Glioblastoma multiforme (GBM) is a malignant astrocytoma and one of the most common glial tumors. GBM is a rapidly progressing and fatal incurable cancer for which novel therapeutic approaches are needed. The standard of care for newly diagnosed GBM is a three-pronged regimen to treat the disease: (i) surgical resection to debulk the lesion; (ii) whole-brain or stereotactic external-beam radiotherapy to irradiate residual disease; and (iii) chemotherapy to again address residual disease. However, all three treatment modalities exhibit limitations regarding untoward damage to normal brain capacity resulting from excision, radiotoxicity, and chemotoxicity; and the probability of recurrence is nearly universal. The approach being explored in this project may potentially afford a clinical method to specifically target the angiogenic and aberrant vascular endothelium in tumors, and locally irradiate those vessels and the adjacent cancer stem cell niches with cytotoxic alpha (α) particles. Alpha particles are monoenergetic, high-energy helium nuclei with a large linear energy transfer and have an effective range on the order of several cell diameters. The α-particle creates a short, dense cylinder of ionizing radiation and deposits large amounts of energy that result in extreme biological damage, making it an extremely potent cytotoxin. Therapeutic studies using a vascular-targeted α-particle-emitting antibody constructs have demonstrated tumor control in animal models of GBM, and prostate and colon carcinoma, and have been shown to impair tumor growth by specifically ablating bone-marrow-derived endothelial progenitor cells. We hypothesize that α-particle-emitting antibody constructs targeted to tumor vasculature may also collaterally damage nearby cancer stem-like cells residing in perivascular niches. Cancer stem cells are believed to drive tumor regrowth following conventional therapy. Like normal stem cells, cancer stem cells are self-renewing and can give rise to multiple neuroepithelial lineages. They are also capable of initiating tumor growth. Therapy targeted to cancer stem cells should lead to sustained tumor regression. Previously, we have demonstrated that GBM-derived neurosphere-forming cells (i) exhibited a dose-dependent response to exposure to α-particle radiation and γ-radiation; (ii) α-radiation was almost a log more potent than γ-radiation; and (iii) repair mechanisms were ineffective in reversing the damage by α-particles, but were effective in reversing low dose γ-radiation.
Preferred Project Dates
- June 16 – August 8
- June 23 – August 15
Students are expected to be in attendance all eight weeks, start and end dates inclusive.