Colorectal Cancer, SMO (Smoothened), activating mutations

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Expand Collapse Colorectal Cancer  - General Description Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the Chromosomal Instability pathway (CIN), as well as MicroSatellite Instability pathway (MSI). These can also occur as spontaneous (uninherited) conditions in some patients. Between 6-10% of CRC's are found to have MSI. Some CRC tumors have been found to have a lot of mutations, or as physicians call it, a "very high mutational load". Some also express a ligand called PD-L1.

These are now recognized features of some CRC's, and immunological treatments may be recommended in these cases. MGH has one of the most extensive Immuno-oncology clinical trials portfolios of any US hospital. Testing for features such as CIN, MSI, a high mutational burden, and the expression of PD-L1 can be conducted at the MGH genetics laboratory, as well as at other large academic centers. Genetic instability such as CIN or MSI lead to the activation of oncogenes such as KRAS, and the inactivation of tumor suppressors such as PTEN, both of which promote tumor growth.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated abnormally, this prevents the production of tumor suppressor proteins important in controlling or stopping cell growth. When tumor suppressor genes are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, or loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; ALK, AKT, APC, beta-catenin, BRCA1 and BRCA2, BRAF, EGFR, ERBB2 (HER2), ERBB3 (HER3), IDH2, KRAS, MET, NRAS, PI3K, ROS, PTEN, SMO,TP53, TRK 1, 2 and 3, and others that are still being identified. Information on these specific genes is available on this website if you select the gene you want to know more about.

Distinct familial syndromes of CRC such as Lynch syndrome have been studied in patients, leading to the identification of other mechanisms contributing to the development of cancer. Before a cell can divide into two daughter cells, DNA has to be replicated so both daughter cells will have a full complement of chromosomes. DNA replication requires an enzyme called DNA Polymerase. DNA Polymerase occasionally makes errors while it is replicating DNA. Cells therefore have a "proof-reading" process that detects mistakes when they occur during DNA replication. DNA Polymerase mistakes mean that incorrect nucleotides have been incorporated into the DNA, causing mutations. Mistakes in the DNA sequence are repaired in a process called mismatch repair (MMR).
MMR involves a complex of multiple proteins. In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic (non-inherited) CRC. Defects in MMR also contribute to microsatellite instability (MIS), described above. The accumulation of these mutations can lead to cancer.

The importance of accurately replicating DNA following various types of mistakes or damage is reflected in the multiple pathways cells have for correcting or repairing broken DNA. Actual breaks in the DNA strands can happen due to exposure to radiation or other DNA damaging agents. In the case of the occurrence of breaks in DNA, there are also mechanisms for detecting these breaks. Double strand breaks (DSB's) in the DNA can be repaired via several mechanisms, including Non-Homologous End Joining (NHEJ) or Homologous Repair (HR). Many proteins are involved in DSB repair. Mutations in any of the many proteins involved in either of these repair pathways (see BRCA1 and BRCA2 genes) lead to damaged DNA, which results in DNA that is incorrectly replicated, causing mutations that contribute to the development of cancer. DNA repair machinery in the cell is important in keeping the genome stable and accurate.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC is available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments, Immune therpies, as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017

Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the Chromosomal Instability pathway (CIN), as well as MicroSatellite Instability pathway (MSI). These can also occur as spontaneous (uninherited) conditions in some patients. Between 6-10% of CRC's are found to have MSI. Some CRC tumors have been found to have a lot of mutations, or as physicians call it, a "very high mutational load". Some also express a ligand called PD-L1.

These are now recognized features of some CRC's, and immunological treatments may be recommended in these cases. MGH has one of the most extensive Immuno-oncology clinical trials portfolios of any US hospital. Testing for features such as CIN, MSI, a high mutational burden, and the expression of PD-L1 can be conducted at the MGH genetics laboratory, as well as at other large academic centers. Genetic instability such as CIN or MSI lead to the activation of oncogenes such as KRAS, and the inactivation of tumor suppressors such as PTEN, both of which promote tumor growth.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated abnormally, this prevents the production of tumor suppressor proteins important in controlling or stopping cell growth. When tumor suppressor genes are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, or loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; ALK, AKT, APC, beta-catenin, BRCA1 and BRCA2, BRAF, EGFR, ERBB2 (HER2), ERBB3 (HER3), IDH2, KRAS, MET, NRAS, PI3K, ROS, PTEN, SMO,TP53, TRK 1, 2 and 3, and others that are still being identified. Information on these specific genes is available on this website if you select the gene you want to know more about.

Distinct familial syndromes of CRC such as Lynch syndrome have been studied in patients, leading to the identification of other mechanisms contributing to the development of cancer. Before a cell can divide into two daughter cells, DNA has to be replicated so both daughter cells will have a full complement of chromosomes. DNA replication requires an enzyme called DNA Polymerase. DNA Polymerase occasionally makes errors while it is replicating DNA. Cells therefore have a "proof-reading" process that detects mistakes when they occur during DNA replication. DNA Polymerase mistakes mean that incorrect nucleotides have been incorporated into the DNA, causing mutations. Mistakes in the DNA sequence are repaired in a process called mismatch repair (MMR).
MMR involves a complex of multiple proteins. In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic (non-inherited) CRC. Defects in MMR also contribute to microsatellite instability (MIS), described above. The accumulation of these mutations can lead to cancer.

The importance of accurately replicating DNA following various types of mistakes or damage is reflected in the multiple pathways cells have for correcting or repairing broken DNA. Actual breaks in the DNA strands can happen due to exposure to radiation or other DNA damaging agents. In the case of the occurrence of breaks in DNA, there are also mechanisms for detecting these breaks. Double strand breaks (DSB's) in the DNA can be repaired via several mechanisms, including Non-Homologous End Joining (NHEJ) or Homologous Repair (HR). Many proteins are involved in DSB repair. Mutations in any of the many proteins involved in either of these repair pathways (see BRCA1 and BRCA2 genes) lead to damaged DNA, which results in DNA that is incorrectly replicated, causing mutations that contribute to the development of cancer. DNA repair machinery in the cell is important in keeping the genome stable and accurate.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC is available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments, Immune therpies, as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017

Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the Chromosomal Instability pathway (CIN), as well as MicroSatellite Instability pathway (MSI). These can also occur as spontaneous (uninherited) conditions in some patients. Between 6-10% of CRC's are found to have MSI. Some CRC tumors have been found to have a lot of mutations, or as physicians call it, a "very high mutational load". Some also express a ligand called PD-L1.

These are now recognized features of some CRC's, and immunological treatments may be recommended in these cases. MGH has one of the most extensive Immuno-oncology clinical trials portfolios of any US hospital. Testing for features such as CIN, MSI, a high mutational burden, and the expression of PD-L1 can be conducted at the MGH genetics laboratory, as well as at other large academic centers. Genetic instability such as CIN or MSI lead to the activation of oncogenes such as KRAS, and the inactivation of tumor suppressors such as PTEN, both of which promote tumor growth.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated abnormally, this prevents the production of tumor suppressor proteins important in controlling or stopping cell growth. When tumor suppressor genes are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, or loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; ALK, AKT, APC, beta-catenin, BRCA1 and BRCA2, BRAF, EGFR, ERBB2 (HER2), ERBB3 (HER3), IDH2, KRAS, MET, NRAS, PI3K, ROS, PTEN, SMO,TP53, TRK 1, 2 and 3, and others that are still being identified. Information on these specific genes is available on this website if you select the gene you want to know more about.

Distinct familial syndromes of CRC such as Lynch syndrome have been studied in patients, leading to the identification of other mechanisms contributing to the development of cancer. Before a cell can divide into two daughter cells, DNA has to be replicated so both daughter cells will have a full complement of chromosomes. DNA replication requires an enzyme called DNA Polymerase. DNA Polymerase occasionally makes errors while it is replicating DNA. Cells therefore have a "proof-reading" process that detects mistakes when they occur during DNA replication. DNA Polymerase mistakes mean that incorrect nucleotides have been incorporated into the DNA, causing mutations. Mistakes in the DNA sequence are repaired in a process called mismatch repair (MMR).
MMR involves a complex of multiple proteins. In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic (non-inherited) CRC. Defects in MMR also contribute to microsatellite instability (MIS), described above. The accumulation of these mutations can lead to cancer.

The importance of accurately replicating DNA following various types of mistakes or damage is reflected in the multiple pathways cells have for correcting or repairing broken DNA. Actual breaks in the DNA strands can happen due to exposure to radiation or other DNA damaging agents. In the case of the occurrence of breaks in DNA, there are also mechanisms for detecting these breaks. Double strand breaks (DSB's) in the DNA can be repaired via several mechanisms, including Non-Homologous End Joining (NHEJ) or Homologous Repair (HR). Many proteins are involved in DSB repair. Mutations in any of the many proteins involved in either of these repair pathways (see BRCA1 and BRCA2 genes) lead to damaged DNA, which results in DNA that is incorrectly replicated, causing mutations that contribute to the development of cancer. DNA repair machinery in the cell is important in keeping the genome stable and accurate.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC is available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments, Immune therpies, as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017

Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the Chromosomal Instability pathway (CIN), as well as MicroSatellite Instability pathway (MSI). These can also occur as spontaneous (uninherited) conditions in some patients. Between 6-10% of CRC's are found to have MSI. Some CRC tumors have been found to have a lot of mutations, or as physicians call it, a "very high mutational load". Some also express a ligand called PD-L1.

These are now recognized features of some CRC's, and immunological treatments may be recommended in these cases. MGH has one of the most extensive Immuno-oncology clinical trials portfolios of any US hospital. Testing for features such as CIN, MSI, a high mutational burden, and the expression of PD-L1 can be conducted at the MGH genetics laboratory, as well as at other large academic centers. Genetic instability such as CIN or MSI lead to the activation of oncogenes such as KRAS, and the inactivation of tumor suppressors such as PTEN, both of which promote tumor growth.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated abnormally, this prevents the production of tumor suppressor proteins important in controlling or stopping cell growth. When tumor suppressor genes are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, or loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; ALK, AKT, APC, beta-catenin, BRCA1 and BRCA2, BRAF, EGFR, ERBB2 (HER2), ERBB3 (HER3), IDH2, KRAS, MET, NRAS, PI3K, ROS, PTEN, SMO,TP53, TRK 1, 2 and 3, and others that are still being identified. Information on these specific genes is available on this website if you select the gene you want to know more about.

Distinct familial syndromes of CRC such as Lynch syndrome have been studied in patients, leading to the identification of other mechanisms contributing to the development of cancer. Before a cell can divide into two daughter cells, DNA has to be replicated so both daughter cells will have a full complement of chromosomes. DNA replication requires an enzyme called DNA Polymerase. DNA Polymerase occasionally makes errors while it is replicating DNA. Cells therefore have a "proof-reading" process that detects mistakes when they occur during DNA replication. DNA Polymerase mistakes mean that incorrect nucleotides have been incorporated into the DNA, causing mutations. Mistakes in the DNA sequence are repaired in a process called mismatch repair (MMR).
MMR involves a complex of multiple proteins. In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic (non-inherited) CRC. Defects in MMR also contribute to microsatellite instability (MIS), described above. The accumulation of these mutations can lead to cancer.

The importance of accurately replicating DNA following various types of mistakes or damage is reflected in the multiple pathways cells have for correcting or repairing broken DNA. Actual breaks in the DNA strands can happen due to exposure to radiation or other DNA damaging agents. In the case of the occurrence of breaks in DNA, there are also mechanisms for detecting these breaks. Double strand breaks (DSB's) in the DNA can be repaired via several mechanisms, including Non-Homologous End Joining (NHEJ) or Homologous Repair (HR). Many proteins are involved in DSB repair. Mutations in any of the many proteins involved in either of these repair pathways (see BRCA1 and BRCA2 genes) lead to damaged DNA, which results in DNA that is incorrectly replicated, causing mutations that contribute to the development of cancer. DNA repair machinery in the cell is important in keeping the genome stable and accurate.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC is available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments, Immune therpies, as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017

PubMed ID's
2188735, 23897299, 20965415
Expand Collapse SMO (Smoothened)  - General Description
CLICK IMAGE FOR MORE INFORMATION
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 activating mutations  in SMO (Smoothened)
Genetic alterations in the several of the genes in the Hedgehog (HH) signal pathway have been found in cancers. As described above, the pathway can be altered via several mechanisms. Some cancers have mutations in SMO, which is a transcription factor, and mutations can also occur in SMO's inhibitor protein, PTCH. Although complicated, the changes in the normal regulation of the HH signal pathway cause overexpression of genes that are tightly regulated in normal cells. The inability of cells to regulate the HH pathway contributes to the development of cancers.
Genetic alterations in the several of the genes in the Hedgehog (HH) signal pathway have been found in cancers. As described above, the pathway can be altered via several mechanisms. Some cancers have mutations in SMO, which is a transcription factor, and mutations can also occur in SMO's inhibitor protein, PTCH. Although complicated, the changes in the normal regulation of the HH signal pathway cause overexpression of genes that are tightly regulated in normal cells. The inability of cells to regulate the HH pathway contributes to the development of cancers.

Genetic alterations in the Smoothened (SMO) gene have been found in CRC. The SMO protein is a cell surface receptor involved in the Hedgehog (HH) signaling pathway in cells. As described above, tight regulation of the HH signaling pathway in cells is essential for preventing cancer.

Genetic alterations in the Smoothened (SMO) gene have been found in CRC. The SMO protein is a cell surface receptor involved in the Hedgehog (HH) signaling pathway in cells. As described above, tight regulation of the HH signaling pathway in cells is essential for preventing cancer.

PubMed ID's
20508156, 15843421, 1651174, 1651562, 1528264, 1338904
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Trial Status: Showing Results: 1-10 of 45 Per Page:
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