“5-aminolevulinic acid-induced protoporphyrin IX fluorescence as an intraoperative biomarker for brain tumors: detection methods and biological correlates”

Thesis Committee

Keith D. Paulsen, Ph.D. (Co-Chair)

David W. Roberts, M.D. (Co-Chair)

Brent T. Harris, M.D., Ph.D.

Frederic Leblond, Ph.D.

Brian W. Pogue, Ph.D.

Jeffrey N. Bruce, M.D.

Abstract

Brain tumors account for ~2% of all cancers, with gliomas accounting for ~70% of all brain tumors. Evidence suggests that extent of resection provides both a quality of life and survival benefit to patients. Recent work has shown the utility of using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence-guided resection (FGR) for increased tumor removal. Briefly, the patient is given a dose of ALA prior to surgery, which leads to overproduction of PpIX in tumor, and provides fluorescence contrast to distinguish normal from tumor intraoperatively.

Although ALA-induced PpIX FGR has shown promise in high-grade gliomas, current studies show a limited sensitivity of PpIX for accurate detection, even in high-grade gliomas. Furthermore, the literature suggests that PpIX might not be an accurate biomarker for other tumor histologies, specifically, low-grade gliomas. Current limitations in detection technologies, lack of systematic study of the targeting capabilities of PpIX, and lack of understanding of the biological basis for PpIX, makes further study of ALA-induced PpIX for FGR in neurosurgery a topic of clinical relevance.

Here we present work investigating both the targeting potential of PpIX in brain tumors and an exploration into important biological correlates of PpIX accumulation. First, we elucidate on the significant tumor detection limitations using the state-of-the-art in clinical PpIX fluorescence imaging. We elaborate on the utility of performing quantitative FGR, demonstrating the broad targeting potential of PpIX beyond high-grade gliomas, and develop a combined approach to FGR using additional optical cancer biomarkers for improved detection.

We then provide a systematic analysis on the biological correlates of PpIX accumulation in tissue. We examined gliomas using gene expression analysis and histopathological techniques, to elucidate a correlation between tumor aggressiveness, e.g., increased proliferation, angiogenesis, migration, and PpIX accumulation. This provides a stronger biological rationale for use of PpIX as a broad targeting agent in FGR, further informing resection decisions. The work presented in this thesis provides a rationale for quantitative fluorescence guided resection, showing the broad targeting potential of PpIX and the important biological correlates of this fluorescence guidance mechanism.