PhD Thesis Proposal: Armin Tavakkoli

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"Advancing CNS Tumor Management: Novel Modalities in Surgery, Radiation, and Chemotherapy"

Abstract

Most central nervous system (CNS) tumors are managed by a combination of surgical resection, radiation, and chemotherapy; however, operative morbidity from invasive surgery, the narrow therapeutic window of conventional radiotherapy, and poor blood–brain barrier penetration of systemic agents are critical unmet needs that hinder tumor control. This proposal presents three complementary strategies to advance CNS tumor therapy and accelerate clinical translation. In Part 1, we investigate laser interstitial thermal therapy (LITT) for treatment of metastatic epidural spinal cord compression, replacing the morbid “separation surgery” with a minimally invasive, image-guided approach that maximizes tumor ablation while preserving neurologic function. In Part 2, we characterize the normal-tissue sparing of ultra-high dose-rate (UHDR) radiation in preclinical models, elucidating key in vivo parameters that optimize the therapeutic index. In Part 3, we evaluate LITT-facilitated, spatially targeted chemotherapy delivery to concentrate cytotoxic agents within tumor tissue, leveraging heat-released chemotherapy and transient blood–brain barrier disruption to minimize systemic toxicity.

Preliminary data demonstrate successful LITT ablation in the first large animal model of metastatic epidural spinal cord compression, UHDR reduction in radiation-induced normal tissue toxicity modulated by tissue oxygenation, and targeted local drug accumulation with LITT-mediated chemotherapy delivery. By integrating minimally invasive surgery, advanced radiotherapy, and spatially targeted chemotherapy, this work lays a cohesive roadmap toward durable, less-morbid control of CNS tumors. The resulting mechanistic insights and optimized treatment parameters will inform early-phase clinical trials and ultimately improve outcomes for patients facing these devastating diagnoses.

Thesis Committee

• P. Jack Hoopes (co-chair)
• Linton T. Evans (co-chair)
• David J. Gladstone
• Charles R. Thomas Jr.
• Claudio Tatsui (MD-Anderson)

Contact

For more information, contact Thayer Registrar at thayer.registrar@dartmouth.edu.