Checkpoint Controls and Targets in Cancer Therapy

ISBN-13: 9781607611776 / Angielski / Twarda / 2009 / 274 str.

Zahid H. Siddik

Opis

Much work over the last two decades has firmly established that loss of cell cycle checkpoint regulation, and resultant unabated cellular proliferation, is an inherent characteristic of cancer. This loss may occur through aberration in any single component involved in signal transduction pathways that orchestrate checkpoint regulation, which may manifest through either a failure to activate the checkpoint or a failure to respond to the activated checkpoint. In normal cells, checkpoint pathways are activated when genetic or cellular homeostasis is compromised, and signals are then transduced to re-stabilize homeostasis, and, failing this, to activate the apoptotic machinery to induce a cellular suicidal response. This implies that both survival and cell death pathways are induced following checkpoint activation, and that the final decision is dependant on the net result of integrating the two sets of signals. It is intriguing that checkpoint pathways are also critical in cancer therapy to provide an apoptotic stimulus when cellular damage induced by the therapeutic agent is detected by the sensor system. Therefore, it is not surprising that failure in pro-survival checkpoint response will render tumor cells hypersensitive to cytotoxics and, conversely, failure in pro-apoptotic checkpoint response will induce genetic instability and/or therapeutic resistance. Understanding the intricacies of checkpoint response is, therefore, central to the design of therapeutic regimen that will enhance antitumor effects. Although early versions of this design entail combination of cytotoxic agents with cell cycle or checkpoint inhibitors, a greater understanding of the concepts could make such combinations clinically more effective. The contributions in this book will consolidate the current state of knowledge on checkpoint responses that may lay the foundation for hypothesis-driven rational approaches in advancing the management of cancer. The immediate attraction of the book to the scientific community is that it represents a timely opportunity to build upon existing concepts of checkpoints to expand our understanding of the inner workings of the critical checkpoint machinery. The present understanding has provided ample appreciation that response to checkpoint activation is manifested through coordinated inhibition of cyclin-dependent kinase (CDK) complexes in G1, S and/or the G2 phase in order to arrest the cell cycle. Kinase inhibition can occur through several mechanisms, including inhibitory phosphorylation of CDK, destruction of the cognate cyclins, and recruitment of CDK inhibitors from the INK and WAF1/CIP1 families. However, the wealth of information from recent discoveries needs to be examined critically to consolidate our conceptual knowledge of checkpoints. At the same time, there is acute awareness in the diversity of checkpoint response between cytotoxic agents, and this serves as a reminder of the magnitude of complexity that is inherent in checkpoint regulation. This volume is intended to bring the cancer research community closer toward an improved understanding of this regulation, how checkpoint abnormalities can impact negatively on cancer therapy, and emerging strategies to target checkpoint response as a therapeutic end-point.

Recenzje

From the reviews: "This nicely organized book focuses on cell cycle checkpoint and cancer biology/therapeutics. ... The book is written for graduate students, residents, and postdoctoral investigators in basic, translational, or clinical cancer research. The contributing authors are active investigators at the forefront of this field. ... This book presents timely, comprehensive reviews of the rapidly progressing field of checkpoint. It should be quite useful for readers who are seeking a solid grasp of updated information in this field." (Hiroaki Kiyokawa, Doody's Review Service, March, 2010)

Spis treści

Part I: Circuitry of Checkpoint Response Chapter 1 G1/S Checkpoint in Normal and Cancer Cells (Bartek J, Copenhagen, Denmark) Chapter 2 S-Phase Checkpoint (Bunz F, Baltimore, MD) Chapter 3 G2/M Checkpoint (Stark GR, Cleveland, OH OR Lukas J, Copenhagen, Denmark) Chapter 4 Mitotic Spindle Checkpoint (Hoffman I, Heidelberg, Germany) Chapter 5 ATM/Chk2 and ATR/Chk1 Pathways (Dunphy WG, Pasadena, CA OR Kastan MB, Memphis, TN) Chapter 7 INK/CIP inhibitor family members (Xiong Y, Chapel Hill, NC OR Rudolph KL, Hannover, Germany) Chapter 8 Centrosome in Checkpoint Response (Muschel RJ, Philadelphia, PA OR Kramer A, Heidelberg, Germany) Chapter 9 14-3-3 Family in Checkpoint Response (Lee M-H, Houston, TX OR Hermeking H, Munich, Germany) Chapter 10 BRCA1/2 in Checkpoint (Deng CX, Bethesda, MD OR Boulton SJ, South Mimms, UK) Chapter 11 Regulation of Checkpoint Response by CDC25 (Ducommun R, Toulouse, France) Chapter 12 DNA Damage Recognition in Checkpoint Response (Marini F, Milano, Italy) Part II: Checkpoint Response and the Aetiology of Cancer Chapter 13 Checkpoint Response and Cancer (Nakanishi M, Nagoya, Japan OR Mollinari M, Milan, Italy) Chapter 14 G1-Phase Cyclins and Cancer (Hinds PW, Boston, MA OR Keyomarsi K, Houston, TX) Chapter 15 Tumor Suppressor p53 and Cancer (El-Deiry WS, Philadelphia, PA OR Zambetti GP, Memphis, TN) Chapter 16 Rb dysfunction and Cancer (Giordano A, Philadelphia, PA) Chapter 17 Chk2 Status in Cancer (Nevanlinna H, Helsinki, Finland) Chapter 18 BRCA1/2 in Cancer (Borgen PI, New York, NY) Part III: Targeting Checkpoint Response in Cancer Therapy Chapter 19 Checkpoint Response and the Balance Between Cell Survival and Cell Death (Kaina B, Mainz, Germany OR Saito T, Tochigi, Japan) Chapter 20 Targeting p53 for checkpoint activation (Eastman A, Lebanon, NH OR Giardina C, Storrs, CT Chapter 21 Targeting Checkpoint Kinases with Small molecule inhibitors (Shapiro GI, Boston, MA OR Toogood PL, Ann Arbor, MI) Chapter 22 p21-Dependent Checkpoint Response and Therapy (Siddik ZH, Houston, TX) Chapter 23 p27 Upregulation as a Target for Therapy-Mediated Cell Death (Bast R, Houston, TX OR Malek NP, Hannover, Germany) Chapter 24 Chk1/Chk2 as checkpoint targets (Zhang H, Abbott Park, IL OR Grant S, Richmond) Chapter 25 Mitotic Spindle Checkpoint as a Target (Taylor SS, Manchester, UK OR Jackson JR, Collegeville, PA) Chapter 26 Targeting Cdc25 in cancer therapy (Rudolph J, Durham, NC)

Blurb

 

There is no question that loss of cell cycle checkpoint regulation is an intrinsic characteristic of cancer. However, many tumors retain parallel checkpoint pathways that are activated by antitumor agents and facilitate therapeutic response. Failures in these therapy-linked checkpoint controls are closely associated with cancers that are highly resistant to therapeutic interventions. Checkpoint Controls and Targets in Cancer provides present-day mechanistic understandings of how multiple sets of proteins orchestrate cell cycle progression, discusses critical checkpoint controls that are evaded for cancer development, focuses on checkpoint pathways associated with antitumor effects, and identifies specific checkpoint regulators for targeting with small molecules in the clinical management of cancer. These aspects of cell cycle checkpoints are articulated critically by renowned experts from both academia and industry, and new concepts are forwarded that challenge existing dogmas. Collectively, Checkpoint Controls and Targets in Cancer provides a unique collection of insightful contributions, which are timely and offer significant interest and appeal to basic, translational and clinical scientists.