Can we rely on synthetic pharmacotherapy for the treatment of glioblastoma?

Introduction: Despite decades of clinical trials utilizing conventional and novel therapeutics, the effective treatment of glioblastoma remains one of the most formidable challenges in oncology. Current standard of care includes surgery and chemoradiation. Synthetic pharmacotherapies continue to be explored as potential therapeutic options for glioblastoma patients.Areas covered: This study reviews synthetic pharmacotherapies that are currently under investigation in phase I-III clinical trials. The authors of this study highlight the mechanisms of action of the synthetic pharmacotherapy agents under investigation, outline the available evidence for their utility based on the literature, and summarize the current landscape.Expert opinion: Although warranting further investigation, the studies generally highlighted here have not shown remarkable changes in clinical benefits beyond what has already been established with radiochemotherapy. As we develop more synthetics, we will likely need to combine them with other synthetics to target multiple separate molecular pathways. There is considerable potential when this treatment strategy is guided by molecular profiling approaches which seek to stratify patients based on treatments that would be most efficacious for them.

Pituitary Adenomas: From Diagnosis to Therapeutics.

Pituitary adenomas are tumors that arise in the anterior pituitary gland. They are the third most common cause of central nervous system (CNS) tumors among adults. Most adenomas are benign and exert their effect via excess hormone secretion or mass effect. Clinical presentation of pituitary adenoma varies based on their size and hormone secreted. Here, we review some of the most common types of pituitary adenomas, their clinical presentation, and current diagnostic and therapeutic strategies.

Current FDA-Approved Therapies for High-Grade Malignant Gliomas.

The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.

Convection Enhanced Delivery in the Setting of High-Grade Gliomas.

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood-brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas.

Clinically Explored Virus-Based Therapies for the Treatment of Recurrent High-Grade Glioma in Adults.

As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of the introduction of either wild-type or engineered viruses to the site of disease, where they exert an antitumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induces tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights the potential to integrate this therapeutic strategy into promising combinatory approaches.

DNX-2401: an investigational drug for the treatment of recurrent glioblastoma.

Introduction: High-grade gliomas (HGG) are extremely aggressive brain malignancies that are fatal. Despite maximal resection, chemotherapy, and radiation, these tumors inevitably recur and present a poor median overall survival (mOS); hence a pressing need for improved treatments.Areas covered: This review assesses DNX-2401 as a treatment of recurrent HGG. Phase I data on efficacy, safety, and tolerability are examined while insights and perspectives on future directions are offered.Expert opinion: This phase I study assessed DNX-2401 in two study groups; one received an intratumoral injection without tumor resection while the second received an intratumoral injection followed by surgical resection 14 days later with a second injection into the resection cavity. In patients that did not receive resection, the mOS was 9.5 months while patients in the resection group had a mOS of 13 months, a promising extension of survival compared to historical controls. Furthermore, this study had numerous long-term survivors living for greater than 2 years. DNX-2401 was well tolerated with no Grade 3/4 adverse events; it provoked an immunologic response to the tumor which may contribute to the complete responses in some patients. Randomized-control trials are necessary and further studies are warranted to identify patients who will benefit most.

Targeted radiotherapy for malignant gliomas.

Malignant glioma remains a disease with poor prognosis despite recent advances in the multidisciplinary care of this disease. Herein we review the evolution of and recent advances in radiation therapy for malignant glioma that have allowed for more targeted therapy, potentially improving efficacy while decreasing normal tissue toxicity. Current and emerging techniques are presented, including stereotactic radiotherapy and radiosurgery, brachytherapy, radioimmunotherapy, and charged particle therapy, as well as the combination of these modalities with novel targeted biochemotherapies.

Stopping cancer in its tracks: using small molecular inhibitors to target glioblastoma migrating cells.

Glioblastoma multiforme (GBM) represents one of the most common aggressive types of primary brain tumors. Despite advances in surgical resection, novel neuroimaging procedures, and the most recent adjuvant radiotherapy and chemotherapy, the median survival after diagnosis is about 12-14 months. Targeting migrating GBM cells is a key research strategy in the fight against this devastating cancer. Though the vast majority of the primary tumor focus can be surgically resected, these migrating cells are responsible for its universal recurrence. Numerous strategies and technologies are being explored to target migrating glioma cells, with small molecular inhibitors as one of the most commonly studied. Small molecule inhibitors, such as protein kinase inhibitors, phosphorylation site inhibitors, protease inhibitors, and antisense oligonucleotides show promise in slowing the progression of this disease. A better understanding of these small molecule inhibitors and how they target various extra- and intracellular signaling pathways may eventually lead to a cure for GBM.

OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.

OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma.

Upward transtentorial herniation, hydrocephalus, and cerebellar edema in hypertensive encephalopathy.

BACKGROUND: Edema of the cerebellum with secondary obstructive hydrocephalus is a rare presentation of hypertensive encephalopathy. The authors report an unusual case of isolated posterior fossa swelling with upward transtentorial herniation and hydrocephalus causing neurologic deterioration. These patients are often initially evaluated by a neurologist because of the acute neurologic symptoms. Prompt diagnosis with aggressive blood pressure control may obviate the need for emergent cerebrospinal fluid (CSF) diversion. REVIEW SUMMARY: This is a case report of a 26-year-old man who presented to the emergency room with confusion and somnolence over a 2-day period. His initial blood pressure was 175/110 mmHg. On examination he was disoriented, with a Glasgow Coma Scale score of 12 points, opening his eyes only to loud verbal stimuli, verbalizing inappropriately, and he was only able to follow simple commands. Neuroimaging revealed edema of the cerebellar folia with noncommunicating hydrocephalus and upward transtentorial herniation. Differential diagnoses of posterior fossa tumor, rhombencephalitis, and hypertensive encephalopathy were entertained. A thorough literature review is included with the discussion of this case. The patient underwent emergent ventriculostomy for CSF drainage and prompt blood pressure control with nitroprusside. After 48 hours of CSF drainage and correction of his hypertension, his neurologic examination normalized. Repeat imaging revealed near resolution of the obstructive hydrocephalus and cerebellar edema. CONCLUSION: Isolated edema of the cerebellum with upward transtentorial herniation and obstructive hydrocephalus is a rare presentation of hypertensive encephalopathy and should be considered in patients with an acute hypertensive crisis and mental status changes. This entity responds to prompt blood pressure control; however, emergent ventriculostomy by a neurosurgical team should be entertained for neurologic deterioration secondary to significant obstructive hydrocephalus, as illustrated in this case.

Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.

Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2. These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid.

Spontaneous cervical epidural hematoma: case report and literature review.

BACKGROUND: Spontaneously occurring epidural hematomas for which no etiology is identified are rare phenomenon. These are often neurosurgical emergencies; therefore, prompt diagnosis and treatment are paramount. Because of the rarity of this condition, we have illustrated in this recent case its presentation, evaluation and management. METHODS: A 63-year-old male presented to our emergency room with right-sided hemiparesis and contralateral hypesthesia, consistent with a C5 Brown-Séquard syndrome. An initial evaluation for cerebral infarction was unremarkable, including a negative brain magnetic resonance image. Further imaging revealed a cervical epidural hematoma of unknown etiology. RESULTS: The patient underwent emergent laminectomy for decompression and evacuation of the hematoma within 24 hours of his presentation to the emergency room. The patient's symptoms improved remarkably after surgery and a 4-month follow-up imaging evaluation revealed no recurrence of his hematoma. CONCLUSION: This report highlights the various presentations, evaluation, and management options for this rare diagnosis. It emphasizes the necessity of prompt diagnosis for possible emergent intervention.

Astroglia induce cytotoxic effects on brain tumors via a nitric oxide-dependent pathway both in vitro and in vivo.

OBJECTIVE: In the central nervous system, astroglia produce nitric oxide (NO) in response to cytokines. We investigated whether cytokine stimulation of astroglia could inhibit brain tumor cell growth in vitro and prolong survival in vivo via an NO-dependent pathway. METHODS: Astroglia cultures were stimulated with the cytokines lipopolysaccharide and interferon-gamma and subsequently seeded with tumor cell lines. Wild-type mice and inducible NO synthase-knockout mice received in vivo cytokine stimulation followed by B16F10 murine melanoma challenge. RESULTS: Our in vitro studies demonstrate that astroglia stimulated to produce NO by the addition of cytokines dose-dependently inhibit the growth of one primary rat brain tumor cell line (9L) and three primary human brain tumor cell lines (H80, U87, and U373). This inhibition of tumor cell growth is also observed in metastatic cell lines (B16F10 melanoma, Lewis lung carcinoma, and CT26 colon). Cultured astrocytes from inducible NO synthase-knockout mice, which are incapable of induction of NO, are without the enhanced tumoricidal effect. Furthermore, when C57BL/6 mice are primed to produce NO through stereotactic intracranial administration of lipopolysaccharide plus interferon-gamma and subsequently challenged with B16F10 murine melanoma, survival is significantly prolonged, with a median survival of 26 days versus 16 days in the control group (P < 0.001). The addition of an NO synthase inhibitor (N(G)-nitro-l-arginine methyl ester) decreases this beneficial effect (median survival, 21 d). CONCLUSION: These findings suggest that NO may have an important role as a defense mechanism molecule against brain tumors; stimulation or modification of this mechanism may represent a new approach to the treatment of primary and metastatic brain tumors.