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Targeting protein phosphatase 2A for the sensitization of TRAIL- and FOLFOX-resistant colorectal cancer

This is a past event.

Friday, December 6 at 11:00am to 12:00pm

AHC3 - Academic Health Center 3, 205
11200 SW 8th ST 33199, Academic Health Center 3, Miami, Florida 33199

Join us for a talk on "Targeting protein phosphatase 2A for the sensitization of TRAIL- and FOLFOX-resistant colorectal cancer ” with Dr. Satya Narayan, Professor, Department of Anatomy & Cell Biology, University of Florida.

The first-line treatment of metastatic colorectal cancer (CRC) with FOLFOX shows some improvement; however, these tumors quickly develop resistance to FOLFOX. CRCs also become resistant to TRAIL, which is a physiological method of killing cancer while sparing normal cells. The mechanism by which TRAIL induces resistance to FOLFOX-resistant cells (FOLFOX-cells) and stem-like cells (SLCs) is unclear. Their strong preliminary data revealed for the first time that AKT pathway-dependent p21 translation is the main mechanism that desensitizes FOLFOX-cells to TRAIL-induced apoptosis. TRAIL induces apoptosis through activation of procaspase-3, and p21 interacts and blocks the activation of procaspase-3. Thus, the downregulation of p21 can be a key approach for TRAIL-mediated sensitization of FOLFOX/TRAIL-cells and SLCs.

They discovered that the activation of protein phosphatase 2A (PP2A) by their recently identified potent and specific PP2A agonist, NSC49L, effectively blocks AKT-mediated events. These exciting discoveries raised the possibility to improve the therapeutic threshold of TRAIL, as clearly supported by their findings that the level of p21 is greatly elevated in FOLFOX-cells and SLCs and p21-knockdown synergistically induces CRC cells to TRAIL-mediated cell death. They hypothesized that the NSC49L treatment modulates PP2A activity to decrease the AKT/mTOR/4EBP1-mediated translation of p21. Decreased level of p21 then could free procaspase-3, which can then increase TRAIL-mediatedapoptosis of FOLFOX/TRAIL-cells and SLCs. They will develop a rationally designed library from the lead molecule NSC49L, and determine the mechanism of NSC49L/potent analogs and TRAIL-dependent sensitization of FOLFOX/TRAIL-cells and SLCs in vitro and in vivo patient-derived xenograft (PDX) models with the hope of identifying a potent and safe PP2A agonist for future TRAIL-based second-line therapy for metastatic CRC.