eBriefing

Trouble at the Checkpoint: DNA Damage and Cancer Treatment

Trouble at the Checkpoint
Reported by
Alan Dove

Posted April 30, 2008

Overview

Before allowing a cell to proceed to the next phase of the cell cycle, checkpoints ensure that everything that was supposed to happen in the previous phase happened without error. Cell cycle checkpoint failure is a major feature of tumor growth, causing cells to divide when they shouldn't. On March 13, 2008, researchers met at the Academy to ponder this phenomenon, and talk about new therapeutic strategies that try to restore checkpoint control when it goes awry.

Among their findings are that tumor cells commonly mutate their checkpoint genes, allowing them to reproduce even with damaged DNA and other defects, and that treating cancer by activating the DNA damage response/checkpoint pathways in tumor cells appears to be a viable strategy for chemotherapy. Several new drugs in development could help circumvent tumor cells' resistance to current treatments.

Journal Articles

Peter Sicinski

Ciemerych MA, Yu Q, Szczepanska K, Sicinski P. 2008. CDK4 activity in mouse embryos expressing a single D-type cyclin. Int. J. Dev. Biol. 52: 299-305.

Geng, Y, Lee YM, Welcker M, et al. 2007. Kinase-independent function of cyclin E. Mol. Cell 25: 127-139. Full Text

Landis MW, Brown NE, Baker GL, et al. 2007. The LxCxE pRb interaction domain of cyclin D1 is dispensable for murine development. Cancer Res. 67: 7613-7620.

David Glover

Archambault V, Zhao X, White-Cooper H, et al. 2007. Mutations in Drosophila Greatwall/Scant reveal its roles in mitosis and meiosis and interdependence with Polo kinase. PLoS Genet. 3: e200. Full Text

Azuma A, Huang P, Matsuda A, Plunkett W. 2001. 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine: a novel anticancer nucleoside analog that causes both DNA strand breaks and G2 arrest. Mol. Pharmacol. 59: 725-731. Full Text

D'Avino PP, Archambault V, Przewloka MR, et al. 2007. Recruitment of Polo kinase to the spindle midzone during cytokinesis requires the Feo/Klp3A complex. PLoS ONE 2: e572. Full Text

Liu X, Matsuda A, Plunkett W. 2008. Ataxia-telangiectasia and Rad3-related and DNA-dependent protein kinase cooperate in G2 checkpoint activation by the DNA strand-breaking nucleoside analogue 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine. Mol. Cancer. Ther. 7: 133-142.

Rodrigues-Martins A, Riparbelli M, Callaini G, et al. 2007. From centriole biogenesis to cellular function: centrioles are essential for cell division at critical developmental stages. Cell Cycle 7: 11-16.

Wu M, Mazurchuk R, Chaudhary ND, et al. 2003. High-resolution magnetic resonance imaging of the efficacy of the cytosine analogue 1-[2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl]-N4-palmitoyl cytosine (CS-682) in a liver-metastasis athymic nude mouse model. Cancer Res. 63: 2477-2482. Full Text

Rachael Hawtin

Hawtin RE, Stockett D, Kimmel RA, et al. 2008. Sensitivity to SNS-595 is related to activation of double strand repair pathways including homologous recombination. Poster presented at the American Association for Cancer Research meeting, San Diego. (PDF, 191 KB)

Hawtin RE, Mamuszka H, Arkin MR, Fox JA. 2008. Ex vivo activity of SNS-595 against biopsies of acute myeloid leukemia, triple negative breast and ovarian cancers supports ongoing and potential clinical indications. Poster presented at the American Association for Cancer Research meeting, San Diego. (PDF, 130 KB)

Lancet J, Kantarjian H, Ravandi F, et al. 2007. A Phase 1b open-label study of the novel DNA replication inhibitor SNS-595 in refractory acute leukemia. Poster presented at the 49th Annual Meeting of the American Society of Hematology, Atlanta. (PDF, 243 KB)

McClendon AK, Osheroff N. 2007. DNA topoisomerase II, genotoxicity, and cancer. Mutat. Res. 623: 83-97.

McGuire W, Matulonis U, Hirte H, et al. 2007. A Phase 2 trial of SNS-595 in women with platinum resistant epithelial ovarian cancer. Poster presented at the 39th Annual Meeting on Women's Cancer hosted by the Society of Gynecologic Oncologists, Tampa. (PDF, 155 KB)

Stockett D, Byl JA, Hawtin RE, et al. 2008. SNS-595 is a potent anti-tumor agent that has a dual mechanism of action: DNA intercalation and site-selective topoisomerase II poisoning. Poster presented at the American Association for Cancer Research meeting, San Diego. (PDF, 259 KB)

René Medema

Jelluma N, Brenkman AB, van den Broek NJ, et al. 2008. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell 132: 233-246.

Laoukili J, Kooistra MR, Bras A, et al. 2005. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat. Cell Biol. 7: 126-136.

Lens SM, Wolthuis RM, Klompmaker R, et al. 2003. Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J. 22: 2934-2947. Full Text (PDF, 717 KB)

Medema RH, Kops GJ, Bos JL, Burgering BM. 2000. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404: 782-787.

Smits VA, Klompmaker R, Arnaud L, et al. 2000. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat. Cell Biol. 2: 672-676.

Tanenbaum ME, Galjart N, van Vugt MA, Medema RH. 2006. CLIP-170facilitates the formation of kinetochore-microtubule attachments. EMBO J. 25: 45-57. Full Text (PDF, 487 KB)

van Vugt MA, Bras A, Medema RH. 2004. Polo-like kinase-1 controlsrecovery from a G2 DNA damage-induced arrest in mammalian cells. Mol. Cell 15: 799-811. Full Text

Chiang Li

Chen CR, Wang W, Rogoff HA, et al. 2005. Dual induction of apoptosis and senescence in cancer cells by Chk2 activation: checkpoint activation as a strategy against cancer. Cancer Res. 65: 6017-6021. Full Text

Li CJ. 2006. Therapeutic biology: checkpoint pathway activation therapy, HIV Tat, and transkingdom RNA interference. J. Cell Physiol. 209: 695-700.

Li Y, Sun X, LaMont JT, et al. 2003. Selective killing of cancer cells by β-lapachone: direct checkpoint activation as a strategy against cancer. Proc. Natl. Acad. Sci. USA 100: 2674-2678. Full Text

Yang Y, Fruehauf J, Xiang S, Li CJ. 2006. Genomic instability in precancerous lesions before inactivation of tumor suppressors p53 and APC in patients. Cell Cycle 5: 1443-1447. Full Text

Speakers

Peter Sicinski, MD, PhD

Harvard Medical School
e-mail | web site | publications

Peter Sicinski is a professor of pathology at Harvard Medical School and the Dana Farber Cancer Institute. Sicinski received his MD and PhD from the Warsaw Medical School in Poland. He spent two years as a visiting scientist at the Medical Research Council in Cambridge, England, before becoming a postdoctoral fellow with Robert A. Weinberg at Massachusetts Institute of Technology. In 1997, Sicinski joined the faculty of Harvard and Dana Farber Cancer Institute, where his research focuses on genes in the cell cycle machinery involved in normal cell development and cancer.

Sicinski has received several awards for his work, including an Abbott Bioresearch Center Award, an AACR–Gertrude B. Elion Cancer Research Award, and was named a Scholar of the Leukemia and Lymphoma Society.

David Glover, PhD

Cyclacel
e-mail | web site | publications

David Glover is chief scientist at Cyclacel. Glover discovered and named the Aurora, Polo, and other mitotic kinases, enzymes that play key roles in the regulation of cell division. He is the Arthur Balfour Professor of Genetics and chair of the Department of Genetics at the University of Cambridge and director of the Cancer Research UK Cell Cycle Genetics Research Group. He has authored over 200 publications and patents.

Rachael Hawtin, PhD

Sunesis Pharmaceuticals
e-mail | web site | publications

Rachael Hawtin is associate director of biology at Sunesis Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company located in South San Francisco, California, focused on the development of small molecule therapeutics for cancer therapy. Rachael obtained her undergraduate degree at the University of Edinburgh, Scotland, and postgraduate degree in molecular biology at the Institute for Virology and Environmental Microbiology in Oxford, England. Her drug development experience encompasses seven years at Sugen, Inc., followed by two years at Chiron Pharmaceuticals (now Novartis), where she focused primarily on the development of small molecule kinase inhibitors for cancer therapy.

Rachael moved to Sunesis Pharmaceuticals, Inc., in August, 2006, where she has been involved in the establishment of translational science research to support Sunesis' drug development pipeline. Her work has focused in particular on the clinical stage compounds SNS-032 and SNS-595.

René H. Medema

University Medical Center, Utrecht
e-mail | web site | publications

René H. Medema is head of the Laboratory of Experimental Oncology, part of the Genomics Center Utrecht. Medema obtained his PhD from the University of Utrecht in 1993. Following his PhD he joined the laboratory of Robert A. Weinberg at the Whitehead Institute for Biomedical Research. In July 1995, he was appointed as assistant professor in the group of G. Rijksen at the Department of Hematology, headed by J. J. Sixma and A. Hagenbeek. In 2001, his group moved to the Netherlands Cancer Institute, headed by A. Berns. In 2005, he became professor of Experimental Oncology in the Department of Medical Oncology, at the University of Utrecht.

Medema's work has focused on transcriptional regulation of the cell cycle, the function of cell cycle checkpoints, and spindle assembly.

Chiang J. Li, MD

Boston Biomedical
e-mail | web site | publications

Chiang Li is chairman, CEO, and CSO of Boston Biomedical in Norwood, MA. Prior to founding that company, Li was the CSO & EVP of ArQule Inc., where his management responsibility included drug discovery, preclinical development, clinical trials, pharmaceutical development, and intellectual property. He currently serves as the chairman of ArQule's Scientific Advisory Board, and is a founder and a board director of Cequent Pharmaceuticals, Inc.

Li graduated from the Harvard-MIT Division of Health Science and Technology, received an MD magna cum laude from Harvard Medical School, and completed clinical residency and fellowship at Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Beth Israel Deaconess Medical Center


Alan Dove

Alan Dove is a science writer and reporter for Nature Medicine, Nature Biotechnology, and Bioscience Technology. He also teaches at the NYU School of Journalism, and blogs at http://dovdox.com.