Targeting Protease-Activated Receptors (PARs) to Treat Glioblastoma

Dr. Scarisbrick's lab discovered human glioblastoma tumors secrete high levels of serine proteases referred to as kallikreins. Kallikreins are the largest contiguous cluster of serine proteases in the human genome. One family member prominently expressed in glioma, kallikrein 6 (KLK6, neurosin) was found to be associated with higher clinical grade and reduced patient survival. Importantly, KLK6 was found to promote the resistance of glioma cells to apoptosis, including cell death-induced by the current standard of care, radiation and temozolomide—as cited in Neuro-Oncology, 2013 (Drucker et al.) and BMC Cancer, 2015 (Drucker et al.).

These data form the basis of two recently issued patents:

  • US 8,530,427 Methods for Modulating Resistance to Apoptosis using KLK6
    Inventors: Isobel Scarisbrick
  • US 2013/0315926 Methods and Materials for Modulating Resistance to Apoptosis
    Inventors: Isobel Scarisbrick

Strong preliminary data suggest that KLK6 pro-survival effects are mediated by activation of PARs and current efforts are focused on determining how the KLK-PAR signaling axis can be targeted to improve therapy response in a murine orthotopic glioblastoma (GBM) xenograft model.

These studies have strong discovery potential to highlight a new highly druggable receptor signaling system involved in promoting the resistance of GBM to radiation and chemotherapies that could be targeted to improve treatment sensitivity. Since Dr. Scarisbrick's lab has also demonstrated the KLK6-PAR signaling axis exerts similar pro-survival effects toward leukemia cell lines, as cited in PLoS ONE, 2011 (Scarisbrick et al.), it is believed this discovery represents a fundamental tumor cell pro-survival signaling pathway that will have therapeutic utility across a range of cancers and likely other conditions in which decreased or elevated levels of apoptosis are an essential part of the pathology. This line of research has significant potential to improve survival in glioblastoma patients and to enhance functional outcomes.