Rishi R Lulla1, Stewart Goldman2, Tohru Yamada2, Craig W Beattie2, Linda Bressler2, Michael Pacini2, Ian F Pollack2, Paul Graham Fisher2, Roger J Packer2, Ira J Dunkel2, Girish Dhall2, Shengjie Wu2, Arzu Onar2, James M Boyett2, Maryam Fouladi2. 1. Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois (R.R.L., S.G.); Division of Surgical Oncology, Department of Surgery, University of Illinois College of Medicine, Chicago, Illinois (T.Y., C.W.B.); Pharmacy Investigational Drug Service, University of Illinois Hospital and Health Sciences System, University of Illinois College of Pharmacy, Chicago, Illinois (L.B., M.P.); Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (I.F.P.); Departments of Neurology, Pediatrics, Neurosurgery, and Human Biology, Stanford University, Palo Alto, California (P.G.F.); Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children's National Health System, Department of Neurology and Pediatrics, The George Washington University, Washington, DC (R.J.P.); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, Weill Cornell Medical College, New York, New York (I.J.D.); Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California (G.D.); Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (S.W., A.O., J.M.B.); Department of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, Neuro-Oncology Program, Cincinnati, Ohio (M.F.) rlulla@luriechildrens.org. 2. Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois (R.R.L., S.G.); Division of Surgical Oncology, Department of Surgery, University of Illinois College of Medicine, Chicago, Illinois (T.Y., C.W.B.); Pharmacy Investigational Drug Service, University of Illinois Hospital and Health Sciences System, University of Illinois College of Pharmacy, Chicago, Illinois (L.B., M.P.); Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (I.F.P.); Departments of Neurology, Pediatrics, Neurosurgery, and Human Biology, Stanford University, Palo Alto, California (P.G.F.); Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children's National Health System, Department of Neurology and Pediatrics, The George Washington University, Washington, DC (R.J.P.); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, Weill Cornell Medical College, New York, New York (I.J.D.); Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California (G.D.); Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (S.W., A.O., J.M.B.); Department of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, Neuro-Oncology Program, Cincinnati, Ohio (M.F.).
Abstract
BACKGROUND: p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. METHODS: Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. RESULTS: Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. CONCLUSIONS: This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.
BACKGROUND:p53 is a promising target in humancancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. METHODS:Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. RESULTS: Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. CONCLUSIONS: This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.
Authors: Genglin Jin; Stephen Cook; Bo Cui; William C Chen; Stephen T Keir; Patrick Killela; Chunhui Di; Cathy A Payne; Simon G Gregory; Roger McLendon; Darell D Bigner; Hai Yan Journal: Neuro Oncol Date: 2010-05-14 Impact factor: 12.300
Authors: Rajeshwari R Mehta; Tohru Yamada; Brad N Taylor; Konstantin Christov; Marissa L King; Dibyen Majumdar; Fatima Lekmine; Chinnaswamy Tiruppathi; Anne Shilkaitis; Laura Bratescu; Albert Green; Craig W Beattie; Tapas K Das Gupta Journal: Angiogenesis Date: 2011-06-11 Impact factor: 9.596
Authors: Lee Jia; Gregory S Gorman; Lori U Coward; Patricia E Noker; David McCormick; Thomas L Horn; J Brooks Harder; Miguel Muzzio; Bellur Prabhakar; Balaji Ganesh; Tapas K Das Gupta; Craig W Beattie Journal: Cancer Chemother Pharmacol Date: 2010-11-18 Impact factor: 3.333
Authors: Greg S Gorman; Lori U Coward; Lea Freeman; Pat E Noker; Craig W Beattie; Lee Jia Journal: J Pharm Biomed Anal Date: 2010-06-30 Impact factor: 3.935
Authors: Paul A Northcott; David J H Shih; John Peacock; Livia Garzia; A Sorana Morrissy; Thomas Zichner; Adrian M Stütz; Andrey Korshunov; Jüri Reimand; Steven E Schumacher; Rameen Beroukhim; David W Ellison; Christian R Marshall; Anath C Lionel; Stephen Mack; Adrian Dubuc; Yuan Yao; Vijay Ramaswamy; Betty Luu; Adi Rolider; Florence M G Cavalli; Xin Wang; Marc Remke; Xiaochong Wu; Readman Y B Chiu; Andy Chu; Eric Chuah; Richard D Corbett; Gemma R Hoad; Shaun D Jackman; Yisu Li; Allan Lo; Karen L Mungall; Ka Ming Nip; Jenny Q Qian; Anthony G J Raymond; Nina T Thiessen; Richard J Varhol; Inanc Birol; Richard A Moore; Andrew J Mungall; Robert Holt; Daisuke Kawauchi; Martine F Roussel; Marcel Kool; David T W Jones; Hendrick Witt; Africa Fernandez-L; Anna M Kenney; Robert J Wechsler-Reya; Peter Dirks; Tzvi Aviv; Wieslawa A Grajkowska; Marta Perek-Polnik; Christine C Haberler; Olivier Delattre; Stéphanie S Reynaud; François F Doz; Sarah S Pernet-Fattet; Byung-Kyu Cho; Seung-Ki Kim; Kyu-Chang Wang; Wolfram Scheurlen; Charles G Eberhart; Michelle Fèvre-Montange; Anne Jouvet; Ian F Pollack; Xing Fan; Karin M Muraszko; G Yancey Gillespie; Concezio Di Rocco; Luca Massimi; Erna M C Michiels; Nanne K Kloosterhof; Pim J French; Johan M Kros; James M Olson; Richard G Ellenbogen; Karel Zitterbart; Leos Kren; Reid C Thompson; Michael K Cooper; Boleslaw Lach; Roger E McLendon; Darell D Bigner; Adam Fontebasso; Steffen Albrecht; Nada Jabado; Janet C Lindsey; Simon Bailey; Nalin Gupta; William A Weiss; László Bognár; Almos Klekner; Timothy E Van Meter; Toshihiro Kumabe; Teiji Tominaga; Samer K Elbabaa; Jeffrey R Leonard; Joshua B Rubin; Linda M Liau; Erwin G Van Meir; Maryam Fouladi; Hideo Nakamura; Giuseppe Cinalli; Miklós Garami; Peter Hauser; Ali G Saad; Achille Iolascon; Shin Jung; Carlos G Carlotti; Rajeev Vibhakar; Young Shin Ra; Shenandoah Robinson; Massimo Zollo; Claudia C Faria; Jennifer A Chan; Michael L Levy; Poul H B Sorensen; Matthew Meyerson; Scott L Pomeroy; Yoon-Jae Cho; Gary D Bader; Uri Tabori; Cynthia E Hawkins; Eric Bouffet; Stephen W Scherer; James T Rutka; David Malkin; Steven C Clifford; Steven J M Jones; Jan O Korbel; Stefan M Pfister; Marco A Marra; Michael D Taylor Journal: Nature Date: 2012-08-02 Impact factor: 49.962
Authors: M A Warso; J M Richards; D Mehta; K Christov; C Schaeffer; L Rae Bressler; T Yamada; D Majumdar; S A Kennedy; C W Beattie; T K Das Gupta Journal: Br J Cancer Date: 2013-02-28 Impact factor: 7.640
Authors: Marília Silva; Gabriel Amaro Monteiro; Arsenio M Fialho; Nuno Bernardes; Cláudia Lobato da Silva Journal: Front Cell Dev Biol Date: 2020-07-09