Choroid Plexus Tumors. Atypical Teratoid Rhabdoid Tumors. Molecular Pathology of Nervous System Tumors. Molecular Genetic Pathology of Meningiomas. Du kanske gillar. Lifespan David Sinclair Inbunden. Spara som favorit. Skickas inom vardagar. Refinements in DNA technology, including next-generation sequencing, have revealed that each medulloblastoma subgroup is associated with specific somatic copy number aberrations that result in characteristic focal gene amplifications oncogenic drivers or deletions resulting in possible loss of tumor suppressor genes that cause deregulation of key signaling receptor tyrosine kinase pathways, histone modifiers histone methyl transferases, methylases, acetylases, and deacetylases , and chromatin-associated genes.
Molecular Pathology of Nervous System Tumors : Matthias A. Karajannis :
The genome of the WNT tumors is relatively stable compared with that of the other groups. Further work is also necessary to understand the reasons why patients with this tumor subtype fare significantly better than other groups. Prospective clinical trials are evaluating reductions in cytotoxic therapy for patients with WNT medulloblastoma to minimize long-term organ damage while still maintaining excellent survival. SHH medulloblastoma is a fairly heterogeneous tumor in terms of clinical and biologic features. Using unsupervised hierarchical clustering of a cohort of 33 SHH tumor samples, Northcott et al have recently shown that adult and pediatric tumors segregate into three fairly equal clusters, with the infants and children groups 1 and 3 clearly separating from adults group 2.
Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct, volume , , page , Northcott PA, Hielscher T, Dubuc A, et al, table 3.
Inhibitors of the SHH pathway, particularly at the level of SMO, have been developed and are being tested in the clinic. While immunohistochemical expression of natriuretic peptide receptor 3 NPR3 antigen has been reported to confirm this subgroup, others have questioned the validity of this marker and it should not be used for clinical purposes until further validation in prospective cohorts of newly diagnosed patients.
These tumors had all the pathologic and molecular characteristics of group 3 medulloblastoma. The preclinical mouse models described above could be used to screen for new agents that are likely to provide benefit in patients with this aggressive malignancy, that does not seem to respond to conventional cytotoxic therapy.
Group 4 tumors can present at any age, although it is rare in infants. While immunohistochemical expression for potassium voltage-gated channel subfamily A member 1 KCNA has been reported to identify this subgroup, others have questioned the validity of this marker and this test should not be used for clinical purposes until further validation in prospective cohorts of newly diagnosed patients. Most female group 4 medulloblastoma tumors lose one copy of the X chromosome, which raises the possibility of the existence of one or more tumor suppressor genes on the X chromosome.
These mutations, along with overexpression of enhancer of zeste homolog 2, keep neural stem cells in an undifferentiated state and might be sustaining tumorigenesis. There is no specific preclinical mouse model that fully recapitulates the human group 4 medulloblastoma, although one has been described that expresses MycN and luciferase under the control of a brain-specific promoter and develops either SHH or non-SHH medulloblastoma depending on the time of tumor initiation.
Children with group 4 medulloblastoma have an intermediate prognosis with conventional cytotoxic therapy, although adult patients with the same tumors have a worse outcome. Since the first seminal publication describing the molecular variants of medulloblastoma using gene expression profiling and transcriptome analysis, 28 there has been a veritable explosion of data in this field, adding new discoveries of novel mutations and copy number aberrations almost on a daily basis and reflecting the incredible complexity of this aggressive tumor.
The emerging data suggest that medulloblastoma is possibly a mixture of different disease entities with different molecular underpinnings and underlying cell or region of origin. While these are exciting times for laboratory scientists and clinicians with the identification of several tumor targets that provides avenues for improving therapeutic efficacy, the plight of the clinical neuro-oncologist and caregivers of patients with medulloblastoma is obvious and justified when faced with this bewildering array of molecular data. One clear consensus to emerge from the recent molecular studies is the reduction of cytotoxic therapy for patients with tumors carrying the WNT signature that seem to have an excellent prognosis with standard cytotoxic therapy.
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Faced with multiple complex signaling pathways and mutated targets, it is not clear, at any given time in the disease course, which of the identified markers within each group are currently oncogenic drivers and which ones are either just passenger mutations or those that were responsible for tumor initiation but are no longer actively contributing to disease progression. While druggable targets abound within the tumor, very few targeted therapies are currently available, much less validated in clinical practice, except for SMO antagonists for SHH tumors.
Also, it is clear that no single agent is going to be effective for a sustained period of time, and combination therapy is probably the best strategy to overcome either de novo or acquired resistance to treatment. It is also unknown if potential agents would be more effective and should be used at the time of diagnosis during a period of treatment-naive minimal residual disease in combination with standard cytotoxic therapy rather than at the time of relapse following multiple treatment regimens and when a tumor potentially becomes more aggressive and drug-resistant.
It is of some relief that emerging data with the use of paired samples from the time of diagnosis and the time of relapse seem to suggest that the molecular group at diagnosis is maintained at relapse and patterns of relapse are group-specific. Finally, there is justifiable concern regarding the possible toxicities, especially in growing children, with the use of therapies that are potentially targeting pathways present in both the tumor and normal tissue eg, the effect of SHH inhibition on growing bone 57 and normal neural stem cells that are sustained by this pathway 58 and should be used with caution in children with appropriate tools to monitor such toxicities.
Challenging issues in pediatric oncology. Nat Rev Clin Oncol. Cancer statistics, CA Cancer J Clin. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma St Jude Medulloblastoma : long-term results from a prospective, multicentre trial.
Lancet Oncol. Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma. Neuro Oncol. Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol. Medulloblastoma comprises four distinct molecular variants.
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Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. Medulloblastoma: clinical and biologic aspects. Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Congenital anomalies and genetic syndromes in cases of medulloblastoma. Med Pediatr Oncol. The WHO classification of tumours of the central nervous system. Brain Pathol. However, GBM would ultimately escape from cabozanitib by diffuse infiltration and blood-brain barrier BBB restoration.
Thus, cabozanitib delivery was limited . Further trials of cabozanitib are encouraged based on the promising results but not ignoring potential shortcomings of this drug. Integrins are a large family of cell surface adhesion molecules, which mediates the adhesion between cells and cell-extracellular matrix. Recently, they have also been identified as an important factor for glioma-associated angiogenesis. Apparent significant activity of cilengitide plus standard of care was also seen in a randomized phase II study, demonstrating median survival of 30 and Additionally, high-dose cilengitide seemed to have more benefits .
Promising results in these trials resulted in a broader interest in cilengitide for glioma therapy. However, no significant improved median OS was found in a recent study evaluating cilengitide combined with standard treatment for patients with newly diagnosed GBM with a methylated MGMT promoter. The cilengitide-treated group had a median OS of Moreover, a case report suggested that cilengitide had significant antitumor activity in treating bevacizumab-refractory high-grade glioma .
This finding might be due to the upregulated integrin signaling in bevacizumab-treated glioma. Further clinical trials could evaluate the antitumor effect of combined VEGF and integrins in glioma patients, especially for those where bevacizumab was ineffective. Moreover, it plays an important role in inhibiting basic fibroblast growth factor and VEGF-mediated angiogenesis  , . However, a few phase II trials of thalidomide observed negative results in either monotherapy or in combination with TMZ, procarbazine, or irinotecan in recurrent high-grade gliomas  ,  ,  , .
The genetically engineered mouse models have definitively implicated this combination . Specific targeting of these signaling pathways is therefore a rational treatment strategy for molecular therapy of glioma. However, the p53 and RB pathways are difficult to target. In contrast, targeting gain-of-function molecules is relatively easier.
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Molecular targets in glioma cells A and glioma-associated endothelial cells B and designed intervention in molecular targeted therapies for malignant glioma. Growth factor receptors, glioma-associated transmembrane proteins, and their downstream intracellular signaling pathways are commonly altered in glioma and have been implicated in gliomagenesis.
Several molecules of them have been explored as the targets to inhibit glioma growth and angiogenesis. Growth factor receptors are critical regulatory proteins in signaling networks of malignant glioma. Another phase II monotherapy trial in patients with recurrent high-grade gliomas demonstrated limited activity of cetuximab PFS-6 of 9.
In short, cetuximab monotherapy has not yet been demonstrated to have clinical benefits, while the outcome of glioma patients treated with cetuximab seems to be associated with EGFRvIII but not amplification alone. Furthermore, addition of gefitinib to radiation demonstrated little improvement compared with radiotherapy alone in terms of median survival in patients with newly diagnosed GBM .
Lapatinib suffered the same fate as erlotinib . Nimotuzumab has the advantage of preferentially binding to areas with a high density of EGFR .
A randomly controlled trial revealed that nimotuzumab had better activity than radiotherapy and chemotherapy alone, as improved treatment efficacy and prolonged survival were observed in malignant glioma patients with nimotuzumab [median OS: A 5-year institutional experience also demonstrated evident clinical benefit in children with high-grade glioma treated by regimens containing prolonged administration of nimotuzumab median OS: In combination, nimotuzumab shows a potential antiglioma activity, which may be worth further investigation. These agents mentioned previously mainly target wild-type EGFR.
Several preclinical studies demonstrated antiglioma activities of L8A4, mAb, and AG in glioma cells and models  ,  ,  , . AG can also enhance the antitumor efficacy of mAb and cytotoxic agents, which indicates the promising future of AG in combination with application prospects . Further testing is under way.