Some glioblastoma patients benefit from ‘ineffective’ treatment, researchers say


glioblastoma multiforme
Highly invasive human brain tumour cells derived from a biopsy in a young patient with glioblastoma multiforme. 

A subgroup of patients with a devastating brain tumor called glioblastoma multiforme benefited from treatment with a class of chemotherapy drugs that two previous large clinical trials indicated was ineffective against the disease, according to a study at the Stanford University School of Medicine.

Specifically, patients in the subgroup who were treated with chemotherapy drugs that block the growth of new blood vessels in the tumor lived an average of about one year longer than those who were given other classes of chemotherapy drugs, the researchers found.

The retrospective study emphasizes the importance of properly categorizing tumors with varied biology in order to best personalize treatment for each patient. Lumping all glioblastoma patients together as one group led to the flawed conclusion that no patients benefited from anti-angiogenesis treatments, the researchers said.

“Traditionally, glioblastoma patients are given this diagnosis based on the histology of their tumor, and then assigned a grade and a stage,” said Daniel Rubin, MD, associate professor of biomedical data science, of radiology and of medicine. “But this information is not always specific enough to clearly inform treatment. We’ve developed a new method of classifying glioblastomas by quantitatively analyzing the magnetic resonance imaging that is routinely performed during diagnosis.”

Rubin is the senior author of the study, which is published in Neuro-Oncology. Postdoctoral scholar Tiffany Ting Liu, PhD, is the lead author of the paper.

A deadly brain tumor

Glioblastoma is one of the most common, and most deadly, brain tumors. About 12,000 people in the United States are diagnosed each year. The median survival is about 15 months after diagnosis. Until recently, clinicians and patients pinned their hopes on a class of chemotherapy drugs called anti-angiogenic compounds that are meant to block the growth of new blood vessels into the tumor. Blocking this growth, they believed, should starve the tumors of oxygen and nutrients. However, two large, phase-3 clinical trials recently reported in The New England Journal of Medicine concluded that one such drug, bevacizumab, conferred no survival benefit on glioblastoma patients.

Liu, Rubin and their colleagues wondered if there might be a subgroup of glioblastoma patients that could still be helped by the treatment. They studied the medical records and diagnostic images of 69 glioblastoma patients who had been treated at a local medical center and 48 patients from a national database known as The Cancer Genome Atlas.

The researchers used specialized software to categorize each patient into one of two groups based on the degree of vascularization of the patients’ brain tumors. Those whose tumors were more highly vascularized—as determined by an imaging technique called perfusion MRI—were significantly more likely to benefit from treatment with anti-angiogenic therapies than those whose tumors were less well vascularized.

Differences in glioblastoma biology

Perfusion MRIs are routinely conducted as part of the diagnostic procedure for brain tumor patients. The researchers found that each of the 117 patients fell neatly into one of two clusters: 51 of the patients had tumors that were highly vascularized, and 66 had tumors that were not as well vascularized. Further investigation showed that the highly vascularized tumors also expressed more genes involved in blood vessel growth and in protecting cells from conditions of low oxygen called hypoxia than tumors of patients in the other group.

The researchers then looked to see what treatments the individual patients had received, and how they fared.

“The most exciting finding was that those members in the highly vascularized group who had received anti-angiogenic treatment lived significantly longer—on average more than a year more—than others in the same group who did not get anti-angiogenic therapy,” said Rubin. “And this analysis was performed using images that already exist as part of the diagnostic procedure for this disease. Our findings speak to the fact that the biology of glioblastoma can vary significantly among individuals, and that certain subgroups of patients may benefit from treatments that appear ineffective when screened across a large unselected mix of patients.”

Rubin and his colleagues hope their study will reignite the conversation about the use of anti-angiogenic therapies in glioblastoma, while also enhancing the understanding of the varied biology of the disease.

“This is a turning point,” said Rubin. “We believe we can identify those people who are likely to benefit from anti-angiogenic treatments, and also begin to think outside the box to identify other types of therapies for those who are unlikely to respond. This shows that subtyping cancers like glioblastoma can have a huge impact on how we treat disease.”

Glioblastoma and Other Malignant Gliomas


Importance  Glioblastomas and malignant gliomas are the most common primary malignant brain tumors, with an annual incidence of 5.26 per 100 000 population or 17 000 new diagnoses per year. These tumors are typically associated with a dismal prognosis and poor quality of life.

Objective  To review the clinical management of malignant gliomas, including genetic and environmental risk factors such as cell phones, diagnostic pitfalls, symptom management, specific antitumor therapy, and common complications.

Evidence Review  Search of PubMed references from January 2000 to May 2013 using the termsglioblastoma, glioma, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,anaplastic oligoastrocytoma, and brain neoplasm. Articles were also identified through searches of the authors’ own files. Evidence was graded using the American Heart Association classification system.

Findings  Only radiation exposure and certain genetic syndromes are well-defined risk factors for malignant glioma. The treatment of newly diagnosed glioblastoma is based on radiotherapy combined with temozolomide. This approach doubles the 2-year survival rate to 27%, but overall prognosis remains poor. Bevacizumab is an emerging treatment alternative that deserves further study. Grade III tumors have been less well studied, and clinical trials to establish standards of care are ongoing. Patients with malignant gliomas experience frequent clinical complications, including thromboembolic events, seizures, fluctuations in neurologic symptoms, and adverse effects from corticosteroids and chemotherapies that require proper management and prophylaxis.

Conclusions and Relevance  Glioblastoma remains a difficult cancer to treat, although therapeutic options have been improving. Optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment.

Recent Advances in Therapy for Glioblastoma


Glioblastoma is the most common primary malignant brain tumor in adults and is a challenging disease to treat. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide. Despite that, recurrence is quite common, and so we continue to search for more effective treatments both for initial therapy and at the time of recurrence. This article will review recent advances in therapy for glioblastoma, including surgery, radiotherapy, cytotoxic chemotherapies, molecularly targeted agents, and immunotherapy; the role of antiangiogenic agents in the treatment of glioblastoma is discussed in a separate article in this issue of the Archives.

Approximately 51 000 primary brain tumors are diagnosed in the United States each year, 36% of which are gliomas.1Of these, half are glioblastoma (GBM), or World Health Organization grade IV astrocytoma. Glioblastoma is the most aggressive form of glioma and, despite recent advances, continues to have a grim prognosis. The current standard of care for GBM begins with maximal safe surgical resection. After surgery, the combination of radiotherapy (RT) with temozolomide followed by adjuvant temozolomide therapy was shown to be significantly, although modestly, better than RT alone in a phase 3 clinical trial coordinated by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada.2Median overall survival in the chemoradiotherapy arm was 14.6 months compared with 12 months in the RT arm. Perhaps more importantly, however, the percentage of patients alive at 2 years increased from approximately 10% to approximately 26%.

A post hoc analysis of tumor tissue in a subset of patients in the phase 3 trial demonstrated that patients whose tumors have methylation of the promoter region of the methylguanine methyltransferase (MGMT) gene (GenBank 4255) survived longer than those whose tumors were not methylated and on average derived greater benefit from the addition of temozolomide to RT.3However, temozolomide provided modest benefit in the nonmethylated group, with borderline statistical significance. There is currently no proven alternative treatment for patients with nonmethylated tumors, so the combination of RT and temozolomide remains the treatment of choice for all patients with GBM at this time.

However, the median progression-free survival after RT with temozolomide and adjuvant temozolomide therapy is only 7 months, and a subset of patients’ tumors show inexorable growth despite combined chemoradiotherapy. Therefore, we continue to search for more effective treatments to treat this difficult disease. This article will review recent advances in the treatment of GBM.

ADVANCES IN SURGICAL TREATMENT

Prospective surgical trials are very difficult to design and implement and, as such, few have been attempted. One recent multicenter phase 3 study from Germany evaluated the utility of 5-aminolevulinic acid (a fluorescent label) to assist surgeons in achieving a radiographic gross total resection of the contrast-enhancing portion of GBM.4Only patients with ring-enhancing tumors that were believed to be potentially fully resectable were eligible to participate. All patients underwent maximal resection of tumor; they were randomized to the use of standard white light or fluorescence for intraoperative guidance. Use of 5-aminolevulinic acid allowed for a significantly higher rate of complete resection of enhancing disease on postoperative magnetic resonance imaging performed within 72 hours of surgery; gross total resection was achieved in 65% of patients in the treatment arm compared with 35% in the conventional surgery arm.

Further analysis of the data from this trial has demonstrated that patients who underwent gross total resection, regardless of the treatment arm, had superior survival to those who received subtotal resection.5Although prospective data specifically addressing the issue of surgical extent of resection have never been collected, it is fairly well accepted at this point that cytoreduction via maximal safe resection improves survival. It also appears that use of 5-aminolevulinic acid intraoperatively may help to maximize resection.

ADVANCES IN RT

The standard of care for RT for GBM is focal, fractionated external beam RT (EBRT), but new techniques and technologies continue to be evaluated. Although no prospective, randomized studies have compared the 2 techniques, intensity-modulated RT (IMRT) is becoming widely used and appears to be fairly comparable to more traditional 3-dimensional EBRT.6A number of dose-intensification techniques, such as brachytherapy, hyperfractionation, and the combination of EBRT with stereotactic radiation “boosts,” have been investigated, but none has been clearly shown to be superior to standard EBRT.

ADVANCES IN MEDICAL THERAPY

Treatment of GBM can be divided into 2 major situations: initial treatment and treatment at disease recurrence. New agents or treatment delivery techniques are typically tested first in the recurrent disease setting, where there are few approved treatment alternatives. Promising agents may then be combined with EBRT and temozolomide in the initial treatment setting because this is the established standard of care.

Alkylating Agents

Many GBMs have or develop resistance to alkylating chemotherapeutic agents such as temozolomide. One common mechanism of resistance is mediated by the enzyme encoded by the MGMTgene, O6-alkylguanine-DNA alkyltransferase. Methylation of the promoter region of the gene silences it, leading to greater sensitivity to temozolomide. One promising strategy for overcoming resistance is simply administering more frequent temozolomide doses in what are referred to as dose-dense or dose-intense schedules.7The Radiation Therapy Oncology Group has recently completed a phase 3 study randomizing patients between the standard 5-day regimen of temozolomide and a dose-intense 21-day monthly regimen of temozolomide after chemoradiotherapy; results are pending. Another strategy is direct enzyme inhibition using O6-benzylguanine, which has been studied in combination with temozolomide.8A second mechanism of resistance is mediated by the poly(adenosine diphosphate–ribose) polymerase (PARP) system; a number of PARP inhibitors have been developed and are being tested in early-phase clinical trials in combination with RT and temozolomide therapy.

Molecularly Targeted Agents

As we learn more about the biology of GBM and its aberrant signaling pathways, the neuro-oncology community has begun to investigate the role of molecularly targeted agents inhibiting these pathways (Figure). Most of the targeted agents are small-molecule tyrosine kinase inhibitors9or monoclonal antibodies. The signaling pathways targeted include tumor growth factor pathways, angiogenesis pathways, and the intracellular signaling pathways that lie downstream of both. The angiogenesis pathways and their associated antiangiogenic agents are covered separately in this issue of the Archives.10

Figure.

Selected growth factor pathways demonstrating targets for new molecular agents, with examples of agents currently under study. EGFR indicates epidermal growth factor receptor; GDP, guanosine diphosphate; Grb2, growth factor receptor-bound 2; GTP, guanosine triphosphate; HGF, hepatocyte growth factor; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; mTOR, mammalian target of rapamycin; P, phosphate group; PDGFR, platelet-derived growth factor receptor; PDK, phosphatidylinositol-dependent kinase; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol 4,5-bisphosphate, PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphate and tensin homologue; and TSC, tuberous sclerosis complex.

Image not available.

A wide variety of targeted agents are being studied in the preclinical setting and in clinical trials. The overall experience at this point has been that monotherapy at recurrence with highly targeted tyrosine kinase inhibitors of all types has shown limited efficacy. It remains an open question for many of these agents whether molecular selection of tumors with particular mutations in the pertinent pathway may optimize efficacy; results of this type of strategy thus far have been mixed. Overall survival in multiple recent single-arm studies combining targeted agents with EBRT and temozolomide for first-line treatment has been modestly superior relative to historical controls. Because results with highly targeted agents have been somewhat disappointing, there has been a move toward combined inhibition of multiple targets, shutting down proximal and distal targets within the same pathway or shutting down targets in separate, parallel pathways. This can be accomplished via a combination of multiple agents or via single agents that inhibit multiple kinases. The potential for greater efficacy by inhibiting multiple pathways is counterbalanced by the corresponding increase in the risk of toxic effects from systemic inhibition of these same pathways.

Epidermal Growth Factor.Epidermal growth factor (EGF) and its receptor, EGFR, have been implicated in the growth of a number of tumors, including GBM. Binding of the EGF ligand to the extracellular portion of the EGFR activates the intracellular tyrosine kinase domain, triggering a variety of signaling cascades. Abnormally increased EGFR signaling activity is frequent in GBMs; it can be the result of overexpression due to polysomy or amplification or the result of mutation (eg, the EGFRvIII mutant, seen in roughly 40% of GBMs, has a constitutively active tyrosine kinase domain owing to a deletion in the extracellular binding domain). Antibodies to EGFR such as cetuximab are currently under evaluation in early-phase clinical trials. The small-molecule EGFR inhibitor erlotinib hydrochloride has been more extensively evaluated as a single agent in recurrent disease and in combination with RT and temozolomide for initial treatment. Results have been disappointing in recurrent disease11and mixed in initial treatment, with one study suggesting mildly improved survival12but a second study failing to show improvement.13

Additional studies to evaluate EGFR inhibitors in combination with other agents are ongoing, as are prospective studies to evaluate subpopulations that may be more likely to derive benefit from this class of agents. Two retrospective studies have found a correlation between activity of the protein kinase B/AKT pathway and erlotinib response in tumors with overexpression of EGFR, although this has not been confirmed prospectively.14,15

Platelet-Derived Growth Factor.Platelet-derived growth factor (PDGF) and its receptor (PDGFR) are also commonly overactive in GBM, and, like activation of EGFR, activation of PDGFR triggers multiple intracellular signaling cascades. Imatinib mesylate is the best-known PDGFR inhibitor, although it also inhibits BCR-ABL and c-KIT. Phase 2 studies have evaluated imatinib in recurrent GBM as a single agent16and in combination with hydroxyurea,17but again, as with EGFR inhibitors, the results have been disappointing overall.

Hepatocyte Growth Factor/Scatter Factor.Hepatocyte growth factor (also known as scatter factor) binds to the c-MET receptor, activating intracellular signaling cascades similar to those triggered by EGFR and PDGFR; c-MET signaling is thought to be associated with invasion. In addition to stimulating c-MET, hepatocyte growth factor activates the EGF and vascular endothelial growth factor pathways. Multiple c-MET inhibitors are currently under evaluation; one, AMG102, is a human monoclonal antibody against hepatocyte growth factor that is currently in phase 2 study. Several small-molecule inhibitors are also currently under investigation.

Phosphoinositide-3 Kinase/AKT/Mammalian Target of Rapamycin Pathway.One of the intracellular second-messenger systems activated by EGFR, PDGFR, and the c-MET receptor is the phosphoinositide-3 kinase pathway, which leads to activation of AKT, also called protein kinase B, and then several targets further downstream, including the mammalian target of rapamycin. The major negative regulator of this pathway is the phosphate and tensin homologue (PTEN); there is frequently mutation of thePTENgene (GenBank 5728) or loss of heterozygosity of the chromosome on which the PTENgene resides in GBM, likely contributing to the overactivity of this pathway. Temsirolimus and everolimus are both inhibitors of the mammalian target of rapamycin, the best-studied of the targets in the phosphoinositide-3 kinase pathway. Temsirolimus as monotherapy was well tolerated but showed little efficacy in recurrent GBM18; combination studies with multiple other agents are ongoing. Perifosine is a direct AKT inhibitor and is also under evaluation in recurrent malignant glioma.

RAS/RAF/Mitogen-Activated Protein Kinase Kinase/Mitogen-Activated Protein Kinase Pathway.Another second-messenger system activated by EGFR and PDGFR begins with the RAS protein, which initiates a number of signaling cascades, including that of mitogen-activated protein kinase, which has been implicated in cell proliferation. Farnesyl transferase inhibitors inhibit the enzyme that activates RAS; the most extensively studied in GBM is tipifarnib (R115777), which was well tolerated with modest activity as a single agent19and is currently being studied in combination with several other agents.

Epigenetic Alterations.The importance of epigenetic alterations in tumors is being increasingly appreciated. For example, histone deacetylases, enzymes that play a role in the chromatin structure that organizes DNA and regulates gene transcription, are known to have a role in multiple cancers, including GBM. Vorinostat, a histone deacetylase inhibitor, has shown modest benefit as a single agent in GBM20and is currently being tested in combination regimens.

Methods for Local Drug Delivery

One of the major challenges of chemotherapy for GBM is the achievement of adequate drug concentration within the tumor itself. The blood-brain barrier, although often impaired in areas of bulky tumor, still acts as a barrier against many drugs, particularly in the periphery of the tumor, which is often highly infiltrative. Therefore, a variety of alternative delivery methods have been evaluated. One such method is the placement of drug-containing wafers. Carmustine (bischloroethylnitrosourea) is a nitrosourea compound, and carmustine-impregnated wafers (Gliadel wafers; MGI Pharma, Bloomington, Minnesota) have been placed into the surgical cavity after tumor resection, with modest efficacy.21The combination of carmustine-impregnated wafer placement with EBRT and temozolomide has not been formally studied, although it appears well tolerated.22

Convection-enhanced delivery is another strategy for local drug delivery. The technique involves the placement of several catheters into a surgical cavity immediately after resection; antineoplastic agents are then delivered through the catheters using convection, which improves distribution within the surrounding tissue where residual tumor cells persist. Early-phase studies using convection-enhanced delivery to deliver cintredekin besudotox (a recombinant protein combining portions of the interleukin 13 andPseudomonasexotoxin proteins) in patients with recurrent malignant gliomas have been promising,23although neither it nor any other agent administered via this technique has received approval yet.

ADVANCES IN IMMUNOTHERAPY

Immunotherapeutic treatment for glioma includes active and passive strategies. Active immunotherapy upregulates an immune response to tumor and can confer long-term immunity that potentially continues to provide protection against future tumor recurrence. Passive immunotherapy involves the transfer of immune effectors to achieve an immediate effect but does not generate long-term immunity.

Active Immunotherapy

A variety of strategies are being pursued to induce cytokine secretion directly within tumors because systemic exposure leads to excessive toxic effects. Techniques using direct cell transplants or genetically engineered viral vectors to induce cytokine production within GBM are currently undergoing preclinical evaluation.24Another area of active research is that of pattern recognition receptors and their agonists.25Double-stranded RNA (dsRNA), a nucleic acid variant normally associated with viruses, is one such agonist. A few clinical trials using poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose), a dsRNA moiety, have included patients with GBM and have been published, with mixed results.26,27

Tumor vaccines attempt to induce the immune system to generate a response against the tumor. One of the few known truly tumor-specific antigens is EGFRvIII. A peptide vaccine in which the sequence encompasses the mutated segment of EGFRvIII has demonstrated a cytotoxic response against gliomas in preclinical studies.28This vaccine, in combination with RT and temozolomide, is being studied in a phase 2/3 trial for patients with newly diagnosed tumors that contain the mutation in question. Several other promising tumor vaccine strategies are also being used in clinical trials.29

Dendritic cells are professional antigen-presenting cells that can be primed with tumor antigen ex vivo30and then readministered to the patient, where they mediate T-cell activation. Numerous preclinical studies demonstrate that dendritic cells pulsed with glioma antigens can prime a cytotoxic lymphocyte response that is tumor specific; phase 1 and 2 clinical trials have been completed using dendritic cell strategies, with encouraging results.31

Passive Immunotherapy

Antibody-mediated drug delivery is a strategy designed with the dual purpose of increasing the local drug concentration while minimizing nonspecific systemic exposure. Monoclonal antibodies targeting glioma-specific structures have been coupled to radionuclides (radioimmunoconjugates), exotoxins (immunotoxins), or chemotherapeutic agents and are administrated locally. Antigens that are overexpressed in tumors relative to normal tissue are typically used, such as mutant EGFR, tenascin, and interleukin 4 or interleukin 13 receptors.32

ADVANCES IN GENE THERAPY

Gene therapy is based on the insertion or modification of genes into a cell to treat a disease. Gene delivery can be accomplished using a variety of vectors, from viruses to cell-based systems to synthetic vectors. In gliomas, viral vectors have been used to deliver suicide genes, proapoptotic genes, p53, cytokines, and caspases.33Such studies have shown promising preclinical results, but clinical trials have been limited by the fact that transduced cells were found only within a very short distance of the delivery site. Synthetic vector research has focused on the use of nanoparticles. Liposomal vectors, for example, have been used to deliver therapeutic genes in the preclinical setting.

OTHER THERAPIES

In conclusion, the survival of patients with GBM continues to improve, albeit more slowly than we would like. A wide variety of new techniques and agents are currently under study, alone and in combination. Increased collective experience in their use and improved understanding of the complex biology of GBM may allow for more rational and effective therapy selection for patients, further extending survival in the years to come.

Immune Cells in the Brain Could be Enlisted to Fight Glioblastoma.


White blood cells called macrophages patrol almost every tissue of the body to gobble up bacteria, dead cells, and other waste. About ten percent of the cells in the brain are macrophages, also known as microglia. These cells have many important functions such as protecting against infections and repairing damaged nerve tissue but have also been shown to promote brain diseases including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.

Mouse glioblastoma tumor with phagocytic macrophages

Now a recent study led by Memorial Sloan-Kettering scientists reveals that macrophages can support the growth and progression of glioblastoma brain tumors – the commonest and most deadly form of primary brain cancer – and that it might be possible to control the disease by manipulating these cells with a drug. The research was done in mice and published in the October issue of the journal Nature Medicine.

“Tumors are often infiltrated by macrophages and can ‘hijack’ these cells to spur their own growth,” explains Johanna Joyce, a member of the Sloan-Kettering Institute’s Cancer Biology and Genetics Program and the senior author of the study. “Our findings suggest macrophages represent a potent therapeutic target in glioblastoma,” a disease that is exceptionally hard to treat with existing therapies.

Complex Tumors

Less than five percent of people with glioblastoma survive longer than five years after they are diagnosed even if they undergo intensive treatment with surgery, chemotherapy, or radiation. “There’s a crucial need for better strategies to control these aggressive tumors,” Dr. Joyce emphasizes.

So far scientists have had little success in developing targeted drugs against glioblastoma cells – drugs that home in on specific genetic mutations or biological pathways. “This is partly because glioblastoma tumors are very heterogeneous,” Dr. Joyce explains, referring to the fact that these tumors contain a highly diverse set of cancer cells with different genetic attributes.

In contrast, tumor-associated macrophages – which often make up as much as one third of the total tumor mass – tend to be more biologically uniform and could therefore be easier to target. Dr. Joyce and her colleagues looked at these cells in mouse models of a subtype of the disease called proneural glioblastoma. They noticed that the more advanced a tumor was, the more infiltrated by macrophages it tended to be.

“A similar pattern has been found when samples of tumor tissue from patients were analyzed,” Dr. Joyce says. “It seemed as if the tumor-infiltrating macrophages were helping the cancer advance.”

The investigators set out to test what would happen if the mouse proneural glioblastoma tumors were depleted of macrophages. They treated the mice with a drug that has been shown to eradicate macrophages in the brain and other organs. It works by inhibiting CSF-1R, a protein known to be essential for macrophage survival.

Surprise Findings

“There were a couple of surprises,” Dr. Joyce says. The first was how striking the drug’s effect was. It stopped newly formed tumors from progressing, caused more-established tumors to shrink, and made the mice live significantly longer.

The second surprise was no less positive, but initially confounding to the researchers. “We thought CSF-1R inhibition would wipe out the tumor-associated macrophages,” Dr. Joyce explains. “But when we looked at the tumors of mice who had been treated, the macrophages were still there” even though the drug had killed macrophages in the surrounding, normal brain tissue.

The researchers found that the macrophages residing in tumors had not succumbed to the drug because certain proteins secreted by the tumors were keeping them alive. But the therapy changed the macrophages’ behavior, blunting their tumor-promoting functions while making them more prone to elicit an anti-tumor response.

For example, these macrophages were induced to attack tumors by “eating” glioblastoma cells, a process known as phagocytosis.

“Our research suggests CSF-1R inhibition actually re-educates macrophages to attack tumor cells rather than support their growth,” Dr. Joyce says. “This is intriguing because if tumor-associated macrophages could be manipulated in the same way in the clinic – and be enlisted to actively fight a person’s cancer – this might ultimately be a more effective therapeutic strategy than to deplete the cells.”

Bringing Macrophage-Targeting Therapies to Patients

There could be several other advantages to developing glioblastoma drugs that act on macrophages and using these drugs in combination with existing therapies such as chemotherapy or radiation.

“Macrophages are genetically more stable than cancer cells, and therefore less likely to develop acquired drug resistance as glioblastoma cells often do,” Dr. Joyce explains. “In addition, we and other researchers have shown that targeting macrophages can increase the effectiveness of some chemotherapy drugs.”

CSF-1R inhibitors are currently being tested in early-stage clinical trials of glioblastoma patients and could be applicable in other diseases as well. “Studies have shown that in several cancer types, including breast, ovarian, thyroid, and pancreatic neuroendocrine tumors, increased numbers of tumor-associated macrophages correlate with poor patient prognosis, so it would be logical to test the drug in these diseases as well,” Dr. Joyce notes.

Source: MSKCC

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.


In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies.

Source: Journal Of Neurosurgery.

 

 

 

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.


In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies.

Source: Journal Of Neurosurgery.

 

 

Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis.


In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM’s unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapie.

Source: Journal of neurosurgery.

 

 

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