The word "cancer" rarely stands alone, usually prefaced with its anatomical location: lung cancer, prostate cancer, brain cancer. With the advancement of high-throughput omics approaches, specific oncogenic events are reorganizing the landscape of cancer classification, at once creating commonalities between cancers arising in diverse anatomical locations and dividing organ-centric classifications of cancer into a multitude of subtypes. The term "precision medicine" postulates that these new, data-driven groupings based on molecular characterization are the key to making rational therapeutic choices.
The majority of this dissertation addresses the disconnect between extensive molecular characterization and poor cancer therapy outcomes for patients with glioblastoma multiforme (GBM). Despite clear evidence that hyperproduction of the ligand for PDGFR (platelet-derived growth factor receptor α) is sufficient to generate GBM of the proneural subtype, anti-PDGFRα therapeutics have proven disappointing in clinical trials. Cell adaptation contributes to therapeutic escape. In GBM, proneural tumor cells adopt transcriptional profiles of the mesenchymal subtype. The interconversion between the proneural and mesenchymal transcriptional classes within a tumor population presents both a challenge and an opportunity for therapeutic approaches. The proneural subtype has a proliferation phenotype and presents druggable targets such as PDGFRα. The mesenchymal subtype presents an invasive phenotype, but the targets are more challenging to drug. The typical screening for combination therapies that synergize to induce cell death is not as advantageous here, where the disease management is expected to include cytostatic drugs that act on two different aspects of the phenotype: proneurally mediated proliferation and mesenchymally mediated invasion. This work examines the applicability of a combination approach against a proneural target, PDGFRα, and mesenchymal targets in the STAT3 (signal transducer and activator of transcription 3) pathway, in the context of a proneural model of GBM.
The work is concluded with collection of work applying precision medicine in other disease contexts, most notably canine lymphoma.
|Commitee:||Bond, Jeffrey, Craig, David, Graveel, Carrie, Kaur, Balveen, Williams, Bart|
|School:||Van Andel Research Institute|
|School Location:||United States -- Michigan|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Oncology|
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