All ETDs from UAB

Advisory Committee Chair

Kevin A Roth

Advisory Committee Members

Christopher A Klug

G Y Gillespie

Mary-Ann Bjornsti

Steven L Carroll

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies of the peripheral nervous system. The majority of MPNSTs arise in patients of the autosomal dominant genetic disorder neurofibromatosis type I (NF1) although they also arise sporadically. In the absence of any effective chemotherapeutic options and with surgery constituting the mainstay of treatment, MPNST patients face an extremely poor prognosis. This underscores the need to develop novel therapeutic strategies against this tumor type. It is well accepted that the crosstalk between autophagy and apoptosis can be exploited to derive maximal therapeutic benefit, especially through combinatorial therapies. However, this interaction is extremely complex and the outcome of any manipulation of the autophagy pathway is highly context dependent. The overarching goal of my studies was to assess the impact of autophagy modulation on cell fate and to identify the factors governing cell death in different therapeutic contexts. The erbB family of receptor tyrosine kinases is known to play a central role in MPNST pathogenesis. However, targeting this pathway using pan erbB inhibitors only yields a cytostatic response. My studies demonstrate that erbB inhibitors induce cytoprotective autophagy which, when blocked at a late stage by inducing lysosomal dysfunction, can trigger apoptotic death. This study provides a mechanistic basis for using late stage autophagy blockers to circumvent the resistance of MPNST cells to apoptotic death in response to pan erbB inhibition. In contrast to its cytoprotective role in the context of pan erbB inhibition, I discovered that autophagy exerts a pro death effect in the cytotoxicity induced by 4-hydroxy tamoxifen. Here, autophagy mediates death through the selective degradation of K ras, a prosurvival protein. This study reveals a novel mechanism for autophagy-dependent death and provides a new insight into an estrogen receptor-independent death mechanism for tamoxifen. Overall, these studies establish autophagy as an important regulator of cell death in MPNSTs and shed light on the mechanisms by which this regulation occurs. The autophagy pathway is a critical therapeutic target and future studies of autophagy modulation hold significant promise for the formulation of effective combinatorial therapies to treat MPNSTs.

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