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102 Gliwice, Poland; (D.R.S.); (S.H.); (N.V.); (A.T.-J.); (A.G.-P.)
| | - Anna Wieczorek
- Division of Medical Biology, Institute of Biology, Jan Kochanowski University, 25-406 Kielce, Poland;
| | - Agnieszka Gogler-Pigłowska
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102 Gliwice, Poland; (D.R.S.); (S.H.); (N.V.); (A.T.-J.); (A.G.-P.)
| | - Dorota Scieglinska
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102 Gliwice, Poland; (D.R.S.); (S.H.); (N.V.); (A.T.-J.); (A.G.-P.)
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Liu L, O’Kelly D, Schuetze R, Carlson G, Zhou H, Trawick ML, Pinney KG, Mason RP. Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors. Molecules 2021; 26:2551. [PMID: 33925707 PMCID: PMC8125421 DOI: 10.3390/molecules26092551] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022] Open
Abstract
Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely fragile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage generates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular microscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations particularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.
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Affiliation(s)
- Li Liu
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Devin O’Kelly
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Regan Schuetze
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Graham Carlson
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA; (G.C.); (M.L.T.); (K.G.P.)
| | - Heling Zhou
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
| | - Mary Lynn Trawick
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA; (G.C.); (M.L.T.); (K.G.P.)
| | - Kevin G. Pinney
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA; (G.C.); (M.L.T.); (K.G.P.)
| | - Ralph P. Mason
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.L.); (D.O.); (R.S.); (H.Z.)
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De Leo S, Trevisan M, Fugazzola L. Recent advances in the management of anaplastic thyroid cancer. Thyroid Res 2020; 13:17. [PMID: 33292371 PMCID: PMC7684758 DOI: 10.1186/s13044-020-00091-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/15/2020] [Indexed: 12/12/2022] Open
Abstract
Anaplastic thyroid cancer (ATC) is undoubtedly the thyroid cancer histotype with the poorest prognosis. The conventional treatment includes surgery, radiotherapy, and conventional chemotherapy. Surgery should be as complete as possible, securing the airway and ensuring access for nutritional support; the current standard of care of radiotherapy is the intensity-modulated radiation therapy; chemotherapy includes the use of doxorubicin or taxanes (paclitaxel or docetaxel) generally with platin (cisplatin or carboplatin). However, frequently, these treatments are not sufficient and a systemic treatment with kinase inhibitors is necessary. These include multitarget tyrosine kinase inhibitors (Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Axitinib, Pazopanib, Pyrazolo-pyrimidine compounds), single target tyrosine kinase inhibitors (Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, PPARγ ligands (e.g. Efatutazone), Everolimus against mTOR, vascular disruptors (e.g. Fosbretabulin), and immunotherapy (e.g. Spartalizumab and Pembrolizumab, which are anti PD-1/PD-L1 molecules). Therapy should be tailored to the patients and to the tumor genetic profile. A BRAF mutation analysis is mandatory, but a wider evaluation of tumor mutational status (e.g. by next-generation sequencing) is desirable. When a BRAFV600E mutation is detected, treatment with Dabrafenib and Trametinib should be preferred: this combination has been approved by the Food and Drug Administration for the treatment of patients with locally advanced or metastatic ATC with BRAFV600E mutation and with no satisfactory locoregional treatment options. Alternatively, Lenvatinib, regardless of mutational status, reported good results and was approved in Japan for treating unresectable tumors. Other single target mutation agents with fair results are Everolimus when a mutation involving the PI3K/mTOR pathway is detected, Imatinib in case of PDGF-receptors overexpression, and Spartalizumab in case of PD-L1 positive tumors. Several trials are currently evaluating the possible beneficial role of a combinatorial therapy in ATC. Since in this tumor several genetic alterations are usually found, the aim is to inhibit or disrupt several pathways: these combination strategies use therapy targeting angiogenesis, survival, proliferation, and may act against both MAPK and PI3K pathways. Investigating new treatment options is eagerly awaited since, to date, even the molecules with the best radiological results have not been able to provide a durable disease control.
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Affiliation(s)
- Simone De Leo
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Piazzale Brescia, 20, 20149, Milan, Italy.
| | - Matteo Trevisan
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Laura Fugazzola
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Piazzale Brescia, 20, 20149, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors. Bioorg Med Chem 2020; 28:115684. [DOI: 10.1016/j.bmc.2020.115684] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/22/2020] [Accepted: 07/28/2020] [Indexed: 11/19/2022]
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Smalley JP, Cowley SM, Hodgkinson JT. Bifunctional HDAC Therapeutics: One Drug to Rule Them All? Molecules 2020; 25:E4394. [PMID: 32987782 PMCID: PMC7583022 DOI: 10.3390/molecules25194394] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics-single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease.
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Affiliation(s)
- Joshua P. Smalley
- Leicester Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester, George Porter Building, University Road, Leicester LE1 7RH, UK;
| | - Shaun M. Cowley
- Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK;
| | - James T. Hodgkinson
- Leicester Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester, George Porter Building, University Road, Leicester LE1 7RH, UK;
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9
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Laetitia G, Sven S, Fabrice J. Combinatorial Therapies in Thyroid Cancer: An Overview of Preclinical and Clinical Progresses. Cells 2020; 9:E830. [PMID: 32235612 PMCID: PMC7226736 DOI: 10.3390/cells9040830] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/25/2020] [Accepted: 03/27/2020] [Indexed: 12/11/2022] Open
Abstract
Accounting for about 2% of cancers diagnosed worldwide, thyroid cancer has caused about 41,000 deaths in 2018. Despite significant progresses made in recent decades in the treatment of thyroid cancer, many resistances to current monotherapies are observed. In our complete review, we report all treatments that were tested in combination against thyroid cancer. Many preclinical studies investigating the effects of inhibitors of the MAPK and PI3K pathways highlighted the importance of mutations in such signaling pathways and their impacts on the subsequent efficacy of targeted therapies, thus reinforcing the need of more personalized therapeutic strategies. Our review also points out the multiple possibilities of combinatory strategies, particularly using therapies targeting proliferation, survival, angiogenesis, and in combination with conventional treatments such as chemotherapies. In any case, resistances to anticancer therapies always develop through the activation of alternative signaling pathways. Combinatory treatments aim to blockade such mechanisms, which are gradually decrypted, thus offering new perspectives for the future. The preclinical and clinical aspects of our review allow us to have a global opinion of the different therapeutic options currently evaluated in combination and to be aware about new perspectives of treatment of thyroid cancer.
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Affiliation(s)
- Gheysen Laetitia
- Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine, Mons University, Avenue du Champ de Mars, 8, B7000 Mons, Belgium; (S.S.); (J.F.)
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10
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Gentile D, Orlandi P, Banchi M, Bocci G. Preclinical and clinical combination therapies in the treatment of anaplastic thyroid cancer. Med Oncol 2020; 37:19. [DOI: 10.1007/s12032-020-1345-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 02/12/2020] [Indexed: 12/30/2022]
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11
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Desai A, Noor A, Joshi S, Kim AS. Takotsubo cardiomyopathy in cancer patients. CARDIO-ONCOLOGY 2019; 5:7. [PMID: 32154014 PMCID: PMC7048040 DOI: 10.1186/s40959-019-0042-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/21/2019] [Indexed: 01/09/2023]
Abstract
Background Cancer is a chronic condition that induces significant emotional and physical stress, which may increase the risk for developing Takotsubo cardiomyopathy (TCM). Main body Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a clinical syndrome that generally presents as chest pain mimicking acute coronary syndrome or as an acute heart failure characterized by severe left ventricular systolic dysfunction in response to emotional, physical, or medical stress. The potential triggers for Takotsubo syndrome in cancer patients include the emotional turmoil of a cancer diagnosis, the inflammatory state of the cancer itself, and the physical stress of cancer surgery, systemic anti-neoplastic therapy, and radiation treatment. TCM is becoming increasingly recognized among patients with cancer and has been associated with adverse outcomes in this patient population. In this study, we searched the Pubmed database using keywords “Takotsubo cardiomyopathy”, “cancer”, and “anti-neoplastic therapy” to review case reports of Takotsubo syndrome occurring in oncologic patients after systemic anti-neoplastic therapy. Clinical presentation, electrocardiogram, laboratory data, transthoracic echocardiogram and coronary angiogram results, and patient outcomes were collected and analyzed. Conclusion Patients with cancer are at an elevated risk for developing stress cardiomyopathy, and it is important to know which cancer drugs have been associated with the development of the Takotsubo syndrome.
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Affiliation(s)
- Aakash Desai
- Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Arish Noor
- Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Saurabh Joshi
- Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.,2Department of Medicine, Division of Cardiology, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-2202 USA
| | - Agnes S Kim
- Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.,2Department of Medicine, Division of Cardiology, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-2202 USA
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12
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Cole DW, Svider PF, Shenouda KG, Lee PB, Yoo NG, McLeod TM, Mutchnick SA, Yoo GH, Kaufman RJ, Callaghan MU, Fribley AM. Targeting the unfolded protein response in head and neck and oral cavity cancers. Exp Cell Res 2019; 382:111386. [PMID: 31075256 DOI: 10.1016/j.yexcr.2019.04.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 03/25/2019] [Accepted: 04/05/2019] [Indexed: 12/18/2022]
Abstract
Many FDA-approved anti-cancer therapies, targeted toward a wide array of molecular targets and signaling networks, have been demonstrated to activate the unfolded protein response (UPR). Despite a critical role for UPR signaling in the apoptotic execution of cancer cells by many of these compounds, the authors are currently unaware of any instance whereby a cancer drug was developed with the UPR as the intended target. With the essential role of the UPR as a driving force in the genesis and maintenance of the malignant phenotype, a great number of pre-clinical studies have surged into the medical literature describing the ability of dozens of compounds to induce UPR signaling in a myriad of cancer models. The focus of the current work is to review the literature and explore the role of the UPR as a mediator of chemotherapy-induced cell death in squamous cell carcinomas of the head and neck (HNSCC) and oral cavity (OCSCC), with an emphasis on preclinical studies.
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Affiliation(s)
- Daniel W Cole
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Peter F Svider
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Kerolos G Shenouda
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Paul B Lee
- Oakland University William Beaumont School of Medicine, Rochester Hills, Michigan, USA
| | - Nicholas G Yoo
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Thomas M McLeod
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Sean A Mutchnick
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - George H Yoo
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA; Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Michael U Callaghan
- Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI, USA
| | - Andrew M Fribley
- Department of Otolaryngology - Head and Neck Surgery, Wayne State University School of Medicine, Detroit, MI, USA; Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
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13
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Lichota A, Gwozdzinski K. Anticancer Activity of Natural Compounds from Plant and Marine Environment. Int J Mol Sci 2018; 19:E3533. [PMID: 30423952 PMCID: PMC6275022 DOI: 10.3390/ijms19113533] [Citation(s) in RCA: 247] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/05/2018] [Accepted: 11/06/2018] [Indexed: 02/07/2023] Open
Abstract
This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure⁻activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are discussed in this paper. This paper presents natural substances from plants, animals, and their aquatic environments. These substances include the vinca alkaloids, mistletoe plant extracts, podophyllotoxin derivatives, taxanes, camptothecin, combretastatin, and others including geniposide, colchicine, artesunate, homoharringtonine, salvicine, ellipticine, roscovitine, maytanasin, tapsigargin, and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from the marine plants and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates (e.g., sponges, tunicates, and soft corals) as well as certain other substances that have been tested on cells and experimental animals and used in human chemotherapy.
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Affiliation(s)
- Anna Lichota
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland.
| | - Krzysztof Gwozdzinski
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland.
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14
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Krajewska J, Jarzab B. Fosbretabulin tromethamine in the treatment of thyroid cancer. Expert Opin Orphan Drugs 2016. [DOI: 10.1517/21678707.2016.1169172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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15
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Zhang C, An T, Wang D, Wan G, Zhang M, Wang H, Zhang S, Li R, Yang X, Wang Y. Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(β-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma. J Control Release 2016; 226:193-204. [PMID: 26896737 DOI: 10.1016/j.jconrel.2016.02.030] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 02/09/2016] [Accepted: 02/15/2016] [Indexed: 01/01/2023]
Abstract
Stepwise pH-responsive nanoparticle system containing charge reversible pullulan-based (CAPL) shell and poly(β-amino ester) (PBAE)/poly(lactic-co-glycolic acid) (PLAG) core is designed to be used as carriers of paclitaxel (PTX) and combretastatin A4 (CA4) for combining antiangiogenesis and chemotherapy to treat hepatocellular carcinoma (HCC). CAPL-coated PBAE/PLGA (CAPL/PBAE/PLGA) nanoparticles displayed step-by-step responses to weakly acidic tumor microenvironment (pH ≈6.5) and endo/lysosome (pH ≈5.5) respectively through the cleavage of β-carboxylic amide bond in CAPL and the "proton-sponge" effect of PBAE, thus realized the efficient and orderly releases of CA4 and PTX. In human HCC HepG2 cells and human umbilical vein endothelial cells, CAPL/PBAE/PLGA nanoparticles significantly enhanced synergistic effects of PTX and CA4 on cell proliferation and cell migration. In HepG2 tumor-bearing mice, CAPL/PBAE/PLGA nanoparticles showed excellent tumor-targeting capability and remarkably increased inhibitory effects of PTX and CA4 on tumor growth and angiogenesis. In conclusion, this novel nanoparticle system is a promising candidate as carrier for drugs against HCC.
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Affiliation(s)
- Cong Zhang
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Tong An
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Dan Wang
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Guoyun Wan
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Mingming Zhang
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Hemei Wang
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Sipei Zhang
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Rongshan Li
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Xiaoying Yang
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China
| | - Yinsong Wang
- School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
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16
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Greene LM, Meegan MJ, Zisterer DM. Combretastatins: more than just vascular targeting agents? J Pharmacol Exp Ther 2015; 355:212-27. [PMID: 26354991 DOI: 10.1124/jpet.115.226225] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 08/25/2015] [Indexed: 01/23/2023] Open
Abstract
Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives. Furthermore, tubulin is a highly validated molecular target of many direct anticancer agents routinely used as front-line chemotherapeutics. The unique vascular targeting properties of the combretastatins have somewhat overshadowed their development as direct anticancer agents and the delineation of the various cell death pathways and anticancer properties associated with such chemotherapeutics. Moreover, the ongoing clinical trial of OXi4503 (combretastatin-A1 diphosphate) together with preliminary preclinical evaluation for the treatment of refractory acute myelogenous leukemia has successfully highlighted both the indirect and direct anticancer properties of combretastatins. In this review, we discuss the development of the combretastatins from nature to the clinic. The various mechanisms underlying combretastatin-induced cell cycle arrest, mitotic catastrophe, cell death, and survival are also reviewed in an attempt to further enhance the clinical prospects of this unique class of VTAs.
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Affiliation(s)
- Lisa M Greene
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (L.M.G., D.M.Z.), and School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology (M.J.M.), Trinity College Dublin, Dublin, Ireland
| | - Mary J Meegan
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (L.M.G., D.M.Z.), and School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology (M.J.M.), Trinity College Dublin, Dublin, Ireland
| | - Daniela M Zisterer
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (L.M.G., D.M.Z.), and School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology (M.J.M.), Trinity College Dublin, Dublin, Ireland
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17
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Inglis DJ, Lavranos TC, Beaumont DM, Leske AF, Brown CK, Hall AJ, Kremmidiotis G. The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer. Cancer Biol Ther 2015; 15:1552-60. [PMID: 25482941 DOI: 10.4161/15384047.2014.956605] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors. The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition. We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery. We investigated tumor adaptation to BNC105-induced hypoxia in animal models of breast and renal cancer. HIF-1α and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2α were upregulated, consistent with increased protein synthesis and increased expression of VEGF-A. We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting VEGF and mTOR signaling. Bevacizumab and pazopanib target the VEGF axis and have been approved for first line use in renal cancer. Everolimus targets mTOR and is currently approved in second line therapy of renal and particular breast cancers. We combined these agents with BNC105 to explore the effects on tumor vasculature, tumor growth inhibition and animal survival. Bevacizumab hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model. Consistent with this, addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model. Combination treatment of BNC105 with everolimus also increased tumor growth inhibition. BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer.
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Key Words
- 4EBP1, eukaryotic translation initiation factor 4E binding protein 1
- GLUT-1, glucose transporter 1
- H&E, hematoxylin and eosin.
- HIF1α, hypoxia-inducible factor 1-alpha
- IFNα, interferon α
- NSCLC, non-small-cell lung carcinoma
- PDGFR, platelet-derived growth factor receptor
- PERK, protein kinase-like endoplasmic reticulum kinase
- PFS, progression free survival
- TKI, tyrosine kinase inhibitor
- VDA, vascular disrupting agent
- VEGF
- VEGF, vascular endothelial growth factor
- breast
- eIF2a, eukaryotic translation initiation factor 2a
- hypoxia
- mTOR
- mTOR, mammalian target of rapamycin
- renal
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Weckman A, Rotondo F, Di Ieva A, Syro LV, Butz H, Cusimano MD, Kovacs K. Autophagy in endocrine tumors. Endocr Relat Cancer 2015; 22:R205-18. [PMID: 25947570 DOI: 10.1530/erc-15-0042] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/06/2015] [Indexed: 12/12/2022]
Abstract
Autophagy is an important intracellular process involving the degradation of cytoplasmic components. It is involved in both physiological and pathological conditions, including cancer. The role of autophagy in cancer is described as a 'double-edged sword,' a term that reflects its known participation in tumor suppression, tumor survival and tumor cell proliferation. Available research regarding autophagy in endocrine cancer supports this concept. Autophagy shows promise as a novel therapeutic target in different types of endocrine cancer, inhibiting or increasing treatment efficacy in a context- and cell-type-dependent manner. At present, however, there is very little research concerning autophagy in endocrine tumors. No research was reported connecting autophagy to some of the tumors of the endocrine glands such as the pancreas and ovary. This review aims to elucidate the roles of autophagy in different types of endocrine cancer and highlight the need for increased research in the field.
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Affiliation(s)
- Andrea Weckman
- Division of NeurosurgeryDepartment of SurgeryDivision of PathologyDepartment of Laboratory Medicine, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8 CanadaDepartment of NeurosurgeryHospital Pablo Tobon Uribe and Clínica Medellin, Medellin, Colombia
| | - Fabio Rotondo
- Division of NeurosurgeryDepartment of SurgeryDivision of PathologyDepartment of Laboratory Medicine, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8 CanadaDepartment of NeurosurgeryHospital Pablo Tobon Uribe and Clínica Medellin, Medellin, Colombia
| | - Antonio Di Ieva
- Division of NeurosurgeryDepartment of SurgeryDivision of PathologyDepartment of Laboratory Medicine, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8 CanadaDepartment of NeurosurgeryHospital Pablo Tobon Uribe and Clínica Medellin, Medellin, Colombia
| | - Luis V Syro
- Division of NeurosurgeryDepartment of SurgeryDivision of PathologyDepartment of Laboratory Medicine, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8 CanadaDepartment of NeurosurgeryHospital Pablo Tobon Uribe and Clínica Medellin, Medellin, Colombia
| | - Henriett Butz
- Division of NeurosurgeryDepartment of SurgeryDivision of PathologyDepartment of Laboratory Medicine, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8 CanadaDepartment of NeurosurgeryHospital Pablo Tobon Uribe and Clínica Medellin, Medellin, Colombia
| | - Michael D Cusimano
- Division of NeurosurgeryDepartment of SurgeryDivision of PathologyDepartment of Laboratory Medicine, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8 CanadaDepartment of NeurosurgeryHospital Pablo Tobon Uribe and Clínica Medellin, Medellin, Colombia
| | - Kalman Kovacs
- Division of NeurosurgeryDepartment of SurgeryDivision of PathologyDepartment of Laboratory Medicine, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8 CanadaDepartment of NeurosurgeryHospital Pablo Tobon Uribe and Clínica Medellin, Medellin, Colombia
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19
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Netea-Maier RT, Klück V, Plantinga TS, Smit JWA. Autophagy in thyroid cancer: present knowledge and future perspectives. Front Endocrinol (Lausanne) 2015; 6:22. [PMID: 25741318 PMCID: PMC4332359 DOI: 10.3389/fendo.2015.00022] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Accepted: 02/05/2015] [Indexed: 01/01/2023] Open
Abstract
Thyroid cancer is the most common endocrine malignancy. Despite having a good prognosis in the majority of cases, when the tumor is dedifferentiated it does no longer respond to conventional treatment with radioactive iodine, the prognosis worsens significantly. Treatment options for advanced, dedifferentiated disease are limited and do not cure the disease. Autophagy, a process of self-digestion in which damaged molecules or organelles are degraded and recycled, has emerged as an important player in the pathogenesis of different diseases, including cancer. The role of autophagy in thyroid cancer pathogenesis is not yet elucidated. However, the available data indicate that autophagy is involved in several steps of thyroid tumor initiation and progression as well as in therapy resistance and therefore could be exploited for therapeutic applications. The present review summarizes the most recent data on the role of autophagy in the pathogenesis of thyroid cancer and we will provide a perspective on how this process can be targeted for potential therapeutic approaches and could be further explored in the context of multimodality treatment in cancer and personalized medicine.
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Affiliation(s)
- Romana T. Netea-Maier
- Department of Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
| | - Viola Klück
- Department of Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
| | - Theo S. Plantinga
- Department of Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
| | - Johannes W. A. Smit
- Department of Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
- *Correspondence: Johannes W. A. Smit, Department of Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center, Geert Grooteplein 8, PO Box 9101, Nijmegen 6500 HB, Netherlands e-mail:
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20
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Luo X, Zhang H, Chen M, Wei J, Zhang Y, Li X. Antimetastasis and antitumor efficacy promoted by sequential release of vascular disrupting and chemotherapeutic agents from electrospun fibers. Int J Pharm 2014; 475:438-49. [PMID: 25218185 DOI: 10.1016/j.ijpharm.2014.09.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 08/17/2014] [Accepted: 09/06/2014] [Indexed: 01/15/2023]
Abstract
The vasculature in tumor microenvironment plays important roles in the tumor growth and metastasis, and the combination of vascular disrupting agents with chemotherapeutic drugs should be effective in inhibiting tumor progression. But the dosing schedules are essential to achieve a balance between vascular collapse and intratumoral uptake of chemotherapeutic agents. In the current study, emulsion and blend electrospinning were used to create compartmental fibers accommodating both combretastatin A-4 (CA4) and hydroxycamptothecin (HCPT). The release durations of CA4 and HCPT were modulated through the structure of fibers for dual drug loadings and the inoculation of 2-hydroxypropyl-β-cyclodextrin in fiber matrices. Under a noncontact cell coculture in Transwell, the sequential release of CA4 and HCPT indicated a sequential killing of endothelial and tumor cells. In an orthotopic breast tumor model, all the CA4/HCPT-loaded fibers showed superior antitumor efficacy and higher survival rate than fibers with loaded individual drug. Compared with fibrous mats with infiltrated free CA4 and fibers with extended release of CA4 for over 30 days, fibers with sustained release of CA4 for 3-7 days from CA4/HCPT-loaded fibers resulted in the most significant antitumor efficacy, tumor vasculature destruction, and the least tumor metastasis to lungs. A judicious selection of CA4 release durations in the combination therapy should be essential to enhance the tumor suppression efficacy and antimetastasis activity.
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Affiliation(s)
- Xiaoming Luo
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Hong Zhang
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Maohua Chen
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Jiaojun Wei
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Yun Zhang
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Xiaohong Li
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
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Vu-Phan D, Koenig RJ. Genetics and epigenetics of sporadic thyroid cancer. Mol Cell Endocrinol 2014; 386:55-66. [PMID: 23933154 PMCID: PMC3867574 DOI: 10.1016/j.mce.2013.07.030] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/31/2013] [Accepted: 07/31/2013] [Indexed: 12/23/2022]
Abstract
Thyroid carcinoma is the most common endocrine malignancy, and although the disease generally has an excellent prognosis, therapeutic options are limited for patients not cured by surgery and radioiodine. Thyroid carcinomas commonly contain one of a small number of recurrent genetic mutations. The identification and study of these mutations has led to a deeper understanding of the pathophysiology of this disease and is providing new approaches to diagnosis and therapy. Papillary thyroid carcinomas usually contain an activating mutation in the RAS cascade, most commonly in BRAF and less commonly in RAS itself or through gene fusions that activate RET. A chromosomal translocation that results in production of a PAX8-PPARG fusion protein is found in follicular carcinomas. Anaplastic carcinomas may contain some of the above changes as well as additional mutations. Therapies that are targeted to these mutations are being used in patient care and clinical trials.
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Affiliation(s)
- Dang Vu-Phan
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.
| | - Ronald J Koenig
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.
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22
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Morani F, Titone R, Pagano L, Galetto A, Alabiso O, Aimaretti G, Isidoro C. Autophagy and thyroid carcinogenesis: genetic and epigenetic links. Endocr Relat Cancer 2014; 21:R13-29. [PMID: 24163390 DOI: 10.1530/erc-13-0271] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Thyroid cancer is the most common cancer of the endocrine system and is responsible for the majority of deaths from endocrine malignancies. Although a large proportion of thyroid cancers belong to well differentiated histologic subtypes, which in general show a good prognosis after surgery and radioiodine ablation, the treatment of radio-resistant papillary-type, of undifferentiated anaplastic, and of medullary-type thyroid cancers remains unsatisfactory. Autophagy is a vesicular process for the lysosomal degradation of protein aggregates and of damaged or redundant organelles. Autophagy plays an important role in cell homeostasis, and there is evidence that this process is dysregulated in cancer cells. Recent in vitro preclinical studies have indicated that autophagy is involved in the cytotoxic response to chemotherapeutics in thyroid cancer cells. Indeed, several oncogenes and oncosuppressor genes implicated in thyroid carcinogenesis also play a role in the regulation of autophagy. In addition, some epigenetic modulators involved in thyroid carcinogenesis also influence autophagy. In this review, we highlight the genetic and epigenetic factors that mechanistically link thyroid carcinogenesis and autophagy, thus substantiating the rationale for an autophagy-targeted therapy of aggressive and radio-chemo-resistant thyroid cancers.
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Affiliation(s)
- Federica Morani
- Laboratory of Molecular Pathology, Department of Health SciencesUnit of Clinical Endocrinology Unit of Oncology, Department of Translational Medicine, Università del Piemonte Orientale 'A. Avogadro', Via Solaroli 17, 28100 Novara, Italy
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23
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Sosa JA, Elisei R, Jarzab B, Balkissoon J, Lu SP, Bal C, Marur S, Gramza A, Yosef RB, Gitlitz B, Haugen BR, Ondrey F, Lu C, Karandikar SM, Khuri F, Licitra L, Remick SC. Randomized safety and efficacy study of fosbretabulin with paclitaxel/carboplatin against anaplastic thyroid carcinoma. Thyroid 2014; 24:232-40. [PMID: 23721245 DOI: 10.1089/thy.2013.0078] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Anaplastic thyroid cancer (ATC), a rare highly vascularized tumor, has a dismal outcome. We conducted an open-label study of doublet carboplatin/paclitaxel chemotherapy with or without fosbretabulin in patients with ATC. METHODS Patients were randomly assigned in a 2:1 ratio to 6 cycles of paclitaxel 200 mg/m(2) followed by carboplatin AUC 6 on day 1 every 3 weeks (CP), or these drugs were given on day 2 after fosbretabulin 60 mg/m(2) (CP/fosbretabulin) on days 1, 8 and 15. After 6 cycles, patients on the fosbretabulin arm without progression could continue to receive fosbretabulin on days 1 and 8 of a 3-week schedule until progression. The primary end point was overall survival (OS). RESULTS Eighty patients were assigned (planned, 180) when enrollment was stopped due to rarity of disease and very low accrual. Median OS was 5.2 months [95% confidence interval (CI) 3.1, 9.0] for the CP/fosbretabulin arm (n=55; hazard ratio 0.73 [95% CI 0.44, 1.21]) and 4.0 months [95% CI 2.8, 6.2] for the CP arm (n=25; p=0.22 [log rank test]). One-year survival for CP/fosbretabulin versus CP was 26% versus 9%, respectively. There was no significant difference in progression-free survival between the two arms. Grade 1-2 hypertension and grade 3-4 neutropenia were more common with CP/fosbretabulin. There were no significant adverse cardiovascular side effects. CONCLUSIONS Although the study did not meet statistical significance in improvement in OS with the addition of fosbretabulin to carboplatin/paclitaxel, it represents the largest prospective randomized trial ever conducted in ATC. The regimen is well tolerated, with AEs and deaths primarily related to ATC and disease progression.
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Affiliation(s)
- Julie A Sosa
- 1 Department of Surgery, Duke University School of Medicine , Durham, North Carolina
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Autophagy, a novel target for chemotherapeutic intervention of thyroid cancer. Cancer Chemother Pharmacol 2013; 73:439-49. [DOI: 10.1007/s00280-013-2363-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 11/16/2013] [Indexed: 01/07/2023]
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Folaron M, Kalmuk J, Lockwood J, Frangou C, Vokes J, Turowski SG, Merzianu M, Rigual NR, Sullivan-Nasca M, Kuriakose MA, Hicks WL, Singh AK, Seshadri M. Vascular priming enhances chemotherapeutic efficacy against head and neck cancer. Oral Oncol 2013; 49:893-902. [PMID: 23890930 PMCID: PMC3772633 DOI: 10.1016/j.oraloncology.2013.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 06/21/2013] [Accepted: 06/26/2013] [Indexed: 12/23/2022]
Abstract
PURPOSE The need to improve chemotherapeutic efficacy against head and neck squamous cell carcinomas (HNSCC) is well recognized. In this study, we investigated the potential of targeting the established tumor vasculature in combination with chemotherapy in head and neck cancer. METHODS Experimental studies were carried out in multiple human HNSCC xenograft models to examine the activity of the vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in combination with chemotherapy. Multimodality imaging (magnetic resonance imaging, bioluminescence) in conjunction with drug delivery assessment (fluorescence microscopy), histopathology and microarray analysis was performed to characterize tumor response to therapy. Long-term treatment outcome was assessed using clinically-relevant end points of efficacy. RESULTS Pretreatment of tumors with VDA prior to administration of chemotherapy increased intratumoral drug delivery and treatment efficacy. Enhancement of therapeutic efficacy was dependent on the dose and duration of VDA treatment but was independent of the chemotherapeutic agent evaluated. Combination treatment resulted in increased tumor cell kill and improvement in progression-free survival and overall survival in both ectopic and orthotopic HNSCC models. CONCLUSION Our results show that preconditioning of the tumor microenvironment with an antivascular agent primes the tumor vasculature and results in enhancement of chemotherapeutic delivery and efficacy in vivo. Further investigation into the activity of antivascular agents in combination with chemotherapy against HNSCC is warranted.
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Affiliation(s)
- Margaret Folaron
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - James Kalmuk
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Jaimee Lockwood
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Costakis Frangou
- Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Jordan Vokes
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Steven G Turowski
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Mihai Merzianu
- Department of Pathology & Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Nestor R Rigual
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Maureen Sullivan-Nasca
- Department of Dentistry & Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Moni A Kuriakose
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Wesley L Hicks
- Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Anurag K Singh
- Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Mukund Seshadri
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Dentistry & Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
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Endoscopic dacryocystorhinostomy with canalicular marsupialization in common canalicular obstruction. Can J Ophthalmol 2013; 48:335-9. [DOI: 10.1016/j.jcjo.2013.02.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 02/21/2013] [Accepted: 03/15/2013] [Indexed: 11/18/2022]
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Aggressive multimodal approach for anaplastic thyroid cancer and long-term survival. Case Rep Oncol Med 2013; 2013:783862. [PMID: 23533874 PMCID: PMC3600220 DOI: 10.1155/2013/783862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 02/03/2013] [Indexed: 11/17/2022] Open
Abstract
Anaplastic thyroid cancer (ATC) comprises 1-2% of all thyroid cancers and is one of the most aggressive cancers with a median survival rate of around four months. The average 5-year survival rate has been reported to be around 3.6%. In this paper, we have discussed management and prognostic variables of a patient with ATC who has survived for more than 5 years. A 59-year-old female was referred to our facility for an elective thyroid and parathyroidectomy for concerns of thyroid papillary cancer and hyperparathyroidism. At the time of surgery, the tumor mass had invaded the muscular layer of esophagus; radicle thyroidectomy parathyroidectomy along with removal of muscle layer of esophagus was performed, and diagnosis of ATC was made. The patient was treated with chemoradiation with a good treatment response and no recurrence of tumor for two and a half years until PET/CT followed by wedge biopsy of lung confirmed ATC recurrence. The patient was treated with another course of radiation treatment with a good treatment response. Since then, the patient has been following in our outpatient oncology clinic and has no evidence of tumor recurrence. Aggressive multimodal approach of combining radicle surgery with chemoradiation treatment in select patients of ATC with no distant metastasis helps improve prognosis.
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Mita MM, Sargsyan L, Mita AC, Spear M. Vascular-disrupting agents in oncology. Expert Opin Investig Drugs 2013; 22:317-28. [PMID: 23316880 DOI: 10.1517/13543784.2013.759557] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Vascular-disrupting agents (VDAs) are a new class of oncology drugs, which specifically target established tumor neovasculature and have a relatively low toxicity profile. VDAs generally have non-overlapping side effects when concomitantly used with conventional cytotoxics. Several members of the VDA class have recently progressed through mid-to-late stages of clinical trials. AREAS COVERED We examined recent publications on preclinical findings and Phase I/II/III clinical trial data on mechanisms of actions, toxicities, and optimal use of VDA class drugs. It is becoming apparent that VDAs should be used in combination with other classes of cytotoxic agents for the optimization of their effect in treating various cancers. In this article we describe doses, timing of delivery, and sequence of combined therapy. We also address the combined mechanisms of actions of VDAs and conventional cytotoxic medications. EXPERT OPINION Vascular-disrupting agents represent a new class of promising anticancer agents, which exhibit synergistic and/or additive effects in combination with many conventional cytotoxics. Pharmacological evaluation of the optimal combinations of VDAs with agents of other classes and drug interactions need to be continued. Further clinical and preclinical studies are required for distinguishing cancer patients' subpopulations that would most benefit from VDAs, identifying tumor biomarkers predictive of response as well as reliable and reproducible imaging and/or biological assays indicative of pharmacodynamic effects, and establishing clinical algorithms for treatment.
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Affiliation(s)
- Monica M Mita
- Experimental Theraputics Program, Samuel Oschin Comprehensive Cancer Center, Cedars Sinai Medical Center, LA, CA, USA.
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Goertz DE, Todorova M, Mortazavi O, Agache V, Chen B, Karshafian R, Hynynen K. Antitumor effects of combining docetaxel (taxotere) with the antivascular action of ultrasound stimulated microbubbles. PLoS One 2012; 7:e52307. [PMID: 23284980 PMCID: PMC3527530 DOI: 10.1371/journal.pone.0052307] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Accepted: 11/12/2012] [Indexed: 11/25/2022] Open
Abstract
Ultrasound stimulated microbubbles (USMB) are being investigated for their potential to promote the uptake of anticancer agents into tumor tissue by exploiting their ability to enhance microvascular permeability. At sufficiently high ultrasound transmit amplitudes it has also recently been shown that USMB treatments can, on their own, induce vascular damage, shutdown blood flow, and inhibit tumor growth. The objective of this study is to examine the antitumor effects of ‘antivascular’ USMB treatments in conjunction with chemotherapy, which differs from previous work which has sought to enhance drug uptake with USMBs by increasing vascular permeability. Conceptually this is a strategy similar to combining vascular disrupting agents with a chemotherapy, and we have selected the taxane docetaxel (Taxotere) for evaluating this approach as it has previously been shown to have potent antitumor effects when combined with small molecule vascular disrupting agents. Experiments were conducted on PC3 tumors implanted in athymic mice. USMB treatments were performed at a frequency of 1 MHz employing sequences of 50 ms bursts (0.00024 duty cycle) at 1.65 MPa. USMB treatments were administered on a weekly basis for 4 weeks with docetaxel (DTX) being given intravenously at a dose level of 5 mg/kg. The USMB treatments, either alone or in combination with DTX, induced an acute reduction in tumor perfusion which was accompanied at the 24 hour point by significantly enhanced necrosis and apoptosis. Longitudinal experiments showed a modest prolongation in survival but no significant growth inhibition occurred in DTX–only and USMB-only treatment groups relative to control tumors. The combined USMB-DTX treatment group produced tumor shrinkage in weeks 4–6, and significant growth inhibition and survival prolongation relative to the control (p<0.001), USMB-only (p<0.01) and DTX-only treatment groups (p<0.01). These results suggest the potential of enhancing the antitumor activity of docetaxel by combining it with antivascular USMB effects.
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Affiliation(s)
- David E Goertz
- Department of Medical Biophysics, University of Toronto, Toronto, Canada.
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Sosa JA, Balkissoon J, Lu SP, Langecker P, Elisei R, Jarzab B, Bal C, Marur S, Gramza A, Ondrey F. Thyroidectomy followed by fosbretabulin (CA4P) combination regimen appears to suggest improvement in patient survival in anaplastic thyroid cancer. Surgery 2012; 152:1078-87. [DOI: 10.1016/j.surg.2012.08.036] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 08/20/2012] [Indexed: 11/29/2022]
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Regalbuto C, Frasca F, Pellegriti G, Malandrino P, Marturano I, Di Carlo I, Pezzino V. Update on thyroid cancer treatment. Future Oncol 2012; 8:1331-48. [DOI: 10.2217/fon.12.123] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Surgery and radioiodine therapy are usually effective for most patients with differentiated thyroid cancer. However, poorly differentiated and anaplastic thyroid carcinomas represent a challenge to physicians on the basis of the current cancer treatment modalities. These cancer subtypes are often lethal and refractory to radioiodine therapy as well as most of the common chemotherapy drugs. Several kinase inhibitors are promising targeted therapies for these malignancies; however, clinical trials involving these drugs have provided controversial results and their clinical use is still under debate. Advanced medullary thyroid carcinomas may also be refractory to conventional therapies and novel kinase inhibitors may also be useful to control tumor progression in certain patients. Novel evidence is emerging that thyroid cancer is a stem cell disease, thereby implying that the driving force of thyroid cancers is a subset of undifferentiated cells (thyroid cancer stem cells) with unlimited growth potential and resistance to conventional therapeutic regimens. Thyroid cancer stem cells have been proposed as responsible for tumor invasiveness, metastasis, relapse and differentiation. Therefore, drugs that selectively target these cells could serve as a cornerstone in the treatment of poorly differentiated thyroid cancer.
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Affiliation(s)
- Concetto Regalbuto
- Endocrinology, Department of Clinical & Molecular Biomedicine of the University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Francesco Frasca
- Endocrinology, Department of Clinical & Molecular Biomedicine of the University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Gabriella Pellegriti
- Endocrinology, Department of Clinical & Molecular Biomedicine of the University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Pasqualino Malandrino
- Endocrinology, Department of Clinical & Molecular Biomedicine of the University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Ilenia Marturano
- Endocrinology, Department of Clinical & Molecular Biomedicine of the University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Isidoro Di Carlo
- Department of Surgical Sciences, Organ Transplantation, & Advanced Technologies, University of Catania, Cannizzaro Hospital, Catania, Italy
| | - Vincenzo Pezzino
- Endocrinology, Department of Clinical & Molecular Biomedicine of the University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
- Centre of Diabetology & Endocrine Diseases, Cannizzaro Hospital, Catania, Italy
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Wein RO. Why is there such a poor prognosis associated with anaplastic thyroid carcinoma? Expert Rev Endocrinol Metab 2012; 7:483-485. [PMID: 30780889 DOI: 10.1586/eem.12.46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Richard O Wein
- a Department of Otolaryngology - Head and Neck Surgery,Tufts Medical Center, 800 Washington Street, Box 850, Boston, MA 02111, USA.
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Dai W, Jin W, Zhang J, Wang X, Wang J, Zhang X, Wan Y, Zhang Q. Spatiotemporally Controlled Co-delivery of Anti-vasculature Agent and Cytotoxic Drug by Octreotide-Modified Stealth Liposomes. Pharm Res 2012; 29:2902-11. [DOI: 10.1007/s11095-012-0797-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 05/25/2012] [Indexed: 10/28/2022]
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Greene LM, O'Boyle NM, Nolan DP, Meegan MJ, Zisterer DM. The vascular targeting agent Combretastatin-A4 directly induces autophagy in adenocarcinoma-derived colon cancer cells. Biochem Pharmacol 2012; 84:612-24. [PMID: 22705646 DOI: 10.1016/j.bcp.2012.06.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Revised: 06/05/2012] [Accepted: 06/06/2012] [Indexed: 12/12/2022]
Abstract
Recent clinical data demonstrated that the vascular targeting agent Combretastatin-A4 phosphate (CA-4P) prolonged survival of patients with advanced anaplastic thyroid cancer without any adverse side effects. However, as a single agent CA-4 failed to reduce tumour growth in the murine CT-26 adenocarcinoma colon cancer model. Furthermore, the molecular mechanism of the innate resistance of HT-29 human adenocarcinoma cells to CA-4 is largely unknown. In this report, we demonstrate for the first time that prolonged exposure to CA-4 and an azetidinone cis-restricted analogue, CA-432 (chemical name; 4-(3-Hydroxy-4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one) induced autophagy in adenocarcinoma-derived CT-26, Caco-2 and HT-29 cells but not in fibrosarcoma-derived HT-1080 cells. Autophagy is a fundamental self-catabolic process which can facilitate a prolonged cell survival in spite of adverse stress by generating energy via lysosomal degradation of cytoplasmic constituents. Autophagy was confirmed by acridine orange staining of vesicle formation, electron microscopy and increased expression of LC3-II. Combretastatin-induced autophagy was associated with a loss of mitochondrial membrane potential and elongation of the mitochondria. Furthermore, inhibition of autophagy by the vacuolar H(+)ATPase inhibitor Bafilomycin-A1 (BAF-A1) significantly enhanced CA-432 induced HT-29 cell death. Both CA-4 and its synthetic derivative, CA-432 induced the formation of large hyperdiploid cells in Caco-2 and CT-26 cells. The formation of these polyploid cells was significantly inhibited by autophagy inhibitor, BAF-A1. Results presented within demonstrate that autophagy is a novel response to combretastatin exposure and may be manipulated to enhance the therapeutic efficacy of this class of vascular targeting agents.
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Affiliation(s)
- Lisa M Greene
- School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland
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Saiselet M, Floor S, Tarabichi M, Dom G, Hébrant A, van Staveren WCG, Maenhaut C. Thyroid cancer cell lines: an overview. Front Endocrinol (Lausanne) 2012; 3:133. [PMID: 23162534 PMCID: PMC3499787 DOI: 10.3389/fendo.2012.00133] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Accepted: 10/23/2012] [Indexed: 01/09/2023] Open
Abstract
Human thyroid cancer cell lines are the most used models for thyroid cancer studies. They must be used with detailed knowledge of their characteristics. These in vitro cell lines originate from differentiated and dedifferentiated in vivo human thyroid tumors. However, it has been shown that mRNA expression profiles of these cell lines were closer to dedifferentiated in vivo thyroid tumors (anaplastic thyroid carcinoma, ATC) than to differentiated ones. Here an overview of the knowledge of these models was made. The mutational status of six human thyroid cancer cell lines (WRO, FTC133, BCPAP, TPC1, K1, and 8505C) was in line with previously reported findings for 10 genes frequently mutated in thyroid cancer. However, the presence of a BRAF mutation (T1799A: V600E) in WRO questions the use of this cell line as a model for follicular thyroid carcinoma (FTC). Next, to investigate the biological meaning of the modulated mRNAs in these cells, a pathway analysis on previously obtained mRNA profiles was performed on five cell lines. In five cell lines, the MHC class II pathway was down-regulated and in four of them, ribosome biosynthesis and translation pathways were up-regulated. mRNA expression profiles of the cell lines were also compared to those of the different types of thyroid cancers. Three datasets originating from different microarray platforms and derived from distinct laboratories were used. This meta-analysis showed a significant higher correlation between the profiles of the thyroid cancer cell lines and ATC, than to differentiated thyroid tumors (i.e., PTC or FTC) specifically for DNA replication. This already observed higher correlation was obtained here with an increased number of in vivo tumors and using different platforms. In summary, this would suggest that some papillary thyroid carcinoma or follicular thyroid carcinoma (PTC or FTC) cell lines (i.e., TPC-1) might have partially lost their original DNA synthesis/replication regulation mechanisms during their in vitro cell adaptation/evolution.
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Affiliation(s)
- Manuel Saiselet
- School of Medicine, IRIBHM, Université Libre de BruxellesBrussels, Belgium
- *Correspondence: Manuel Saiselet, IRIBHM, Faculté de Médecine CP602, Université Libre de Bruxelles, Campus Erasme Bat. C, 4-177A, 808 Route de Lennik, 1070 Bruxelles, Belgium. e-mail:
| | - Sébastien Floor
- School of Medicine, IRIBHM, Université Libre de BruxellesBrussels, Belgium
| | - Maxime Tarabichi
- School of Medicine, IRIBHM, Université Libre de BruxellesBrussels, Belgium
| | - Geneviève Dom
- School of Medicine, IRIBHM, Université Libre de BruxellesBrussels, Belgium
| | - Aline Hébrant
- School of Medicine, IRIBHM, Université Libre de BruxellesBrussels, Belgium
| | | | - Carine Maenhaut
- School of Medicine, IRIBHM, Université Libre de BruxellesBrussels, Belgium
- Welbio - Université Libre de BruxellesBrussels, Belgium
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Comparison between nonspecific and necrosis-avid gadolinium contrast agents in vascular disrupting agent-induced necrosis of rodent tumors at 3.0T. Invest Radiol 2011; 46:531-8. [PMID: 21577133 DOI: 10.1097/rli.0b013e31821a2116] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE : To compare a commercial contrast agent (CA) Dotarem and a necrosis-avid CA (NACA) for their ability to evaluate the therapeutic necrosis with a vascular disrupting agent (VDA) on magnetic resonance imaging in rodent liver tumors to determine which could better correlate with the histopathologic outcome. METHODS : After the VDA treatment, 16 rats with 32 liver rhabdomyosarcomas were randomized into Dotarem and NACA groups (n = 8 per group) for both interindividual and intraindividual comparisons. T2-weighted imaging, T1-weighted imaging (T1WI), contrast-enhanced T1-weighted imaging (CE-T1WI), and diffusion-weighted imaging were performed at baseline, after VDA treatment and CA injections. The enhancing efficacy of CAs at immediate and delayed enhancement on CE-T1WI in viable tumor and necrosis was compared. Tumor necrosis ratios calculated from NACA and Dotarem were compared and correlated with gold-standard histopathology. RESULTS : On the immediate CE-T1WI, viable tumor was enhanced by either CA. On the delayed CE-T1WI at 30 minutes, both CAs failed to demarcate viable tumor from necrosis. At 24 hours post-NACA, the necrosis was clearly distinguished from viable tumor and thus derived necrosis ratio matched that from histopathology (P = 0.99); necrosis ratio from Dotarem was significantly lower than that from NACA and histopathology (P < 0.05, both), with a higher correlation of NACA than that of Dotarem with histopathology (r = 0.99 vs. r = 0.82). CONCLUSIONS : NACA better evaluated VDA-induced tumor necrosis than nonspecific CA on T1WI in tumor models of rat liver. NACA showed a closer correlation with histopathology than nonspecific CA for the delineation of true necrosis. Delayed enhancement on T1WI with nonspecific CA is not suitable for the assessment of VDA-induced tumor necrosis.
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Fu XH, Li J, Zou Y, Hong YR, Fu ZX, Huang JJ, Zhang SZ, Zheng S. Endostar enhances the antineoplastic effects of combretastatin A4 phosphate in an osteosarcoma xenograft. Cancer Lett 2011; 312:109-16. [DOI: 10.1016/j.canlet.2011.08.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2011] [Revised: 08/07/2011] [Accepted: 08/08/2011] [Indexed: 01/22/2023]
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Burns CJ, Fantino E, Powell AK, Shnyder SD, Cooper PA, Nelson S, Christophi C, Malcontenti-Wilson C, Dubljevic V, Harte MF, Joffe M, Phillips ID, Segal D, Wilks AF, Smith GD. The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo. J Pharmacol Exp Ther 2011; 339:799-806. [PMID: 21917561 DOI: 10.1124/jpet.111.186965] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639-4642, 2009; Mol Cancer Ther 8:3036-3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC(50) 3.7 ± 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound.
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Derbel O, Limem S, Ségura-Ferlay C, Lifante JC, Carrie C, Peix JL, Borson-Chazot F, Bournaud C, Droz JP, de la Fouchardière C. Results of combined treatment of anaplastic thyroid carcinoma (ATC). BMC Cancer 2011; 11:469. [PMID: 22044775 PMCID: PMC3219746 DOI: 10.1186/1471-2407-11-469] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Accepted: 11/01/2011] [Indexed: 11/18/2022] Open
Abstract
Background Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis. Methods We retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin. Results Thirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months. Conclusion Despite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.
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Affiliation(s)
- Olfa Derbel
- University of Lyon-Leon-Berard Cancer Center, Department of Medical Oncology, Lyon, France.
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Monitoring antivascular therapy in head and neck cancer xenografts using contrast-enhanced MR and US imaging. Angiogenesis 2011; 14:491-501. [PMID: 21901534 DOI: 10.1007/s10456-011-9233-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Accepted: 08/25/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND The overall goal of this study was to non-invasively monitor changes in blood flow of squamous cell carcinoma of the head and neck (SCCHN) xenografts using contrast-enhanced magnetic resonance (MR) and ultrasound (US) imaging. METHODS Experimental studies were performed on mice bearing FaDu tumors and SCCHN xenografts derived from human surgical tissue. MR examinations were performed using gadofosveset trisodium at 4.7T. Change in T1-relaxation rate of tumors (ΔR1) and tumor enhancement parameters (amplitude, area under the curve-AUC) were measured at baseline and 24 h after treatment with a tumor-vascular disrupting agent (tumor-VDA), 5,6-dimethylxanthenone-4-acetic acid (DMXAA; ASA404) and correlated with tumor necrosis and treatment outcome. CE-US was performed using microbubbles (Vevo MicroMarker®) to assess the change in relative tumor blood volume following VDA treatment. RESULTS A marked decrease (up to 68% of baseline) in T1-enhancement of FaDu tumors was observed 1 day after VDA therapy indicative of a reduction in blood flow. Early (24 h) vascular response of individual tumors to VDA therapy detected by MRI correlated with tumor necrosis and volume estimates at 10 days post treatment. VDA treatment also resulted in a significant reduction in AUC and amplitude of patient tumor-derived SCCHN xenografts. Consistent with MRI observations, CE-US revealed a significant reduction in tumor blood volume of patient tumor-derived SCCHN xenografts after VDA therapy. Treatment with VDA resulted in a significant tumor growth inhibition of patient tumor derived SCCHN xenografts. CONCLUSIONS These findings demonstrate that both CE-MRI and CE-US allow monitoring of early changes in vascular function following VDA therapy. The results also demonstrate, for the first time, potent vascular disruptive and antitumor activity of DMXAA against patient tumor-derived head and neck carcinoma xenografts.
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Yang T, Wang Y, Li Z, Dai W, Yin J, Liang L, Ying X, Zhou S, Wang J, Zhang X, Zhang Q. Targeted delivery of a combination therapy consisting of combretastatin A4 and low-dose doxorubicin against tumor neovasculature. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2011; 8:81-92. [PMID: 21664295 DOI: 10.1016/j.nano.2011.05.003] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Revised: 04/15/2011] [Accepted: 05/03/2011] [Indexed: 12/12/2022]
Abstract
UNLABELLED The present study demonstrates the applicability of a novel strategy that employs targeted delivery of combined treatment against tumor neovasculature. Briefly, a ligand of integrins, cyclic arginine-glycine-aspartic acid-tyrosine-lysine pentapeptide (cRGDyK), was conjugated to the PEG end of polyethylene glycol-b-poly lactic acid (PEG-b-PLA), and doxorubicin was chemically linked to the PLA end of PEG-b-PLA. The targeted dual-drug micelle system was prepared by mixing combretastatin A4 (an antivascular agent), PEG-b-PLA, and the above two conjugates using a solution-casting method. The targeted micelles significantly enhanced cellular uptake of the drug by B16-F10 cells and human umbilical vein endothelial cells through a receptor-mediated endocytosis. The cRGDyK-modified dual-drug system achieved an optimal antitumor effect, lifespan increase, antineovasculature, antiproliferation, and apoptosis induction, revealing the advantage of active targeting and the modified combination therapy. In conclusion, the integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment. FROM THE CLINICAL EDITOR A ligand of integrins was conjugated to PEG-b-PLA, and doxorubicin was chemically linked to the PLA. Efficiency was demonstrated in a cancer model. The integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment.
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MESH Headings
- Animals
- Antibiotics, Antineoplastic/administration & dosage
- Antibiotics, Antineoplastic/chemistry
- Antibiotics, Antineoplastic/therapeutic use
- Antineoplastic Agents, Phytogenic/administration & dosage
- Antineoplastic Agents, Phytogenic/chemistry
- Antineoplastic Agents, Phytogenic/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/chemistry
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Doxorubicin/administration & dosage
- Doxorubicin/chemistry
- Doxorubicin/therapeutic use
- Drug Carriers/chemistry
- Drug Delivery Systems
- Human Umbilical Vein Endothelial Cells
- Humans
- Lactates/chemistry
- Lactates/therapeutic use
- Melanoma, Experimental
- Mice
- Mice, Inbred C57BL
- Micelles
- Neovascularization, Pathologic/drug therapy
- Peptides, Cyclic/chemistry
- Peptides, Cyclic/therapeutic use
- Polyethylene Glycols/chemistry
- Polyethylene Glycols/therapeutic use
- Stilbenes/administration & dosage
- Stilbenes/chemistry
- Stilbenes/therapeutic use
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Affiliation(s)
- Tingyuan Yang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
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Perri F, Lorenzo GD, Scarpati GDV, Buonerba C. Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options. World J Clin Oncol 2011; 2:150-7. [PMID: 21611089 PMCID: PMC3100480 DOI: 10.5306/wjco.v2.i3.150] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 01/27/2011] [Accepted: 02/03/2011] [Indexed: 02/06/2023] Open
Abstract
Anaplastic thyroid carcinoma (ATC) is the rarest, but deadliest histologic type among thyroid malignancies, with a dismal median survival of 3-9 mo. Even though ATC accounts for less than 2% of all thyroid tumors, it is responsible for 14%-39% of thyroid carcinoma-related deaths. ATC clinically presents as a rapidly growing mass in the neck, associated with dyspnoea, dysphagia and vocal cord paralysis. It is usually locally advanced and often metastatic at initial presentation. For operable diseases, the combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin and cisplatin, is the best treatment strategy. Cytotoxic drugs for advanced/metastatic ATC are poorly effective. On the other hand, targeted agents might represent a viable therapeutic option. Axitinib, combretastatin A4, sorafenib and imatinib have been tested in small clinical trials of ATC, with a promising disease control rate ranging from 33% to 75%. Other clinical trials of targeted therapy for thyroid carcinoma are currently ongoing. Biological agents that are under investigation include pazopanib, gefitinib and everolimus. With the very limited therapeutic armamentarium available at the present time, targeted therapy constitutes an exciting new horizon for ATC. In future, biological agents will probably represent the standard of care for this aggressive malignancy, in the same fashion as it has recently occurred for other chemo-refractory tumors, such as kidney and hepatic cancer.
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Affiliation(s)
- Francesco Perri
- Francesco Perri, Department of Skin, Musculoskeletal System and Head-neck, INT Foundation G. Pascale, Napoli 80131, Italy
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Kojic SL, Strugnell SS, Wiseman SM. Anaplastic thyroid cancer: a comprehensive review of novel therapy. Expert Rev Anticancer Ther 2011; 11:387-402. [DOI: 10.1586/era.10.179] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Preclinical Efficacy of Vascular Disrupting Agents in Non–Small-Cell Lung Cancer. Clin Lung Cancer 2011; 12:81-6. [DOI: 10.1016/j.cllc.2011.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Revised: 06/22/2010] [Accepted: 06/22/2010] [Indexed: 11/21/2022]
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Risinger AL, Westbrook CD, Encinas A, Mülbaier M, Schultes CM, Wawro S, Lewis JD, Janssen B, Giles FJ, Mooberry SL. ELR510444, a novel microtubule disruptor with multiple mechanisms of action. J Pharmacol Exp Ther 2011; 336:652-60. [PMID: 21148249 PMCID: PMC3061540 DOI: 10.1124/jpet.110.175331] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 12/08/2010] [Indexed: 11/22/2022] Open
Abstract
Although several microtubule-targeting drugs are in clinical use, there remains a need to identify novel agents that can overcome the limitations of current therapies, including acquired and innate drug resistance and undesired side effects. In this study, we show that ELR510444 has potent microtubule-disrupting activity, causing a loss of cellular microtubules and the formation of aberrant mitotic spindles and leading to mitotic arrest and apoptosis of cancer cells. ELR510444 potently inhibited cell proliferation with an IC(50) value of 30.9 nM in MDA-MB-231 cells, inhibited the rate and extent of purified tubulin assembly, and displaced colchicine from tubulin, indicating that the drug directly interacts with tubulin at the colchicine-binding site. ELR510444 is not a substrate for the P-glycoprotein drug transporter and retains activity in βIII-tubulin-overexpressing cell lines, suggesting that it circumvents both clinically relevant mechanisms of drug resistance to this class of agents. Our data show a close correlation between the concentration of ELR510444 required for inhibition of cellular proliferation and that required to cause significant loss of cellular microtubule density, consistent with its activity as a microtubule depolymerizer. ELR510444 also shows potent antitumor activity in the MDA-MB-231 xenograft model with at least a 2-fold therapeutic window. Studies in tumor endothelial cells show that a low concentration of ELR510444 (30 nM) rapidly alters endothelial cell shape, similar to the effect of the vascular disrupting agent combretastatin A4. These results suggest that ELR510444 is a novel microtubule-disrupting agent with potential antivascular effects and in vivo antitumor efficacy.
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Affiliation(s)
- A L Risinger
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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Wang Y, Yang T, Wang X, Dai W, Wang J, Zhang X, Li Z, Zhang Q. Materializing sequential killing of tumor vasculature and tumor cells via targeted polymeric micelle system. J Control Release 2011; 149:299-306. [DOI: 10.1016/j.jconrel.2010.10.027] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2010] [Revised: 10/06/2010] [Accepted: 10/24/2010] [Indexed: 02/03/2023]
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Siemann DW. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by Tumor-Vascular Disrupting Agents. Cancer Treat Rev 2011; 37:63-74. [PMID: 20570444 PMCID: PMC2958232 DOI: 10.1016/j.ctrv.2010.05.001] [Citation(s) in RCA: 447] [Impact Index Per Article: 31.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2010] [Revised: 04/28/2010] [Accepted: 05/02/2010] [Indexed: 02/06/2023]
Abstract
The vasculature of solid tumors is fundamentally different from that of normal vasculature and offers a unique target for anti-cancer therapy. Direct vascular-targeting with Tumor-Vascular Disrupting Agents (Tumor-VDAs) is distinctly different from anti-angiogenic strategies, and offers a complementary approach to standard therapies. Tumor-VDAs therefore have significant potential when combined with chemotherapy, radiotherapy, and angiogenesis-inhibiting agents. Preclinical studies with the different Tumor-VDA classes have demonstrated key tumor-selective anti-vascular and anti-tumor effects.
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Affiliation(s)
- Dietmar W Siemann
- Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, USA.
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Wang H, Marchal G, Ni Y. Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer. World J Radiol 2011; 3:1-16. [PMID: 21286490 PMCID: PMC3030722 DOI: 10.4329/wjr.v3.i1.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 01/13/2011] [Accepted: 01/20/2011] [Indexed: 02/06/2023] Open
Abstract
Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulin-destabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.
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Wang Z, Chui WK, Ho PC. Nanoparticulate Delivery System Targeted to Tumor Neovasculature for Combined Anticancer and Antiangiogenesis Therapy. Pharm Res 2010; 28:585-96. [DOI: 10.1007/s11095-010-0308-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Accepted: 10/18/2010] [Indexed: 11/30/2022]
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