Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury
Sahra Bodo, Cécile Campagne, Tin Htwe Thin, Daniel S Higginson, H Alberto Vargas, Guoqiang Hua, John D Fuller, Ellen Ackerstaff, James Russell, Zhigang Zhang, Stefan Klingler, HyungJoon Cho, Matthew G Kaag, Yousef Mazaheri, Andreas Rimner, Katia Manova-Todorova, Boris Epel, Joan Zatcky, Cristian R Cleary, Shyam S Rao, Yoshiya Yamada, Michael J Zelefsky, Howard J Halpern, Jason A Koutcher, Carlos Cordon-Cardo, Carlo Greco, Adriana Haimovitz-Friedman, Evis Sala, Simon N Powell, Richard Kolesnick, Zvi Fuks, Sahra Bodo, Cécile Campagne, Tin Htwe Thin, Daniel S Higginson, H Alberto Vargas, Guoqiang Hua, John D Fuller, Ellen Ackerstaff, James Russell, Zhigang Zhang, Stefan Klingler, HyungJoon Cho, Matthew G Kaag, Yousef Mazaheri, Andreas Rimner, Katia Manova-Todorova, Boris Epel, Joan Zatcky, Cristian R Cleary, Shyam S Rao, Yoshiya Yamada, Michael J Zelefsky, Howard J Halpern, Jason A Koutcher, Carlos Cordon-Cardo, Carlo Greco, Adriana Haimovitz-Friedman, Evis Sala, Simon N Powell, Richard Kolesnick, Zvi Fuks
Abstract
Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.
Trial registration: ClinicalTrials.gov NCT02570919 NCT01223248.
Keywords: Cancer; DNA repair; Oncology; Vascular Biology.
Conflict of interest statement
Conflict of interest: BE and HJH are members of a start-up company, O2M, to market the pO2 imaging technology. YY is a speaker for Varian Medical Systems, BrainLab, and Vision RT, and a volunteer for the Medical Advisory Board of the Chordoma Foundation. ES, RK, AHF, and ZF are inventors on a patent application related to this work (62/078,280). RK and ZF are cofounders of Ceramedix Holding LLC. The following authors are listed inventors on patents and/or patent applications: CC (US20170246098A1), DSH (62729321 and 62688350), HC (11/478033), YM (6,556,856 and WO 00/40990), BE (9,392,957), HJH (4,714,886; 5,431,901; 7,444,011; 8,644,955 B1; and 9,392,957 B1), AHF (15/525,856), RK (09/503,852; 10/217,259; 12/599,280; 13/974,405; 14/854,891; 14/162,494; 14/402,875; 15/502,162; 15/525,856; and 15/643,430), and ZF (15/525,856; 15/643,430; and PCT/US2017/049378).
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Source: PubMed