Molecularly driven therapies in the treatment of primary brain tumors.

Gamma knife treatment is a clinically effective, safe, and cost-effective adjunctive therapy for primary malignant brain tumors. For most brain metastases, radiosurgery is the treatment of choice and will result in effective tumor control in more than 90% of treated tumors.

Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a patient’s own immune cells to generate directed anti-tumor activity, are emerging technologies that hold promise to improve the treatment of primary brain tumors in children and adults. Here, we review recent advances in chimeric antigen receptor (CAR) T-cell therapies for the treatment of aggressive primary brain tumors, including glioblastoma and diffuse midline glioma, H3 K27M-mutant. We highlight current approaches, discuss encouraging investigational data, and describe key challenges in the development and implementation of these types of therapies in the neuro-oncology setting.

The place of hydroxyurea in the treatment of primary brain tumors.

Existing drug delivery methods have not led to a significant increase in survival for patients with malignant primary brain tumors. While the combination of conventional therapies consisting of surgery, radiotherapy, and chemotherapy has improved survival for some types of brain tumors (e.g., WNT medulloblastoma), other types of brain tumors (e.g., glioblastoma and diffuse midline glioma) still have a poor prognosis. The reason for the differences in response can be largely attributed to the blood–brain barrier (BBB), a specialized structure at the microvasculature level that regulates the transport of molecules across the blood vessels into the brain parenchyma. This structure hampers the delivery of most chemotherapeutic agents for the treatment of primary brain tumors. Several drug delivery methods such as nanoparticles, convection enhanced delivery, focused ultrasound, intranasal delivery, and intra-arterial delivery have been developed to overcome the BBB in primary brain tumors. However, prognosis of most primary brain tumors still remains poor. The heterogeneity of the BBB in primary brain tumors and the distinct vasculature of tumors make it difficult to design a drug delivery method that targets the entire tumor. Drug delivery methods that combine strategies such as focused ultrasound and nanoparticles might be a more successful approach. However, more research is needed to optimize and develop new drug delivery techniques to improve survival of patients with primary brain tumors.

Possible advantages of magnetic resonance (MR)-guided radiation therapy (MRgRT) for the treatment of brain tumors include improved definition of treatment volumes and organs at risk (OARs) that could allow margin reductions, resulting in limited dose to the OARs and/or dose escalation to target volumes. Recently, hybrid systems integrating a linear accelerator and an magnetic resonance imaging (MRI) scan (MRI-linacs, MRL) have been introduced, that could potentially lead to a fully MRI-based treatment workflow. We performed a systematic review of the published literature regarding the adoption of MRL for the treatment of primary or secondary brain tumors (last update November 3, 2022), retrieving a total of 2487 records; after a selection based on title and abstracts, the full text of 74 articles was analyzed, finally resulting in the 52 papers included in this review. Several solutions have been implemented to achieve a paradigm shift from CT-based radiotherapy to MRgRT, such as the management of geometric integrity and the definition of synthetic CT models that estimate electron density. Multiple sequences have been optimized to acquire images with adequate quality with on-board MR scanner in limited times. Various sophisticated algorithms have been developed to compensate the impact of magnetic field on dose distribution and calculate daily adaptive plans in a few minutes with satisfactory dosimetric parameters for the treatment of primary brain tumors and cerebral metastases. Dosimetric studies and preliminary clinical experiences demonstrated the feasibility of treating brain lesions with MRL. The adoption of an MRI-only workflow is feasible and could offer several advantages for the treatment of brain tumors, including superior image quality for lesions and OARs and the possibility to adapt the treatment plan on the basis of daily MRI. The growing body of clinical data will clarify the potential benefit in terms of toxicity and response to treatment.

To review relevant advances in the past half-decade in the treatment of primary brain tumors via modification of blood-brain barrier (BBB) permeability. BBB disruption is becoming increasingly common in the treatment of primary brain tumors. Use of mannitol in BBB disruption for targeted delivery of chemotherapeutics via superselective intra-arterial cerebral infusion (SIACI) is the most utilized strategy to modify the BBB. Mannitol is used in conjunction with chemotherapeutics, oligonucleotides, and other active agents. Convection-enhanced delivery has become an attractive option for therapeutic delivery while bypassing the BBB. Other technologic innovations include laser interstitial thermal therapy (LITT) and focused ultrasound (FUS) which have emerged as prime modalities to directly target tumors and cause significant local BBB disruption. In the past 5years, interest has significantly increased in studying modalities to disrupt the BBB in primary brain tumors to enhance treatment responses and improve clinical outcomes.

BackgroundAggressive primary brain tumors such as glioblastoma are uniquely challenging to treat. The intracranial location poses barriers to therapy, and the potential for severe toxicity. Effective treatments for primary brain...

Photodynamic therapy in the treatment of brain tumours. A feasibility study

We have previously shown that primary brain tumor from patients and cell lines possess type I alpha 1 procollagen. Procollagen type I, III, and IV have also been reported to be expressed in certain glioma subtypes. Although the function of these procollagens is not known, they are most likely involved in invasion and signaling. We have further investigated whether manipulation of the secretion of these procollagens can be used to kill glioma cells. We have studied the expression of procollagen type I alpha 1 and2 (Pro-col1A1 & A2), procollagen type III alpha 1 (Pro-col3A1) and procollagen type IV alpha 1&2 (Proc-col4A1 & A2) in 5 cell lines (Glioma-1, U-373, U-118, U-87, and A-172) using real time RT-PCR (qPCR) and western blot when antibody was available. Our data showed that A-172 expressed all 5 types of procollagen, while U-87, U-118 and Glioma-1 expressed primary Pro-colA1 and A2, and U-373 expressed only pro-col1A2 and pro-col4A1 and A2. Hsp47, which is a major chaperone in the folding of procollagen type I, is not expressed in U-373. This cell line also possessed very high levels of GRP-78 which is indicative of increased ER stress. We also investigated the presence of collagen receptor Endo 180 and DDR1 (discodin domain receptor 1) in these cell lines. Endo 180 was present in all 5 cell lines, but to a much lesser extent in U-373. The DDR1 expression by qPCR was the highest in A-172 followed by U-118 (>5 arbitrary units) while U-373, U-87 and Glioma-1 have less than 3 arbitrary units. It is known that procollagen needs to be folded at ER and then secreted out of the cells, where it will be processed to form collagen. Collagen can then bind DDR1, a receptor tyrosine kinase which plays a role in attachment, migration, proliferation and survival. In this regard, we have detected pro-col1A1 and A2 in the media which verified that pro-col1A1 and A2 are secreted outside the cells. We hypothesize that inability to secrete procollagen will result in both ER stress and inability for signaling. To accomplish this, we have studied the cytotoxic effect of brefeldin (BFA) which is known to block the transport of secretory protein from ER/Golgi network to the cell surface in these five cell lines. All five cell lines are very sensitive to brefeldin with IC50 of 3.0 ng/ml for U-118, A-172 and U-87. In U-373 and Glioma-1 the IC50 was 5.0 ng/ml. Interestingly, cancer stem cells isolated from U-87 did not possess pro-co1A1, but DDR1 mRNA was present and was 3 times higher than in the non stem cells. They also have different metabolic profiling than their parental cells, such as they do not express argininosuccinate synthetase, a key enzyme to synthesize arginine which made them sensitive to arginine deprivation treatment. Whether these differences exist in vivo is not known. Overall, our data indicate that the expression of procollagen and its secretory pathway can be used as a new paradigm to treat primary brain tumor through ER stress-mediated cell death. Citation Format: Min You, Shu-Mei Chen, Chunjing Wu, Ying-Ying Li, Lynn Feun, Medhi Wangpaithitr, Vy Dinh, Niramol Savaraj. Targeting procollagen secretory pathway for the treatment of primary brain tumor through ER stress. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4052. doi:10.1158/1538-7445.AM2013-4052

Rehabilitation outcome in children after treatment of primary brain tumor

Despite aggressive multimodal strategies, the prognosis in patients affected by primary brain tumors is still very unfavorable. Glial tumors seem to be able to create a favorable environment for the invasion of neoplastic cells into the cerebral parenchyma when they interact with the extracellular matrix via cell surface receptors. The major problem in drug delivery into the brain is due to the presence of the blood brain barrier which limits drug penetration. Nanotechnology involves the design, synthesis and characterization of materials that have a functional organization at least in one dimension on the nanometer scale. Nanoengineered devices in medical applications are designed to interface and interact with cells and tissues at the molecular level. Nanoparticle systems can represent ideal devices for delivery of specific compounds to brain tumors, across the blood brain barrier. In this brief review, we report the results of studies related to the emerging novel applications of nanoparticle systems in diagnosis and treatment of primary brain tumors, and also the patents of studies that adopt nanoparticle systems as drug delivery carriers in brain tumor diagnosis and therapy.

Objective: Recent advances in treatment of primary brain tumors have increased the interest in radiological imaging in respect to both the diagnosis of tumor and the evaluation of the efficiency of therapy. Conventional Magnetic Resonance (MR) imaging is commonly used for diagnosis and follows up of the primary brain tumors, but it fails in grading of the tumors. MR spectroscopy permits in-vivo biochemical evaluation of brain lesions. Methods: Twenty three patients with histopathologic diagnosis of primary brain tumor and control group consisting of 23 healthy volunteers were investigated. In addition to conventional MR imaging of all patients were underwent point resolved spectroscopy (PRESS) sequence via single voxel MR spectroscopy. Using MR spectroscopy, metabolites [N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI), lipid, lactate and alanine] and their ratio to creatine (Cr) were measured quantitatively. Results: MR spectroscopic imaging of neuroglial primary brain tumors revealed that the NAA/Cr and mI/Cr ratios were decreased. In extra axial primary brain tumors, which consist of meningioma, NAA wasn’t detected, Cho/Cr ratio was remarkably increased, mI/Cr, lipid/Cr and lactate/Cr ratios were mildly increased. Alanine peak was detected only in meningioma. In high grade neuroglial tumors in proportion to low grade ones NAA/Cr and mI/Cr ratios were decreased, Cho/Cr, lipid/Cr and lactate/Cr ratios were remarkably increased. Conclusion: MR spectroscopy provides extra information in classification of primary brain tumors as intra-axial and extra-axial, and in grading of neuroglial primary brain tumors as high grade or low grade. It was concluded that using conventional MR imaging in cooperation with MR spectroscopy is beneficial in differential diagnosis and in grading of primary brain tumors.

Treatment and resolution of primary and metastatic brain tumors have long presented a challenge to oncologists. In response to the dismal survival outcomes associated with conventional therapies, various immunotherapy modalities, such as checkpoint inhibitors, vaccine, cellular immunotherapy and viral immunotherapy have been actively explored over the past couple of decades. Although improved patient survival has been more frequently noted in treatment of brain metastases, little progress has been made in improving patient survival in cases of primary brain tumors, specifically glioblastoma, which is the representative primary brain tumor discussed in this review. Herein, we will first overview the findings of recent clinical studies for treatment of primary and metastatic brain tumors with immunotherapeutic interventions. The clinical efficacy of these immunotherapies will be discussed in the context of their ability or inability to overcome inherent characteristics of the tumor as well as restricted antigen presentation and its immunosuppressive microenvironment. Additionally, this review aims to briefly inform clinicians in the field of neuro-oncology on the relevant aspects of the immune system as it pertains to the central nervous system, with special focus on the differing modes of antigen presentation and tumor microenvironment of primary and metastatic brain tumors and the role these differences may play in the efficacy of immunotherapy in eradicating the tumor.

Alan Baker, MD, Chief Resident in Surgery, Peter Bent Brigham Hospital: Our discussion this morning is on the recent advances and treatment of primary brain tumors. As you all know, the treatment of these lesions was initiated in this hospital by Harvey Cushing, our first chief of surgery, some 60 years ago. We are very pleased to be able to update this work with a case presentation followed by discussion by several knowledgeable participants. I would like first to introduce John Walsh, who will moderate this session. Dr. Walsh: The Department of Neurosurgery would like to present data and comments about some of the more recent concepts in advances of the treatment of primary brain tumors. Keasley Welch will talk about the natural history of malignant brain tumors; Robert Cassady will then discuss radiotherapy; Emil Frei, chemotherapy; and Paul Kornblith, immunologic aspects. To start, we will describe a patient. A

Gliomas, defined as tumors of glial origin, represent between 2-5 percent of all adult cancer and comprise the majority of primary brain tumors. Infiltrating gliomas, with an incidence of more than 40 percent of brain tumors, are the most common and destructive primary brain tumors for which conventional therapies have not significantly improved patient outcome. In fact, patients suffering from malignant gliomas have poor prognoses and the majority have local tumor recurrence after treatment. Tumor growth and spread of tumor cells depend basically upon angiogenesis and on functional abnormalities of tumor cells in the control of apoptosis, as they are paradigmatic for their intrinsic resistance to multiple pro-apoptotic stimuli. Therefore, promising strategies for treatment of brain cancer would be directed to appropriate neutralization of angiogenesis and sensibilization of cancer cells to undergo apoptosis. However, despite advances in this field, high-grade gliomas remain incurable with survival often measured in months. Therefore there is a need to discover new and more potent cocktails of drugs to target the key molecular pathways involved in glioma angiogenesis and apoptosis. This review deals with the effects of two groups of molecules closely linked to neural tissue, which have been implicated in brain cancer: nitric oxide and peptides of the adrenomedullin family. These molecules exert vasodilatory and proangiogenic actions. Adrenomedullin also has antiapoptotic functions at appropriate concentrations. The inhibition of these functions, in the case of cancer, may provide new pharmacological strategies in the treatment of this disease.