DNA inhibitors for the treatment of brain tumors

ABSTRACT

Introduction: The worldwide incidence of central nervous system (CNS) primary tumors is increasing. Most of the chemotherapeutic agents used for treating these cancer types induce DNA damage, and their activity is affected by the functional status of repair systems involved in the detection or correction of DNA lesions. Unfortunately, treatment of malignant high-grade tumors is still an unmet medical need.

Areas covered: We summarize the action mechanisms of the main DNA inhibitors used for the treatment of brain tumors. In addition, studies on new agents or drug combinations investigated for this indication are reviewed, focusing our attention on clinical trials that in the last 3 years have been completed, terminated or are still recruiting patients.

Expert opinion: Much still needs to be done to render aggressive CNS tumors curable or at least to transform them from lethal to chronic diseases, as it is possible for other cancer types. Drugs with improved penetration in the CNS, toxicity profile, and activity against primary and recurrent tumors are eagerly needed. Targeted agents with innovative mechanisms of action and ability to harness the cells of the tumor microenvironment against cancer cells represent a promising approach for improving the clinical outcome of CNS tumors.

KEYWORDS:

• Glioblastoma
• chemotherapy
• DNA damage
• DNA inhibitors
• temozolomide
• clinical trials
• brain tumors
• anti-VEGF therapy
• monoclonal antibodies
• immune checkpoint inhibitors

Article highlights

• The treatment of aggressive brain tumors remains a condition where there is an unmet medical need.

• DNA inhibitors are certainly effective drugs but carry too many and severe side effects.

• The penetration in the brain of DNA inhibitors drugs should be improved.

• Co-administration of drugs with different mechanisms of action might help to circumvent the molecular mechanisms of resistance to treatment.

• Manipulating the tumor microenvironment to directly kill tumor cells without damaging the healthy tissue represents an innovative therapeutic strategy that should be implemented.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The studies performed in the laboratory of Grazia Graziani were supported by the Italian Association for Cancer Research (AIRC) under IG 2017—ID. 20353 project.