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Designing a broad-spectrum integrative approach for cancer prevention and treatment.

ABSTRACT: Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

SUBMITTER: Block KI

PROVIDER: S-EPMC4819002 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Block Keith I KI Gyllenhaal Charlotte C Lowe Leroy L Amedei Amedeo A Amin A R M Ruhul ARMR Amin Amr A Aquilano Katia K Arbiser Jack J Arreola Alexandra A Arzumanyan Alla A Ashraf S Salman SS Azmi Asfar S AS Benencia Fabian F Bhakta Dipita D Bilsland Alan A Bishayee Anupam A Blain Stacy W SW Block Penny B PB Boosani Chandra S CS Carey Thomas E TE Carnero Amancio A Carotenuto Marianeve M Casey Stephanie C SC Chakrabarti Mrinmay M Chaturvedi Rupesh R Chen Georgia Zhuo GZ Chen Helen H Chen Sophie S Chen Yi Charlie YC Choi Beom K BK Ciriolo Maria Rosa MR Coley Helen M HM Collins Andrew R AR Connell Marisa M Crawford Sarah S Curran Colleen S CS Dabrosin Charlotta C Damia Giovanna G Dasgupta Santanu S DeBerardinis Ralph J RJ Decker William K WK Dhawan Punita P Diehl Anna Mae E AME Dong Jin-Tang JT Dou Q Ping QP Drew Janice E JE Elkord Eyad E El-Rayes Bassel B Feitelson Mark A MA Felsher Dean W DW Ferguson Lynnette R LR Fimognari Carmela C Firestone Gary L GL Frezza Christian C Fujii Hiromasa H Fuster Mark M MM Generali Daniele D Georgakilas Alexandros G AG Gieseler Frank F Gilbertson Michael M Green Michelle F MF Grue Brendan B Guha Gunjan G Halicka Dorota D Helferich William G WG Heneberg Petr P Hentosh Patricia P Hirschey Matthew D MD Hofseth Lorne J LJ Holcombe Randall F RF Honoki Kanya K Hsu Hsue-Yin HY Huang Gloria S GS Jensen Lasse D LD Jiang Wen G WG Jones Lee W LW Karpowicz Phillip A PA Keith W Nicol WN Kerkar Sid P SP Khan Gazala N GN Khatami Mahin M Ko Young H YH Kucuk Omer O Kulathinal Rob J RJ Kumar Nagi B NB Kwon Byoung S BS Le Anne A Lea Michael A MA Lee Ho-Young HY Lichtor Terry T Lin Liang-Tzung LT Locasale Jason W JW Lokeshwar Bal L BL Longo Valter D VD Lyssiotis Costas A CA MacKenzie Karen L KL Malhotra Meenakshi M Marino Maria M Martinez-Chantar Maria L ML Matheu Ander A Maxwell Christopher C McDonnell Eoin E Meeker Alan K AK Mehrmohamadi Mahya M Mehta Kapil K Michelotti Gregory A GA Mohammad Ramzi M RM Mohammed Sulma I SI Morre D James DJ Muralidhar Vinayak V Muqbil Irfana I Murphy Michael P MP Nagaraju Ganji Purnachandra GP Nahta Rita R Niccolai Elena E Nowsheen Somaira S Panis Carolina C Pantano Francesco F Parslow Virginia R VR Pawelec Graham G Pedersen Peter L PL Poore Brad B Poudyal Deepak D Prakash Satya S Prince Mark M Raffaghello Lizzia L Rathmell Jeffrey C JC Rathmell W Kimryn WK Ray Swapan K SK Reichrath Jörg J Rezazadeh Sarallah S Ribatti Domenico D Ricciardiello Luigi L Robey R Brooks RB Rodier Francis F Rupasinghe H P Vasantha HPV Russo Gian Luigi GL Ryan Elizabeth P EP Samadi Abbas K AK Sanchez-Garcia Isidro I Sanders Andrew J AJ Santini Daniele D Sarkar Malancha M Sasada Tetsuro T Saxena Neeraj K NK Shackelford Rodney E RE Shantha Kumara H M C HMC Sharma Dipali D Shin Dong M DM Sidransky David D Siegelin Markus David MD Signori Emanuela E Singh Neetu N Sivanand Sharanya S Sliva Daniel D Smythe Carl C Spagnuolo Carmela C Stafforini Diana M DM Stagg John J Subbarayan Pochi R PR Sundin Tabetha T Talib Wamidh H WH Thompson Sarah K SK Tran Phuoc T PT Ungefroren Hendrik H Vander Heiden Matthew G MG Venkateswaran Vasundara V Vinay Dass S DS Vlachostergios Panagiotis J PJ Wang Zongwei Z Wellen Kathryn E KE Whelan Richard L RL Yang Eddy S ES Yang Huanjie H Yang Xujuan X Yaswen Paul P Yedjou Clement C Yin Xin X Zhu Jiyue J Zollo Massimo M

Seminars in cancer biology 20151201

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are ...[more]

PMID: 26590477

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Project description:UnlabelledPathological neovascularization is a hallmark of late stage neovascular (wet) age-related macular degeneration (AMD) and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV), while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF) exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD.Methods and findingsLodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH), Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2). Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1). The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG) assessing retinal and by histology.ConclusionsLodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic use. Our results support the concept that broad spectrum antiangiogenic drugs are promising agents for AMD treatment and prevention.

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Designing a broad-spectrum integrative approach for cancer prevention and treatment.

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Designing a broad-spectrum integrative approach for cancer prevention and treatment.

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