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Molecular Physiology & Biophysics

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

AUTHORS

Block KI , Gyllenhaal C , Lowe L , Amedei A , Amin AR , Amin A , Aquilano K , Arbiser J , Arreola A , Arzumanyan A , Ashraf SS , Azmi AS , Benencia F , Bhakta D , Bilsland A , Bishayee A , Blain SW , Block PB , Boosani CS , Carey TE , Carnero A , Carotenuto M , Casey SC , Chakrabarti M , Chaturvedi R , Chen GZ , Chen H , Chen S , Chen YC , Choi BK , Ciriolo MR , Coley HM , Collins AR , Connell M , Crawford S , Curran CS , Dabrosin C , Damia G , Dasgupta S , DeBerardinis RJ , Decker WK , Dhawan P , Diehl AM , Dong JT , Dou QP , Drew JE , Elkord E , El-Rayes B , Feitelson MA , Felsher DW , Ferguson LR , Fimognari C , Firestone GL , Frezza C , Fujii H , Fuster MM , Generali D , Georgakilas AG , Gieseler F , Gilbertson M , Green MF , Grue B , Guha G , Halicka D , Helferich WG , Heneberg P , Hentosh P , Hirschey MD , Hofseth LJ , Holcombe RF , Honoki K , Hsu HY , Huang GS , Jensen LD , Jiang WG , Jones LW , Karpowicz PA , Keith WN , Kerkar SP , Khan GN , Khatami M , Ko YH , Kucuk O , Kulathinal RJ , Kumar NB , Kwon BS , Le A , Lea MA , Lee HY , Lichtor T , Lin LT , Locasale JW , Lokeshwar BL , Longo VD , Lyssiotis CA , MacKenzie KL , Malhotra M , Marino M , Martinez-Chantar ML , Matheu A , Maxwell C , McDonnell E , Meeker AK , Mehrmohamadi M , Mehta K , Michelotti GA , Mohammad RM , Mohammed SI , Morre DJ , Muralidhar V , Muqbil I , Murphy MP , Nagaraju GP , Nahta R , Niccolai E , Nowsheen S , Panis C , Pantano F , Parslow VR , Pawelec G , Pedersen PL , Poore B , Poudyal D , Prakash S , Prince M , Raffaghello L , Rathmell JC , Rathmell WK , Ray SK , Reichrath J , Rezazadeh S , Ribatti D , Ricciardiello L , Robey RB , Rodier F , Rupasinghe HP , Russo GL , Ryan EP , Samadi AK , Sanchez-Garcia I , Sanders AJ , Santini D , Sarkar M , Sasada T , Saxena NK , Shackelford RE , Shantha Kumara HM , Sharma D , Shin DM , Sidransky D , Siegelin MD , Signori E , Singh N , Sivanand S , Sliva D , Smythe C , Spagnuolo C , Stafforini DM , Stagg J , Subbarayan PR , Sundin T , Talib WH , Thompson SK , Tran PT , Ungefroren H , Vander Heiden MG , Venkateswaran V , Vinay DS , Vlachostergios PJ , Wang Z , Wellen KE , Whelan RL , Yang ES , Yang H , Yang X , Yaswen P , Yedjou C , Yin X , Zhu J , Zollo M , . Seminars in cancer biology. 2015 12 ; 35 Suppl(). S276-304

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.

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.

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