Brain Tumors, SMO (Smoothened)

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Expand Collapse Brain Tumors  - General Description Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Expand Collapse SMO (Smoothened)  - General Description
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The Hedgehog (HH) signal pathway is involved in regulating cell differentiation during embryonic development, determination of cell polarity, and regulating cell proliferation and growth. The HH signal is received by cells through a cell surface receptor complex that is a combination of the patched (PTCH) surface transmembrane protein, and the smoothened (SMO) transmembrane receptor.
The signal is propagated from the cell surface by a protein called Glioma-Associated Oncogene homolog (GLI). Both SMO and GLI are transcription factors that bind to HH-responsive genes on the DNA in the nucleus.

As depicted in the left half of the figure above, in the absence of HH ligand, PTCH inhibits SMO, which results in GLI being held in the cytoplasm of the cell by the Suppressor of Fused (SUFU) protein. In the presence of an HH ligand, depicted in the right half of the figure above, PTCH no longer suppresses SMO, and a signal is transmitted that causes SUFU to release GLI, and GLI then accumulates in the nucleus of the cell. In the nucleus, it binds to and activates its target genes that are involved in proliferation and cell growth, such as Cyclin D1, Myc; target genes that are involved in apoptosis, such as Bcl-2; target genes that promote angiogenesis, called ANG 1 and ANG2; as well as other genes involved in stem cell self-renewal, and genes involved in the epithelial to mesenchymal (EMT) transition, all cancer-related processes. The HH signal pathway is complicated, and in addition to the direct effects described above and depicted in the figure above, the HH pathway is acted upon by other signal pathways in the cell, some of which have been found to be hyper-activated in some tumors.

Abnormal activation of the HH cellular signaling pathway has been found in multiple types of cancer, including basal cell carcinoma, brain tumors-including glioma and medulloblastoma, leukemia, as well as a subset of solid tumors such as breast, lung, pancreas and prostate cancers. Some cancers harbor mutations in PTCH, or SMO, or SUFU, such as those found in basal cell carcinomas and medulloblastomas. Recent studies have demonstrated activating mutations in 3-5% of meningiomas. Recently, a variant of GLI was discovered and found to be expressed at high levels in some glioblastomas and some breast cancers. This variant, called tGLI activates a distinct set of genes from its normal counterpart, and these genes promote cell migration, invasion, and angiogenesis. HH pathway activation can also occur in some tumors without the mutations described above, and in these cases is caused by HH ligand-dependent mechanisms involving an autocrine or paracrine feedback signaling loop, as has been found in some gliomas, pancreatic, colorectal, and metastatic prostate carcinomas. Clinical research is currently underway to target SMO or GLI in clinical trials. There are ongoing clinical trials of the SMO inhibitor vismodegib in meningiomas, as well as novel inhibitors of other members of the HH Pathway (for information, call Regina Silver at MGH, 617-643-1939). There is also a need for therapeutic agents to target tGLI, the variant of GLI recently discovered in some gliomas and some breast cancers. More research is needed to determine the best treatment for tumors harboring abnormal activation of the Hedgehog (HH) signal pathway.

Graphic adapted from Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors, Rimkus, TK, Carpenter, RL, Qasam, S, Chan, M, and Lo, HW; Cancers (Basel) 2016
The Hedgehog (HH) signal pathway is involved in regulating cell differentiation during embryonic development, determination of cell polarity, and regulating cell proliferation and growth. The HH signal is received by cells through a cell surface receptor complex that is a combination of the patched (PTCH) surface transmembrane protein, and the smoothened (SMO) transmembrane receptor.
The signal is propagated from the cell surface by a protein called Glioma-Associated Oncogene homolog (GLI). Both SMO and GLI are transcription factors that bind to HH-responsive genes on the DNA in the nucleus.

As depicted in the left half of the figure above, in the absence of HH ligand, PTCH inhibits SMO, which results in GLI being held in the cytoplasm of the cell by the Suppressor of Fused (SUFU) protein. In the presence of an HH ligand, depicted in the right half of the figure above, PTCH no longer suppresses SMO, and a signal is transmitted that causes SUFU to release GLI, and GLI then accumulates in the nucleus of the cell. In the nucleus, it binds to and activates its target genes that are involved in proliferation and cell growth, such as Cyclin D1, Myc; target genes that are involved in apoptosis, such as Bcl-2; target genes that promote angiogenesis, called ANG 1 and ANG2; as well as other genes involved in stem cell self-renewal, and genes involved in the epithelial to mesenchymal (EMT) transition, all cancer-related processes. The HH signal pathway is complicated, and in addition to the direct effects described above and depicted in the figure above, the HH pathway is acted upon by other signal pathways in the cell, some of which have been found to be hyper-activated in some tumors.

Abnormal activation of the HH cellular signaling pathway has been found in multiple types of cancer, including basal cell carcinoma, brain tumors-including glioma and medulloblastoma, leukemia, as well as a subset of solid tumors such as breast, lung, pancreas and prostate cancers. Some cancers harbor mutations in PTCH, or SMO, or SUFU, such as those found in basal cell carcinomas and medulloblastomas. Recent studies have demonstrated activating mutations in 3-5% of meningiomas. Recently, a variant of GLI was discovered and found to be expressed at high levels in some glioblastomas and some breast cancers. This variant, called tGLI activates a distinct set of genes from its normal counterpart, and these genes promote cell migration, invasion, and angiogenesis. HH pathway activation can also occur in some tumors without the mutations described above, and in these cases is caused by HH ligand-dependent mechanisms involving an autocrine or paracrine feedback signaling loop, as has been found in some gliomas, pancreatic, colorectal, and metastatic prostate carcinomas. Clinical research is currently underway to target SMO or GLI in clinical trials. There are ongoing clinical trials of the SMO inhibitor vismodegib in meningiomas, as well as novel inhibitors of other members of the HH Pathway (for information, call Regina Silver at MGH, 617-643-1939). There is also a need for therapeutic agents to target tGLI, the variant of GLI recently discovered in some gliomas and some breast cancers. More research is needed to determine the best treatment for tumors harboring abnormal activation of the Hedgehog (HH) signal pathway.

Graphic adapted from Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors, Rimkus, TK, Carpenter, RL, Qasam, S, Chan, M, and Lo, HW; Cancers (Basel) 2016
PubMed ID's
26891329, 2333466, 23348505
Expand Collapse SMO (Smoothened)  in Brain Tumors
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene
Trial Status: Showing Results: 1-10 of 15 Per Page:
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Protocol # Title Location Status Match
NCT02523014 A Study Looking at Targeted Therapy According to Tumor Markers for People With Meningiomas A Study Looking at Targeted Therapy According to Tumor Markers for People With Meningiomas MGH Open DG
NCT02335918 A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors MGH Open D
NCT02573324 A Study of ABT-414 in Subjects With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification A Study of ABT-414 in Subjects With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification MGH Open D
NCT02927340 A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions MGH Open D
NCT01987830 Bevacizumab w / Temozolomide PET & Vascular MRI For GBM Bevacizumab w / Temozolomide PET & Vascular MRI For GBM MGH Open D
NCT01295944 Carboplatin and Bevacizumab for Recurrent Ependymoma Carboplatin and Bevacizumab for Recurrent Ependymoma MGH Open D
NCT02764151 First in Patient Study for PF-06840003 in Malignant Gliomas First in Patient Study for PF-06840003 in Malignant Gliomas MGH Open D
NCT02525692 Oral ONC201 in Adult Recurrent Glioblastoma Oral ONC201 in Adult Recurrent Glioblastoma MGH Open D
NCT02709889 Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors MGH Open D
NCT01391143 Safety Study of MGA271 in Refractory Cancer Safety Study of MGA271 in Refractory Cancer MGH Open D
Trial Status: Showing Results: 1-10 of 15 Per Page:
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