Fully functional PTEN is well known to suppress tumor growth by antagonizing the PI3K/Akt tumor survival pathway. Pagano’s group discovered a novel mechanism by which PTEN protects cells from cancer by preventing the geranylgeranylated protein FBXL2 from binding and degrading IP3R3. IP3R3 is an important anti-cancer “sensor” recognizing hyper-proliferating cells that use abnormally high levels of energy, and targeting them to self-destruct as an anti-cancer safety mechanism. The PTEN gene binds to IP3R3, protecting its cancer-sensing function. However PTEN is defective in many cancers, and as such, FBXL2 is left unchecked; too much IP3R3 is degraded and fast-multiplying cells are less able to self-destruct.
“FXBL2 may be partially responsible for cancer growth in the many patients with genetic changes that happen to disable PTEN,” said Pagano. The drug GGTI-2418 blocks this cancer-causing activity of FBXL2 by inhibiting its geranylgeranylation which is required for FBXL2 to bind and degrade IP3R3. GGTI-2418 was co-discovered and developed by Sebti and NYU President Andrew Hamilton, Ph.D., while he was at Yale University. .
Another fascinating consequence of this discovery is that cancers with defective PTEN activate two tumor survival circuits to evade cell death, the PI3K/Akt and the FBXL2 pathways. “These findings have important translational implications as patients whose tumors harbor defective PTEN may benefit greatly from a combination of inhibitors of FBXL2 geranylgeranylation, such as GGTI-2418, and inhibitors of Akt, such as TCN-P,” said Sebti. Both GGTI-2418 and TCN-P were co-discovered by Sebti and are now developed by the clinical-stage oncology company Prescient Therapeutics Ltd.
The researchers also found that using GGTI-2418 to block FBXL2 from degrading IP3R3 made the tumors in mice more vulnerable to photodynamic therapy (PDT).”This experimental drug, by itself and with a form of light therapy, countered FBXL2 to let abnormal cells self-destruct,” said Pagano “We will be looking to collaborate with Dr. Sebti on clinical studies combining GGTI-2418 with PDT or TCN-P in patients with low PTEN.”