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

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

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.