Pharmacologic Regulation of DNA Damage Checkpoints to Treat Cancer

Organizers: George Zavoico, Cantor Fitzgerald; Daniel C. Adelman, Sunesis Pharmaceuticals

Speakers: Peter Sicinski, Dana-Farber Cancer Institute, Harvard Medical School; David Glover, Cyclacel Pharmaceuticals, Inc.; Rachael Hawtin, Sunesis Pharmaceuticals, Inc.; René Medema, University Medical Center, The Netherlands; Chiang Li, Beth Israel Deaconess Medical Center, Harvard Medical School; Boston Biomedical, Inc.

In this symposium, new discoveries in cell-cycle regulation will be presented, followed by recent clinical investigations highlighting promising new drug candidates that appear to restore checkpoint control and direct tumor cells to apoptosis.

The Cancer and Signaling Discussion Group provides a forum for an exploration of the molecular networks that ensure proper cell cycle progression and how alterations in these networks modulate gene expression, cause mutations, and fuel the steps involved in carcinogenesis. Meetings of the group will focus on specific themes as they relate to signal transduction dysregulation in oncogenesis and will cover basic, clinical and diagnostic aspects of the field.

Agenda

1:00 – 1:10 pm
Introduction
George Zavoico

1:10 – 1:50 pm
Peter Sicinski

1:50 – 2:30 pm
David Glover

2:30 – 3:10 pm
Rachael Hawtin

3:10 – 3:30 pm
Coffee/Tea Break

3:30 – 4:10 pm
Rene Medema

4:10 – 4:50 pm
Chiang Li

4:50 – 5:10 pm
Panel Discussion

Kinase-independent Function of Cyclin E
Peter Sicinski, MD, PhD, Dana-Farber Cancer Institute, Harvard Medical School

E-type cyclins are thought to drive cell cycle progression by activating cyclin-dependent kinases, primarily CDK2. We previously found that cyclin E-null cells failed to incorporate MCM helicase onto DNA replication origins during G₀ -> S phase progression. We now report that kinase-deficient cyclin E mutant can restore MCM loading and S phase entry in cyclin E-null cells. We found that cyclin E is loaded onto chromatin during G₀ -> S progression. In the absence of cyclin E, CDT1 is normally loaded onto chromatin, whereas MCM is not, indicating that cyclin E acts between CDT1- and MCM-loading. We observed a physical association of cyclin E1 with CDT1 and with MCMs. We propose that cyclin E facilitates MCM loading in a kinase-independent fashion, through physical interaction with CDT1 and MCM. Our work indicates that – in addition to their function as CDK-activators - E-cyclins play kinase-independent function in cell cycle progression.

Efficient DNA-Damage Checkpoint Arrest with Novel Nucleoside Analogues
David M. Glover, PhD, FRSE, Cyclacel Pharmaceuticals, Inc., Cambridge Division

Several nucleoside analogues that act through the DNA damage checkpoint have been used in cancer therapy with limited success. I will discuss new analogues of 2-deoxycytidine that are incorporated into DNA during replication and lead to single-stranded breaks through beta-elimination. The resulting G2 Chk1 mediated checkpoint arrest is significantly more robust than that seen with previously used nucleosides. One such analogue has had considerable success against both solid and hematological tumors in animal models and has demonstrated anti-tumor activity in patients with solid tumors and relapsed/refractory AML and MDS. Inhibition of checkpoint pathways offers scope for further increases in the efficacy of such compounds.

Elucidating the Mechanism of Action and Potential Markers of Sensitivity and Response to the Potent Anti-Tumor Agent SNS-595
Rachael Hawtin, PhD, Sunesis Pharmaceuticals, Inc.

SNS-595 is a replication-dependent agent that induces DNA damage, irreversible G2 arrest and apoptosis by intercalation of DNA and poisoning of topoisomerase II. SNS-595 is under clinical investigation in acute leukemia and ovarian cancer. Clinical responses have been observed in these indications, as well as in NSCLC and SCLC. The DNA repair pathways that influence cell sensitivity to SNS-59