Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers.

Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O-alkylguanine lesions.

The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors.

Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors.

Mechanism-based design of agents that selectively target drug-resistant glioma.

Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors.

Oncometabolites as Regulators of DNA Damage Response and Repair.

Dysregulation of DNA damage response and repair (DDR) contributes to oncogenesis, yet also generates the potential for targeted cancer therapies by exploiting synthetic lethal interactions. Oncometabolites, small intermediates of metabolism overproduced in certain cancers, have emerged as a new mechanism of DDR modulation through their effects on multiple DNA repair pathways. Increasing evidence suggests that oncometabolite-induced DDR defects may offer the opportunity for tumor-selective chemo- and radio-sensitization.

Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51.

Combining the anti-angiogenic agent cediranib with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib improves progression-free survival compared to olaparib alone in ovarian cancer patients through an unknown mechanism. PARP inhibitors are used primarily in the treatment of patients with DNA repair-associated (BRCA1/2) mutated cancers because these mutations cause a deficit in homology-directed DNA repair (HDR) that confers sensitivity to these agents. However, the combination of cediranib and olaparib was effective in patients without BRCA1/2 mutations.