GBM radiosensitizers: dead in the water…or just the beginning?

The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers. However, many of  the previous radiosensitizing strategies were not based on clear pre-clinical evidence, and in many cases blood-barrier penetration was not considered. Furthermore, DNA repair inhibitors have only recenly arrived in the clinic, and likely represent potent agents for glioma radiosensitization. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization

Biodegradable PEG-poly(ω-pentadecalactone- co - p -dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drugloaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(u-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co- DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors

SAMHD1 promotes DNA end resection to facilitate DNA repair by homologous recombination

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV- 1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity

Targeting DNA repair in gliomas

Purpose of review: Gliomas represent a disparate group of malignancies with varying clinical outcomes despite a tremendous amount of time, effort, and resources dedicated to their management and understanding. The most aggressive entity, glioblastoma, has a dismal prognosis with poor local control despite intense local and systemic treatment, including radiation therapy. Recent findings: Given the heterogeneity in genotype, phenotype, and patient outcomes, researchers and clinicians have turned their attention toward attacking DNA damage response and repair mechanisms in gliomas in an effort to develop novel chemo and radiosensitizers. However, despite extensive work in both the laboratory and the clinic, no sensitizers have yet to emerge as clear options in the treatment of glioma, often because of meager preclinical data or an inability to penetrate the blood–brain barrier. Summary: This review will examine current understanding of molecular DNA repair targets in glioma and their potential exploitation to improve local control and, ultimately, overall survival of patients afflicted with these diseases

Loss of ATRX confers DNA repair defects and PARP inhibitor sensitivity

Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and represents a potential target for cancer therapies. ATRX is known to function as a histone chaperone that helps incorporate histone variant, H3.3, into the genome. Studies have implicated ATRX in key DNA damage response (DDR) pathways but a distinct role in DNA repair has yet to be fully elucidated. To further investigate the function of ATRX in the DDR, we created isogenic wild-type (WT) and ATRX knockout (KO) model cell lines using CRISPR-based gene targeting. These studies revealed that loss of ATRX confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors, which was linked to an increase in replication stress, as detected by increased activation of the ataxia telangiectasia and Rad3-related (ATR) signaling axis. ATRX mutations frequently co-occur with mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2), and the latter mutations also induce HR defects and PARP inhibitor sensitivity. We found that the magnitude of PARP inhibitor sensitivity was equal in the context of each mutation alone, although no further sensitization was observed in combination, suggesting an epistatic interaction. Finally, we observed enhanced synergistic tumor cell killing in ATRX KO cells with ATR and PARP inhibition, which is commonly seen in HR-defective cells. Taken together, these data reveal that ATRX may be used as a molecular marker for DDR defects and PARP inhibitor sensitivity, independent of IDH1/2 mutations. These data highlight the important role of common glioma-associated mutations in the regulation of DDR, and novel avenues for molecularly guided therapeutic intervention

CDKN2A Copy Number Loss Is an Independent Prognostic Factor in HPV-Negative Head and Neck Squamous Cell Carcinoma

BackgroundHPV infection is associated with high p16 expression and good prognosis in head and neck squamous cell carcinomas (HNSCCs). Analysis of CDKN2A, the gene encoding p16, may further elucidate the association between p16 expression and prognosis. We sought to determine whether CDKN2A copy number loss was associated with poor survival in HPV-negative HNSCCs.MethodsThe Cancer Genome Atlas HNSCC clinical and genomic data were obtained and integrated. Patients <80 years old with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Stratifying by copy number loss status, CDKN2A mRNA and p16 protein expression levels were examined and overall survival (OS) and disease-free survival (DFS) were evaluated.Results401 patients with HPV-negative HNSCC were identified. 146 patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group. Median OS for patients with and without CDKN2A copy number loss was 16.5 and 46.6 months, respectively (p = 0.007). Median DFS for both groups was 11.6 and 19.2 months, respectively (p = 0.03). In both univariate and multivariable analyses, stage IV designation, receipt of chemotherapy and CDKN2A copy number loss were predictive of OS.ConclusionCDKN2A copy number loss predicted poor survival independently of other patient and treatment factors and may be a clinically useful prognostic factor