GRP78 is a member of the chaperone family of proteins, which help a multitude of different cellular and extra-cellular proteins to attain their correct 3 dimensional structure through assisted protein folding. GRP78 specifically helps mature a number of cell surface receptor proteins, which allow cancer cells to sense growth stimulatory signals in the environment.

In addition to its chaperone function, GRP78 also plays a unique role in the cellular stress response. GRP78 not only functions as a cellular stress sensor, it also plays a key role in the way cells respond and adapt to stress, thus influencing the cell’s decision to survive or die (apoptosis). Due to their location and lifestyle, many tumor cells finds themselves in a perpetual state of stress: When tumors reach a certain size, nutrients and oxygen becomes scarce due to the relative absence of blood vessels. In addition, tumor cells have a much increased need to synthesize protein, lipids, and DNA in order to multiply.  Finally, tumor cells are under constant attack by the immune system, and by treatment administered during chemotherapy regimens.

One way for tumors to cope with the increased stress is by up-regulation of GRP78, and GRP78 is in fact over-expressed in many tumors, including 70% of breast cancers and the majority of high-grade gliomas (brain tumors), and high GRP78 expression is significantly associated with the development of the deadly form of prostate cancer, castration-resistant prostate cancer.

This places a high dependence on GRP78 for cancer cell survival, and consistent with this, animal studies show that lowering the expression of GRP78 is tolerated by normal cells and organs, while cancer cell growth and survival is inhibited. In addition, numerous studies also show that resistance to established therapy can be overcome by inhibiting GRP78. Taken together, available data suggest that GRP78 inhibitors may have broad applicability within oncology combined with a favourable safety margin. Unfortunately, drugging of GRP78 has so far been challenging.

In collaboration with our partners CRT and ICR, Nuevolution recently discovered potent (nano molar) and selective inhibitors of GRP78, the first of its kind. The 3D structure of inhibitors in complex with GRP78 have been determined, and is currently being exploited to guide optimization towards lead stage.