Oncologica has established the first comprehensive predictive test for Cdc7 inhibitors using its state of the art Next Generation Sequencing platform validated for the delivery of Oncologica’s precision oncology clinical services.
Our newly developed Cdc7 companion Dx “OncoCheckpoint” analyses the major signalling components of the DNA replication origin activation checkpoint for all activating/inactivating genetic aberrations that lead to loss of checkpoint control and therefore predictive of response to Cdc7 inhibitors.
The test has been specifically designed to use a DNA/RNA input extracted from routine formalin fixed paraffin wax embedded (FFPE) pathology biopsies/resection specimens so is ideally suited to support clinical trials and for use in routine clinical practice.
The DNA replication initiation machinery is a powerful regulator of the proliferative state in human cells and dysregulation of this machinery occurs during tumourigenesis contributing to uncontrolled cell proliferation. Cdc7 kinase is a highly conserved serine/threonine protein kinase, a core component of the DNA replication machinery and therefore of major interest to Biopharma as a new anti-cancer target with clinical utility in a broad range of cancer types.
Cdc7 inhibitors have major potential as a new generation of anti-cancer agents which target Cdc7 kinase, an enzyme that plays a crucial role in DNA replication and DNA repair. The uncontrolled cell proliferation as a result of aberrant expression of Cdc7 is observed in a broad range of cancer types including colon, lung, breast, ovarian, pancreatic, bladder and melanoma.
Inhibition of Cdc7 kinase results in cancer cell-specific killing as a result of abrogation of the G1-S DNA origin activation checkpoint and/or disruption of the DNA damage response network 1,2.
Co-development of drug and companion diagnostic provides the fastest route to drug approval.
Biopharma are engaged in the development of Cdc7 inhibitors with many compounds now entering clinical trials.
Oncologica’s new Cdc7 companion Dx is therefore ideally placed to support Cdc7 drug development programmes and provides an
essential tool for the safe and effective use of Cdc7 inhibitors.
G1/S Cell cycle arrest
Inhibition of Cdc7 in normal cells leads to G1/S cell cycle arrest as a result of the activation of the DNA replication origin activation checkpoint.
This arrest is reversible and cells remain viable. In contrast, a subset of cancers have a defective checkpoint leading to S phase entry with insufficient levels of Cdc7 kinase activity required for efficient DNA origin firing.
This results in stalling and collapse of replication forks, the induction of double-strand breaks and tumour cancer cell specific apoptotic cell death.
Moreover, progression into S phase results in sensitivity to agents targeting the DDR S phase checkpoint.
Companion Diagnostic for Cdc7 directed therapies
We have shown the DNA origin activation checkpoint is regulated by a complex molecular circuitry of sensor, transducer and effector proteins many of which are encoded by oncogenes and tumour suppressors commonly mutated in cancer.
This checkpoint also includes antisense regulatory networks.
A companion diagnostic that provides full coverage and analysis of this complex DNA origin activation checkpoint is therefore essential to accurately identify patients who will respond to Cdc7 directed therapies.
functioning checkpoint will lead to G1/S cytostatic arrest as observed in normal cells and therefore will have little therapeutic benefit.
These arrested cancer cells will also fail to respond to Cdc7 inhibitors when used in the alternative strategy of targeting the DNA Damage Repair Pathway (DDR), a checkpoint operating in S phase in which Cdc7 recruits lesion bypass machinery to stalled replication forks.
Our newly developed Cdc7 CDx “Oncocheckpoint” analyses the major checkpoint components including antisense regulators for activating/inactivating genetic aberrations including hot spot mutations, deletions, insertions, copy number variations and fusions that lead to loss of checkpoint control and therefore predictive of response to Cdc7 inhibitors.
Notably the test has been specifically designed to use DNA/RNA input extracted from routine FFPE pathology samples so is ideally suited to support clinical trials and for use in routine clinical practice.
1: Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53-mutant breast cancers.
Rodriguez-Acebes S, Proctor I, Loddo M, Wollenschlaeger A, Rashid M, Falzon M, Prevost AT, Sainsbury R, Stoeber K, Williams GH.
Am J Pathol. 2010 Oct;177(4):2034-45. doi: 10.2353/ajpath.2010.100421. Epub 2010 Aug 19.
2: Cdc7 kinase is a predictor of survival and a novel therapeutic target
in epithelial ovarian carcinoma.
Kulkarni AA, Kingsbury SR, Tudzarova S, Hong HK, Loddo M, Rashid M, Rodriguez-Acebes S, Prevost AT, Ledermann JA, Stoeber K,
Clin Cancer Res. 2009 Apr 1;15(7):2417-25. doi: 10.1158/1078-0432.CCR-08-1276. Epub 2009 Mar 24.