Insights & Perspectives Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model Charles H. Lineweaver 1) *, Paul C. W. Davies 2) and Mark D. Vincent 3) In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the- weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the- weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. Keywords: .adaptive immunity; cancer therapy; carcinogenesis; evolution of multicellularity Introduction Current cancer therapy is based on radiation, chemotherapy, and surgery. Radiation and chemotherapy target cancer cell proliferation by damaging DNA. However, DNA damage interferes with normal cellular proliferation throughout the body and often has significant toxicity (e.g. [1]). Modern molecularly targeted therapies have, on the whole, proven less selectively toxic to cancer cells than hoped, and are unquestionably associated with a range of unusual and sometimes debilitating adverse effects; as an additional disap- pointment, they often exercise very temporary benefits before resistance sets in. The effectiveness of surgery is com- promised by the invisibility of micro- metastases, irresectability of either the primary tumor or overt metastases, and the common reactivation of dormant secondary micrometastases [2, 3]. Simi- lar problems apply to radiotherapy. Despite certain clear benefits of current therapies, more effective and better- tolerated approaches are needed. The main challenge facing cancer researchers is to develop therapies that more specifically target cancer cells, while leaving normally functioning cells unscathed. However, since the capabil- ities of cancer cells seem to be based on accessing normal cellular functions that play important roles in embryogenesis and tissue self-renewal [4, 5], targeting these capabilities without producing side-effects on normal cells is difficult. Finding a therapeutic window between proliferating cancer cells and proliferat- ing normal cells remains a major challenge in the design of successful cancer therapies [6]. Current therapeutic treatments at- tack the strengths of cancer: they predominantly target what cancer cells, and all cells, have deeply embedded in their genomes – strategies for cellular proliferation. It may seem rational to treat a proliferative disease with anti- proliferative drugs. However, after 4 billion years of evolution (the first 3 billion of which were characterized by the largely unregulated proliferation of unicellular organisms) cellular prolifer- ation is probably the most protected, least vulnerable, most redundant and most entrenched capability that any cell has. The redundant and robust supports for cellular proliferation are 2 billion years older than the many layers of recent differentiation and regulation that evolved with multicellular eukar- yotes. Thus proliferation, not terminal DOI 10.1002/bies.201400070 1) Planetary Science Institute, Research School of Astronomy and Astrophysics and the Research School of Earth Sciences, Australian National University, Canberra, ACT, Australia 2) Beyond Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ, USA 3) Department of Oncology, University of Western Ontario, London, Ontario, Canada *Corresponding author: Charles H. Lineweaver E-mail: charley.lineweaver@anu.edu.au www.bioessays-journal.com 827 Bioessays 36: 827–835, ß 2014 WILEY Periodicals, Inc. Think again