Strategies To Sensitize Bladder Cancer Cells To Small Molecule Inhibitors Targeting The Pi3K Pathway

Author

Giovanni Nitti, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

8-2014

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

David J. McConkey, Ph.D.

Committee Member

Craig Logsdon, Ph.D.

Committee Member

Gary Gallick, Ph.D.

Committee Member

Zahid Siddik, Ph.D.

Committee Member

Douglas Boyd, Ph.D.

Abstract

After many years of cancer research, it is well accepted by the scientific community that the future cure for this disease lies in a personalized therapeutic approach. Anticipating therapeutic outcome based on the genetic signature of a tumor has become the new paradigm. The PI3K pathway represents an ideal target for bladder cancer, as many of the key proteins of this pathway are altered or mutated in this particular type of cancer. Several small molecule inhibitors have been developed to target this pathway, but their efficacy has been shown to be heterogeneous among different cell lines and mostly cytostatic but not cytotoxic in the case of bladder cancer. Understanding the genetic heterogeneity that underlies the efficacy of PI3K-pathway inhibitors in bladder cancer models is critical for informing future single-agent and combination therapies. I currently have available in our laboratory three small molecule inhibitors that target the PI3K pathway at three different levels: IGF-1 receptor, AKT, and double mTOR inhibitor, which targets both TORC1 and TORC2. In this thesis, I investigate the link between sensitivity to small molecule inhibitors targeting the PI3K pathway and the genetic signature of a large panel of bladder cancer cell lines. I investigate novel strategies to sensitize bladder cancer cells to such inhibitors by targeting autophagy, perhaps one of the main resistance mechanisms used by bladder cancer cells to evade apoptosis and I outline the intricate regulation of downstream pathways in cell lines dependent on more than one growth factor receptor. Understanding the mechanisms that bladder cancer cells use to escape currently available small molecule inhibitors may help us in designing combined approaches that are able to overcome these biological processes.

Keywords

Bladder cancer, PI3K, mTOR, AKT, IGF-1R, small molecule inhibitor, pathway, autophagy, signaling, marker