DDDR-46. Oral NEO212 is a well-tolerated temozolomide derivative with superior therapeutic activity in preclinical chemoradiation models of glioblastoma
Year: 2025
Type: conference-abstract
Abstract: BACKGROUND The Stupp protocol remains the cornerstone of glioma control for all newly diagnosed patients. This is despite the fact that most GB patients who harbor tumors with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoters or are deficient in mismatch repair (dMMR) fail to respond to this protocol. To address this problem, we are developing a novel TMZ conjugate—called NEO212—with improved tumor penetration. We hypothesize that the superior on-target alkylation by NEO212 differentially generates DNA lesions (i.e., N-methylpurine adducts) that are more efficiently converted into lethal double-strand breaks (DSB) by radiotherapy (RT). METHODS We used rodent models stereotactically implanted with GB cell lines or primary, radioresistant human GB stem cells, representing different treatment resistance mechanisms. Several efficacy studies were conducted in which the animals were dosed with either NEO212 or TMZ without or with RT. Overall survival was recorded, and histological analyses quantified tumor DNA damage, apoptosis, microvessel density, and impact on bone marrow. Comparative pharmacokinetic and target organ biodistribution studies were also completed with oral NEO212 or TMZ in tumor bearing animals. The intact drugs and their metabolites were measured by high-performance liquid chromatography (HPLC) methods in plasma and target organs. RESULTS At clinically-relevant dosages, NEO212 shows about 30% more tumoral brain accumulation (P<0.0001) and 75% less bone marrow accumulation (P=0.0001) compared to TMZ at Cmax. Replacing TMZ with NEO212 in a schedule designed to mimic the Stupp protocol achieved a strikingly superior extension of survival, especially in TMZ- and RT-resistant models. While NEO212 displayed pronounced radiation-sensitizing, DNA-damaging, pro-apoptotic, and anti-angiogenic effects in tumor tissue, it did not cause bone marrow toxicity. CONCLUSION NEO212 is a candidate drug to potentially replace TMZ on the standard Stupp protocol. It has the potential to become the first chemotherapeutic agent to significantly extend overall survival in TMZ-resistant patients when combined with radiation.
Source: Neuro-Oncology
Authors: Radu Minea, Thu Zan Thein, Stephen Swenson, Weijun Wang, Axel Schönthal, Thomas Chen
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416140286
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