Combination therapy to checkmate Glioblastoma: clinical challenges and advances.
ABSTRACT: Combination therapy is increasingly becoming the cornerstone of current day antitumor therapy. Glioblastoma multiforme is an aggressive brain tumor with a dismal median survival post diagnosis and a high rate of disease recurrence. The poor prognosis can be attributed to unique treatment limitations, which include the infiltrative nature of tumor cells, failure of anti-glioma drugs to cross the blood-brain barrier, tumor heterogeneity and the highly metastatic and angiogenic nature of the tumor making cells resistant to chemotherapy. Combination therapy approach is being developed against glioblastoma with new innovative combination drug regimens being tested in preclinical and clinical trials. In this review, we discuss the pathophysiology of glioblastoma, diagnostic markers, therapeutic targeting strategies, current treatment limitations, novel combination therapies in the context of current treatment options and the ongoing clinical trials for glioblastoma therapy.
Project description:Treating adult low-grade gliomas (LGGs) is particularly challenging due to the highly infiltrative nature of this type of brain cancer. Although surgery, radiotherapy, and chemotherapy are the mainstay treatment modalities for LGGs, the optimal combination management plan for a particular patient based on individual symptoms and the risk of treatment-induced toxicity remains unclear. This review highlights the competency and limitations of standard treatment options while providing an essential therapeutic update regarding current clinical trials aimed at implementing targeted therapies with morbidity rates lower than those for current LGG treatments and also augmenting the killing of cancerous cells while maintaining an improved quality of life.
Project description:Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease.
Project description:Glioma accounts for the majority of human brain tumors. With prevailing treatment regimens, the patients have poor survival rates. In spite of current development in mainstream glioma therapy, a cure for glioma appears to be out of reach. The infiltrative nature of glioma and acquired resistance substancially restrict the therapeutic options. Better elucidation of the complicated pathobiology of glioma and proteogenomic characterization might eventually open novel avenues for the design of more sophisticated and effective combination regimens. This could be accomplished by individually tailoring progressive neuroimaging techniques, terminating DNA synthesis with prodrug-activating genes, silencing gliomagenesis genes (gene therapy), targeting miRNA oncogenic activity (miRNA-mRNA interaction), combining Hedgehog-Gli/Akt inhibitors with stem cell therapy, employing tumor lysates as antigen sources for efficient depletion of tumor-specific cancer stem cells by cytotoxic T lymphocytes (dendritic cell vaccination), adoptive transfer of chimeric antigen receptor-modified T cells, and combining immune checkpoint inhibitors with conventional therapeutic modalities. Thus, the present review captures the latest trends associated with the molecular mechanisms involved in glial tumorigenesis as well as the limitations of surgery, radiation and chemotherapy. In this article we also critically discuss the next generation molecular therapeutic strategies and their mechanisms for the successful treatment of glioma.
Project description:The current standard care of treatment for glioblastoma multiforme (GBM) is never curative and exclusively involves the use of cytoxics upfront (e.g., radiation and chemotherapy). Current clinical protocols involve the use of single-agent targeted therapies, which inhibit specific pathways. Given the functional redundancies present in human tumors and escape mechanisms, it is highly unlikely that such a monotherapy approach will be successful in the treatment of GBM. Future directions of therapy for GBMs will likely involve the use of therapeutic cocktails, including more than one target specific inhibitors based on tumor escape mechanism, genetic, epigenetic and molecular signatures. This review addresses some of the relevant issues.Correlative clinical studies from various clinical trials and preclinical studies have provided the meticulous use of chemotherapeutics and radiation based on molecular profiling of tumors. Alkylating agents such as temozolomide lose their efficacy if DNA repair enzyme expression is upregulated. The alternative strategies include targeting the enzyme or one can use poly (ADP) ribose inhibitor to inhibit base excision repair pathway rather than mismatch repair pathway. Currently, several inhibitors in this category are in clinical trials. Next, we have addressed new avenues including radiosensitizers, hypoxia, metabolism, angiogenesis, invasive and infiltrative nature of tumors and potential molecular targets, which can be exploited for clinical trials. Finally, we have included some aspect of genome-wide association studies and correlative analysis and the lessons learned to design better clinical trials.Advances in profiling the noncoding RNAs, genetic, epigenetic profiles, metabolomics, genomics and proteomics may uncover important resistance mechanisms in GBM. Personalized therapy using various therapeutic cocktails targeting these resistance mechanisms may prove even more effective in the future management of GBMs.
Project description:Glioblastoma is the most common adult primary brain tumor and carries a dismal prognosis. Radiation is a standard first-line therapy, typically deployed following maximal safe surgical debulking, when possible, in combination with cytotoxic chemotherapy. For other systemic cancers, standard of care is being transformed by immunotherapies, including checkpoint-blocking antibodies targeting CTLA-4 and PD-1/PD-L1, with potential for long-term remission. Ongoing studies are evaluating the role of immunotherapies for GBM. Despite dramatic responses in some cases, randomized trials to date have not met primary outcomes. Challenges have been attributed in part to the immunologically "cold" nature of glioblastoma relative to other malignancies successfully treated with immunotherapy. Radiation may serve as a mechanism to improve tumor immunogenicity. In this review, we critically evaluate current evidence regarding radiation as a synergistic facilitator of immunotherapies through modulation of both the innate and adaptive immune milieu. Although current preclinical data encourage efforts to harness synergistic biology between radiation and immunotherapy, several practical and scientific challenges remain. Moreover, insights from radiation biology may unveil additional novel opportunities to help mobilize immunity against GBM.
Project description:Despite aggressive treatment regimes, glioma remains a largely fatal disease. Current treatment limitations are attributed to the precarious locations within the brain where such tumors grow, their highly infiltrative nature precluding complete resection and lack of specificity among agents capable of attenuating their growth. Here, we show that in vitro, glioma cells of diverse origins internalize a peptide encompassing a tubulin-binding site (TBS) on the neurofilament light protein. The internalized peptide disrupts the microtubule network, inhibits migration and proliferation, and leads to apoptosis. Using an intracerebral transplant model, we show that most, if not all, of these responses to peptide exposure also occur in vivo. Notably, a single intratumor injection significantly attenuates tumor growth, while neither peptide uptake nor downstream consequences are observed elsewhere in the host nervous system. Such preferential uptake suggests that the peptide may have potential as a primary or supplementary glioblastoma treatment modality by exploiting its autonomous microtubule-disrupting activity or engaging its capacity to selectively target glioma cells with other cell-disrupting cargos.
Project description:Anti-angiogenic treatment of glioblastoma characteristically results in therapy resistance and tumor progression via diffuse infiltration. Monitoring tumor progression in these patients is thwarted because therapy results in tumor invisibility in contrast-enhanced (CE) MRI. To address this problem, we examined whether tumor progression could be monitored by metabolic mapping using (1)H MR spectroscopic imaging (MRSI).We treated groups of BALB/c nu/nu mice carrying different orthotopic diffuse-infiltrative glioblastoma xenografts with bevacizumab (anti-vascular endothelial growth factor [VEGF] antibody, n = 13), cabozantinib (combined VEGF receptor 2/c-Met tyrosine kinase inhibitor, n = 11), or placebo (n = 15) and compared CE-MRI with MRS-derived metabolic maps before, during, and after treatment. Metabolic maps and CE-MRIs were subsequently correlated to histology and immunohistochemistry.In vivo imaging of choline/n-acetyl aspartate ratios via multivoxel MRS is better able to evaluate response to therapy than CE-MRI. Lactate imaging revealed that diffuse infiltrative areas in glioblastoma xenografts did not present with excessive glycolysis. In contrast, glycolysis was observed in hypoxic areas in angiogenesis-dependent compact regions of glioma only, especially after anti-angiogenic treatment.Our data present MRSI as a powerful and feasible approach that is superior to CE-MRI and may provide handles for optimizing treatment of glioma. Furthermore, we show that glycolysis is more prominent in hypoxic areas than in areas of diffuse infiltrative growth. The Warburg hypothesis of persisting glycolysis in tumors under normoxic conditions may thus not be valid for diffuse glioma.
Project description:OPINION STATEMENT:At this time, there are no FDA-approved immune therapies for glioblastoma (GBM) despite many unique therapies currently in clinical trials. GBM is a highly immunosuppressive tumor and there are limitations to a safe immune response in the central nervous system. To date, there have been several failures of phase 3 immune therapy clinical trials in GBM. These trials have targeted single components of an antitumor immune response. Learning from these failures, the future of immunotherapy for GBM appears most hopeful for combination of immune therapies to overcome the profound immunosuppression of this disease. Understanding biomarkers for appropriate patient selection as well as tumor progression are necessary for implementation of immunotherapy for GBM.
Project description:The current therapy for glioblastoma multiforme involves total surgical resection followed by combination of radiation therapy and temozolomide. Unfortunately, the efficacy for such current therapy is limited, and newer approaches are sorely needed to treat this deadly disease. We have recently described the isolation of bacterial proteins and peptides with anticancer activity. In phase I human clinical trials, one such peptide, p28, derived from a bacterial protein azurin, showed partial and complete regression of tumors in several patients among 15 advanced-stage cancer patients with refractory metastatic tumors where the tumors were no longer responsive to current conventional drugs. An azurin-like protein called Laz derived from Neisseria meningitides demonstrates efficient entry and high cytotoxicity towards glioblastoma cells. Laz differs from azurin in having an additional 39-amino-acid peptide called an H.8 epitope, which allows entry and high cytotoxicity towards glioblastoma cells. Since p28 has been shown to have very little toxicity and high anti-tumor activity in advanced-stage cancer patients, it will be worthwhile to explore the use of H.8-p28, H.8-azurin, and Laz in toxicity studies and glioblastoma therapy in preclinical and human clinical trials.
Project description:Glioblastoma multiforme (GBM) is commonly known as the most aggressive primary CNS tumor in adults. The mean survival of it is 14 to 15 months, following the standard therapy from surgery, chemotherapy, to radiotherapy. Efforts in recent decades have brought many novel therapies to light, however, with limitations. In this paper, authors reviewed current treatments for GBM besides surgery. In the past decades, only radiotherapy, temozolomide (TMZ), and tumor treating field (TTF) were approved by FDA. Though promising in preclinical experiments, therapeutic effects of other novel treatments including BNCT, anti-angiogenic therapy, immunotherapy, epigenetic therapy, oncolytic virus therapy, and gene therapy are still either uncertain or discouraging in clinical results. In this review, we went through current clinical trials, underlying causes, and future therapy designs to present neurosurgeons and researchers a sketch of this field.