Targeting extracellular matrix remodeling sensitizes glioblastoma to ionizing radiation.

Background: The median survival of Glioblastoma multiforme (GBM) patients is 14+ months due to poor responses to surgery and chemoradiation. Means to counteract radiation resistance are therefore highly desirable. We demonstrate the membrane bound matrix metalloproteinase MT1-MMP promotes resistance of GBM to radiation, and that using a selective and brain permeable MT1-MMP inhibitor, (R)-ND336, improved tumor control can be achieved in preclinical studies. Methods: Public microarray and RNA-sequencing data were used to determine MT1-MMP relevance in GBM patient survival. Glioma stem-like neurospheres (GSCs) were used for both in vitro and in vivo assays. An affinity resin coupled with proteomics was used to quantify active MT1-MMP in brain tissue of GBM patients. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP and inhibition via the MT1-MMP inhibitor (R)-ND336, were used to assess the role of MT1-MMP in radio-resistance. Results: MT1-MMP expression inversely correlated with patient survival. Active MT1-MMP was present in brain tissue of GBM patients but not in normal brain. shRNA- or (R)-ND336-mediated inhibition of MT1-MMP sensitized GSCs to radiation leading to a significant increase in survival of tumor-bearing animals. MT1-MMP depletion reduced invasion via the effector protease MMP2; and increased the cytotoxic response to radiation via induction of replication fork stress and accumulation of double strand breaks (DSBs), making cells more susceptible to genotoxic insult. Conclusions: MT1-MMP is pivotal in maintaining replication fork stability. Disruption of MT1-MMP sensitizes cells to radiation and can counteract invasion. (R)-ND336, which efficiently penetrates the brain, is therefore a novel radio-sensitizer in GBM.

WP1066 induces cell death in a schwannomatosis patient-derived schwannoma cell line.

Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1, are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2-related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies.

Multifocal Intracranial Ganglioglioma in a Sexagenarian: Case Report and Review of the Current Literature.

BACKGROUND: Gangliogliomas are rare, well-differentiated, low-grade neoplasms that most often occur unifocally in children and most commonly affect the temporal lobe. Gangliogliomas that occur in patients age >40 years tend to have worse prognoses. These tumors generally stain positively for neural and glial cell markers, as well as CD34. Here we report an unprecedented case of multifocal intracranial ganglioglioma in an adult age >40 who had a favorable course, and review the current literature on multifocal intracranial gangliogliomas. CASE DESCRIPTION: A 60-year-old female presented to her ophthalmologist with blurry vision in the right eye and an unremarkable neurologic exam. She was referred for brain imaging, which showed multiple lesions in both cerebral hemispheres. Biopsy of the right occipital lesion was elected, as it enhanced the most on magnetic resonance imaging. CONCLUSIONS: Multifocal intracranial gangliogliomas are exceedingly rare tumors, especially in adults. These tumors present unique management barriers because as they are multifocal at the time of diagnosis, making resection more technically challenging. In our review, the average age at diagnosis was 19.2 years, and 80% of the cases had at least 1 lesion in the temporal lobe. Two studies opted for resection of intracranial tumors, whereas the remaining studies performed biopsy with conservative management and serial imaging. Biopsy was performed in all cases. We present the first case of an intracranial multifocal ganglioglioma in a patient age >40 years with lesions in the occipital lobe, corpus callosum, and frontal lobe at presentation.