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Access Type
WSU Access
Date of Award
January 2021
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Cancer Biology
First Advisor
Asfar A. Azmi
Abstract
Pancreatic Neuroendocrine Tumors (PNETs) remain an unmet clinical need and their incidence has significantly increased over the past two decades, likely due to improving awareness, classification, and newer diagnostic modalities. Surgery without margins is the only curative option in patients with localized tumors; however, there is no effective therapy for patients with advanced or metastatic disease. Sadly, 65% of PNET patients die within 5 years after diagnosis. Current therapeutic approaches for advanced PNET patients include chemotherapy, targeted therapies (Everolimus and sunitinib), hormonal therapies [somatostatin analogs (octreotide or lanreotide)], and peptide receptor radionuclide therapy (PRRT). Regrettably, all these therapeutic modalities fail to show objective response in patients with PNETs in the clinic as most patients acquire resistance. My dissertation covers the identification and validation of novel targets that could improve the dismal outcome of patients with advanced PNETs. I have recently identified p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT) as two new therapeutic targets in PNETs. PAK4 is the downstream effector of Cdc42 and Rac1 (members of the Rho family of GTPases) and is involved in critical cellular processes such as cell motility, proliferation, and survival. More importantly, PAK4 protein has been implicated in the activation of Ras/Raf/Mek/Erk and PI3K/Akt/mTOR signaling pathways in cancer. The later signaling pathways is considered the major driver of PNETs. Similarly, NAMPT is an enzyme that catalyzes the rate-limiting step in the principal salvage pathway of NAD biosynthesis in mammals. Tumor cells have highly active glycolytic, pentose, and fatty acid synthesis pathways that require persistent high levels of NAD. Consequently, most cancers rely more heavily on NAMPT for rapid NAD biosynthesis. First I show using tissue expression and RNA interference studies that PNET tumors depend on both PAK4 and NAMPT for proliferation. I have demonstrated that targeted inhibition of PAK4-NAMPT signaling by a dual inhibitor (KPT-9274, a Phase I drug) can suppress PNET proliferation and reduce the growth of subcutaneous xenograft. Metabolomics analysis of KPT-9274 treated PNET cells reveals significant alterations in a series of metabolites related to NAD signaling. Recently, I have also shown that KPT-9274 could synergistically enhance the anti-tumor activity of a clinically used drug Everolimus in PNET cell lines (combination index <1). Molecular analysis of combination treatment showed down-regulation of known Everolimus resistance drivers such as mTORC1, mTORC2, PI3K, ERK, FAK, RICTOR, and ß-catenin. Importantly, a combination of KPT-9274 (150mg/kg) and Everolimus (2.5 mg/kg; used at sub-optimal dose) dramatically inhibited the growth of PNET cell line-derived sub-cutaneous xenograft tumors. My investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNETs that warrant further clinical investigations.
Recommended Citation
Mpilla, Gabriel Benyomo, "Pak4-Nampt Dual Inhibition As A Novel Strategy For Therapy Resistant Pancreatic Neuroendocrine Tumors" (2021). Wayne State University Dissertations. 3427.
https://digitalcommons.wayne.edu/oa_dissertations/3427