NEO 212 Inhibits Migration and Invasion of Glioma Stem Cells

A Novel Temozolomide–Perillyl Alcohol Conjugate Exhibits Superior Activity against Breast Cancer Cells In Vitro and Intracranial Triple-Negative Tumor Growth In Vivo.

Authors: Thomas C. Chen^1,2, Hee-Yeon Cho¹, Weijun Wang¹, Manasai Barath³, Natasha Sharma⁴, Florance M. Hofman², Axel H. Schönthal³.Nagore I. Marín-Ramos¹, Thu Zan Thein¹, Stephen D. Swenson¹

Glioblastoma multiforme (GBM) is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature. It remains one of the primary diagnoses in CNS-based disease and because of its high rate of tumor recurrence, and resistance to standard measures of care has one of the lowest rates of survivability amongst CNS-based cancer treatments. Currently, Temozolomide (TMZ) remains the gold-standard for the pharma-therapeutic treatment of GBM. Despite great progress made in radiotherapy, surgery, and chemotherapy, there has been little improvement to patient outcomes. The main problem with GBM is that once the tumor recurs, there are few treatment options available to patients; and repeated surgeries and radiation have a high potential for morbidity. Thus, chemotherapeutic agents with greater efficacy than TMZ are badly needed.

Recent research has suggested that GBM tumor recurrence is a result of a small subpopulation of drug-resistant glioma stem cells (GSC), also known as tumor-initiating cells. These cells show a capacity for self-renewal and in vivo tumor initiation, as well as resistance to antitumor drugs such as TMZ. A recent study has demonstrated that GSCs are the first to proliferate and repopulate the tumor when TMZ treatment is discontinued.

NeOnc Technologies in an effort to address this issue, conducted a study using it NEO 212 conjugate of TMZ and Perillyl Alcohol (POH) to see its effect on a GSC population within a GBM tumor site. Initial studies have shown that NEO 212 is more effective at stopping and limiting GBM tumor growth than TMZ alone. In this study, Human GBM tissues were cultured to isolate the GSC containing cancer cells. Test animals were then implanted with the culture and a course of NEO 212 was administered and the effects observed. The results showed that Neo 212 decreases migration and invasion of primary cultures of patient-derived GSCs. Furthermore, in an in vivo orthotopic glioma model, NEO 212 decreased tumor progression by reducing the invasion of GSCs, thereby increasing the survival time of the test animals.

Departments of ¹Neurosurgery, ²Pathology, and ³ Molecular Microbiology & Immunology, and ⁴Pharmaceutical Sciences, University of Southern California, Los Angeles, CA.