Gregg Siegal receives an STW Open Technology Program grant for his project New Targets to Address Old Problems in Oncology

Principal Investigators:
Dr. Gregg Siegal
Prof. Dr. Leon Mullenders (LUMC)

Cancer remains a leading killer despite the billions invested and the advent of modern "targeted drugs". Ultimately, to successfully treat the majority of cancers, it is nearly certain that combinations of drugs will have to be used that can block multiple signalling pathways that are required for cell growth. Therefore it is
critical to examine novel pathways for the ability to specifically kill cancer cells. Every cell in the human body has the propensity to die in an ordered manner, known as apoptosis. Driving cancer cells into apoptosis is an attractive approach to treat the disease but one that frequently cannot be exploited since p53, a key protein required for apoptosis,is often missing or mutated.

Recently it has been shown that survival of cancer cells is exquisitely dependent on a DNA damage repair process known as Transcription Coupled Repair (TCR). This pathway is activated when transcription is blocked by DNA damage in transcribed genes. Notably, inhibition of TCR can cause cells to enter apoptosis even in the absence of p53. The Cockayne Syndrome B (CSB) protein is directly responsible for loading the TCR machinery at stalled transcription complexes and enabling the subsequent removal of damaged DNA. Once the damage has been removed, transcription continues and the cell continues to grow. CSB is a critical “choke point” for TCR and this fact suggests it could make an excellent target for novel anticancer drugs.

There are two overarching goals of this project. First, we will determine the effects of inhibition of the biological function of CSB on a wide variety of cancer cells. Specifically we will assess whether these cells are driven into apoptosis when CSB function is abrogated in a manner that simulates the effect of a small molecule inhibitor. Second, we will assess the ability to inhibit the biological function of CSB (using small molecules (its “druggability”) with chemical characteristics appropriate for eventual elaboration towards orally available drugs.