Overview
Glioblastoma, the most prevalent malignant tumor in the central nervous system, is characterized by high invasiveness and a propensity to recur, contributing to a relatively elevated mortality rate. Patients diagnosed with high-grade glioblastomas typically experience a median survival period of less than 14 months. Presently, the standard treatment for glioblastoma involves surgical resection combined with postoperative radiotherapy and chemotherapy, with postoperative chemotherapy playing a pivotal role in enhancing patient prognosis. Temozolomide (TMZ), a cutting-edge oral alkylating agent known for its advantageous properties, including easy traversal of the blood-brain barrier, induces DNA alkylation in tumor cells, fostering apoptosis. Currently, it serves as a frontline medication for postoperative chemotherapy in glioblastoma. However, clinical resistance to TMZ chemotherapy significantly hampers its efficacy in later stages. We have recently discovered and validated that 5-aminoimidazole-4-carboxamide (AICA), derived from TMZ, can transform into 5-aminoimidazole-4-carboxamide ribonucleotide-5-phosphate (AICAR) in GBM cells. Hypoxanthine phosphoribosyltransferase 1 (HPRT1) has been identified as the catalyst for the AICA reaction, generating AICAR. AICAR acts as an endogenous activator of AMP-activated protein kinase (AMPK), fostering chemoresistance in glioblastoma through the activation of the AMPK signaling pathway. 6-mercaptopurine (6-MP) competes effectively to inhibit HPRT1 activity, thereby impeding TMZ-induced AMPK activation and significantly heightening glioblastoma cell sensitivity to TMZ. In this project, we propose an innovative strategy involving the combination of 6-MP with TMZ for the treatment of glioblastoma.
Eligibility
Inclusion Criteria:
- Age between 18 and 65, no gender restrictions.
- Histologically confirmed glioblastoma as the primary tumor after surgery.
- Patients with recurrent glioblastoma confirmed by MRI after standard treatment (surgery, Stupp regimen) failure, supported by RANO criteria evaluation.
- At least one measurable intracranial tumor lesion according to RANO criteria.
- No prior treatment with 6-mercaptopurine or similar drugs.
- General condition assessed by Karnofsky Performance Status (KPS) score ≥ 60.
- Normal bone marrow function: white blood cell count ≥ 3.5 × 10^9/L, neutrophil count ≥ 2.0 × 10^9/L, hemoglobin count ≥ 90 g/L, platelet count ≥ 80 × 10^9/L.
- Normal organ functions such as heart and lung, and no severe internal diseases.
- Willing to sign an informed consent form, good compliance, able to attend regular follow-ups, and voluntarily agree to comply with the study protocol.
Exclusion Criteria:
- Participants who do not consent.
- Vulnerable populations such as pregnant women, children, and adolescents.
- No history of or concurrent malignancy within the past 5 years.
- Abnormal liver function (total bilirubin > 1.5 times the upper limit of normal, ALT/AST > 2 times the upper limit of normal).
- Impaired kidney function (serum creatinine > 1.5 times the upper limit of normal).
- Presence of organic heart disease leading to clinical symptoms or cardiac dysfunction (NYHA ≥ Grade 2).
- Factors significantly affecting oral drug absorption, such as difficulty swallowing, intestinal obstruction, etc.