A subset of CB002 xanthine analogs bypass p53-signaling to restore a p53 transcriptome and target an S-phase cell cycle checkpoint in tumors with mutated-p53
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, United States; The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States
David T Dicker
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, United States; The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States
John Santiago
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States
Jennifer Sanders
The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States; Department of Pediatrics, The Warren Alpert Medical School, Brown University, Providence, United States
Xiaobing Tian
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, United States; The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States
Nagib Ahsan
COBRE Center for Cancer Research Development, Proteomics Core Facility, Rhode Island Hospital, Providence, United States
Avital Lev
The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States
Lanlan Zhou
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, United States; The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, United States; The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, United States; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, United States; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, United States; Hematology-Oncology Division, Department of Medicine, Rhode Island Hospital and Brown University, Providence, United States
Mutations in TP53 occur commonly in the majority of human tumors and confer aggressive tumor phenotypes, including metastasis and therapy resistance. CB002 and structural-analogs restore p53 signaling in tumors with mutant-p53 but we find that unlike other xanthines such as caffeine, pentoxifylline, and theophylline, they do not deregulate the G2 checkpoint. Novel CB002-analogs induce pro-apoptotic Noxa protein in an ATF3/4-dependent manner, whereas caffeine, pentoxifylline, and theophylline do not. By contrast to caffeine, CB002-analogs target an S-phase checkpoint associated with increased p-RPA/RPA2, p-ATR, decreased Cyclin A, p-histone H3 expression, and downregulation of essential proteins in DNA-synthesis and DNA-repair. CB002-analog #4 enhances cell death, and decreases Ki-67 in patient-derived tumor-organoids without toxicity to normal human cells. Preliminary in vivo studies demonstrate anti-tumor efficacy in mice. Thus, a novel class of anti-cancer drugs shows the activation of p53 pathway signaling in tumors with mutated p53, and targets an S-phase checkpoint.
