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SMO (Smoothened), W535L (trp535leu)

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Mass General Hospital Cancer Center treats patients with many cancer types. To learn more about the different cancer types that can be treated at the Cancer Center, please visit the Cancer Center website at the following page: http://www.massgeneral.org/cancer/services/
Expand Collapse SMO (Smoothened)  - General Description 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) 2016The 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
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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 W535L (trp535leu)  in SMO (Smoothened)
The W535L mutation in SMO results from a single nucleotide change that alters the amino acid sequence of the SMO protein. A tryptophan (trp) normally found at position 535 is replaced by a Leucine in the mutated form of the protein.
The W535L mutation in SMO results from a single nucleotide change that alters the amino acid sequence of the SMO protein. A tryptophan (trp) normally found at position 535 is replaced by a Leucine in the mutated form of the protein.

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Your Matched Clinical Trials

Trial Matches: (G) - Gene, (M) - Mutation
Trial Status: Showing all 1 result Per Page:
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 G
MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

Additional clinical trials may be applicable to your search criteria, but they may not be available at MGH. These clinical trials can typically be found by searching the clinicaltrials.gov website.
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