Drug target discovery
The obligatory progression of prostate cancer to castration resistance (CR) under androgen deprivation therapy equals a death sentence as no life extending treatment options are currently available. The molecular pathways leading to CR remain ill defined, thus hampering the development of effective drugs for castration resistant prostate cancer (CRPC). The recognition that CRPCs are typically addicted to the androgen receptor (AR) has focused drug development efforts on AR blockers. We are using functional genomics strategies to identify and characterize cell autonomous pathways that are causally linked to the progression to CRPC and thus bear promise as novel drug targets.
We are using a variety of high content and in silico screening techniques to identify novel agents that selectively inhibit prostate cancer cell growth in tissue culture and in animal models. We have recently discovered compound SMIP004, a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. The compound induces a pro-apoptotic pathway, which initiates with disruption of mitochondrial respiration leading to oxidative stress. This, in turn, elicits cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation, drives transcriptional downregulation of the androgen receptor, and activates pro-apoptotic signaling through MAPK activation downstream of the unfolded protein response pathway. SMIP004 potently inhibits the growth of prostate cancer xenografts in mice. Our current work focuses on the further development of SMIP004 and on the identification of other compounds with a novel mechanism of action against prostate cancer.
Systems Biology of the Oxidative Stress Response
Oxidative stress (OS) is intimately linked to ageing-related diseases, including neurodegenerative disorders, inflammatory conditions, cancer, and diabetes. OS is known to trigger a transcriptional program primarily geared toward recovery, but triggering cell death if the damage is irreparable. Whereas this program is relatively well characterized at the level of mRNA abundance, almost nothing is known about the coordination with posttranscriptional layers of gene expression control. We explore the hypothesis that gene expression in response to OS is shaped by an integrated multi-layered program that precisely coordinates transcriptional and posttranscriptional mechanisms to maximize survival. The aim is to describe these mechanisms quantitatively and validating them experimentally both by acquiring global gene expression datasets and by formalizing the connections in mathematical terms. Understanding these programs will help us in developing novel ways to manipulate them in states of disease.
We are also addressing the interaction of stress response and protein quality control pathways. In particular, we are interested in the coupling of protein synthesis and degradation by the proteasome. We have discovered that the translation initiation factor eIF3 complex is involved in this control, probably through direct interactions with ribosomes and the proteasome. We are performing genetic and biochemical experiments to unravel the role of eIF3 in protein quality control.