@article{a6826ba353fb431a85083f4068bd71c5,
title = "Why Great Mitotic Inhibitors Make Poor Cancer Drugs",
abstract = "Chemotherapy is central to oncology, perceived to operate only on prolific cancerous tissue. Yet, many non-neoplastic tissues are more prolific compared with typical tumors. Chemotherapies achieve sufficient therapeutic windows to exert antineoplastic activity because they are prodrugs that are bioactivated in cancer-specific environments. The advent of precision medicine has obscured this concept, favoring the development of high-potency kinase inhibitors. Inhibitors of essential mitotic kinases exemplify this paradigm shift, but intolerable on-target toxicities in more prolific normal tissues have led to repeated failures in the clinic. Proliferation rates alone cannot be used to achieve cancer specificity. Here, we discuss integrating the cancer specificity of prodrugs from classical chemotherapeutics and the potency of mitotic kinase inhibitors to generate a class of high-precision cancer therapeutics.",
keywords = "cell cycle, chemotherapy, cyclin-dependent kinases, kinesin, precision oncology, pro-drug, targeted therapy",
author = "Yan, {Victoria C.} and Butterfield, {Hannah E.} and Poral, {Anton H.} and Yan, {Matthew J.} and Yang, {Kristine L.} and Pham, {Cong Dat} and Muller, {Florian L.}",
note = "Funding Information: This work was supported by the following grants to F.L.M.: NIH 1R21CA226301, American Cancer Society RSG-15-145-01-CDD, National Comprehensive Cancer Network YIA170032, and the Andrew Sabin Family Foundation Fellows Award. Funding from the University of Texas MD Anderson Cancer Center/Glioblastoma Moon Shot, CABI/GE In-Kind Research Grant (MI2), Brockman Medical Research Foundation and the SPORE in Brain Cancer (2P50CA127001) funds are gratefully acknowledged. We dedicate this work to the memory of Kenneth Scott, a brilliant cancer researcher who, at the prime of his life, succumbed to the very illness he was working to eradicate. Funding Information: This work was supported by the following grants to F.L.M.: NIH 1R21CA226301 , American Cancer Society RSG-15-145-01-CDD , National Comprehensive Cancer Network YIA170032 , and the Andrew Sabin Family Foundation Fellows Award. Funding from the University of Texas MD Anderson Cancer Center /Glioblastoma Moon Shot, CABI/GE In-Kind Research Grant (MI2), Brockman Medical Research Foundation and the SPORE in Brain Cancer ( 2P50CA127001 ) funds are gratefully acknowledged. We dedicate this work to the memory of Kenneth Scott, a brilliant cancer researcher who, at the prime of his life, succumbed to the very illness he was working to eradicate. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = nov,
doi = "10.1016/j.trecan.2020.05.010",
language = "English (US)",
volume = "6",
pages = "924--941",
journal = "Trends in Cancer",
issn = "2405-8033",
publisher = "Cell Press",
number = "11",
}