Searching On:

Disease:

Gene:

Colorectal Cancer, SMO (Smoothened)

View:
Expand Collapse Colorectal Cancer  - General Description A cancer that begins in the colon is often called colon cancer and a cancer that begins in the rectum is often called rectal cancer, but sometimes the term colorectal cancer is used for a cancer that begins in either place. This year about 132,700 people in the U.S. will be diagnosed with cancer of the colon or rectum. However, nearly 1.1 million remain alive today after having been diagnosed with colorectal cancer.

The colon and rectum are parts of the large intestine. In the colon, which accounts for most of the length of the large intestine, water and nutrients are extracted from partly-digested food before the food is turned into waste. The waste then enters the rectum before being pushed out of the body, leaving via the short anal canal and the anus (cancers also develop in the anus and anal canal, but they aren't classified as colorectal cancers). Most colon cancers and rectal cancers are adenocarcinomas, tumors that begin in gland-like cells lining the colon or rectum. Other types of cancerous tissues account for only 2% to 5% of colorectal cancers.

Colorectal cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the colon/rectal cancer cells cause secondary tumors to grow. The main sites to which colorectal cancer spreads are the liver, lungs and peritoneum. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist examines it to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include chest x-rays, MRI, CT scans and PET scans.

The FDA has approved several targeted therapies for treatment of patients with metastatic colorectal cancer. These include bevacizumab (Avastin), cetuximab (Erbitux), panitumumab (Vectibix) and ziv-afibercept (Zaltrap).

Despite significant improvements in the treatment of colorectal cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
The prognosis of patients with colon cancer is clearly related to the degree of tumor penetration through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor. This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most have not been prospectively validated (including allelic loss of chromosome 18q or thymidylate synthase expression). Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been associated with improved survival (independent of tumor stage) in a population-based series of 607 patients younger than 50 years of age with colorectal cancer. Treatment decisions generally depend on factors such as physician/patient preferences and the stage of the disease, rather than the age of the patient. Racial differences in overall survival after adjuvant therapy have been observed (although not in disease-free survival), suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Source: National Cancer Institute, 2012
A cancer that begins in the colon is often called colon cancer and a cancer that begins in the rectum is often called rectal cancer, but sometimes the term colorectal cancer is used for a cancer that begins in either place. This year about 132,700 people in the U.S. will be diagnosed with cancer of the colon or rectum. However, nearly 1.1 million remain alive today after having been diagnosed with colorectal cancer.

The colon and rectum are parts of the large intestine. In the colon, which accounts for most of the length of the large intestine, water and nutrients are extracted from partly-digested food before the food is turned into waste. The waste then enters the rectum before being pushed out of the body, leaving via the short anal canal and the anus (cancers also develop in the anus and anal canal, but they aren't classified as colorectal cancers). Most colon cancers and rectal cancers are adenocarcinomas, tumors that begin in gland-like cells lining the colon or rectum. Other types of cancerous tissues account for only 2% to 5% of colorectal cancers.

Colorectal cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the colon/rectal cancer cells cause secondary tumors to grow. The main sites to which colorectal cancer spreads are the liver, lungs and peritoneum. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist examines it to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include chest x-rays, MRI, CT scans and PET scans.

The FDA has approved several targeted therapies for treatment of patients with metastatic colorectal cancer. These include bevacizumab (Avastin), cetuximab (Erbitux), panitumumab (Vectibix) and ziv-afibercept (Zaltrap).

Despite significant improvements in the treatment of colorectal cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
The prognosis of patients with colon cancer is clearly related to the degree of tumor penetration through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor. This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most have not been prospectively validated (including allelic loss of chromosome 18q or thymidylate synthase expression). Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been associated with improved survival (independent of tumor stage) in a population-based series of 607 patients younger than 50 years of age with colorectal cancer. Treatment decisions generally depend on factors such as physician/patient preferences and the stage of the disease, rather than the age of the patient. Racial differences in overall survival after adjuvant therapy have been observed (although not in disease-free survival), suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Source: National Cancer Institute, 2012
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 SMO (Smoothened)  in Colorectal Cancer
Somatic mutations in APC are found in the vast majority of sporadic colorectal tumors, while germline mutations in APC are a causative genetic factor for familial adenomatous polyposis.

APC mutations do not significantly affect the prognosis of colorectal cancer patients.

While there are a number of small molecule inhibitors in development that target the Wnt pathway, there is currently no matched targeted therapy available for colorectal cancer patients harboring an APC mutation.

Somatic mutations in APC are found in the vast majority of sporadic colorectal tumors, while germline mutations in APC are a causative genetic factor for familial adenomatous polyposis.

APC mutations do not significantly affect the prognosis of colorectal cancer patients.

While there are a number of small molecule inhibitors in development that target the Wnt pathway, there is currently no matched targeted therapy available for colorectal cancer patients harboring an APC mutation.

PubMed ID's
20508156, 15843421, 1651174, 1651562, 1528264, 1338904
Expand Collapse No mutation selected
The mutation of a gene provides clinicians with a very detailed look at your cancer. Knowing this information could change the course of your care. To learn how you can find out more about genetic testing please visit http://www.massgeneral.org/cancer/news/faq.aspx or contact the Cancer Center.
Our Colorectal Cancer Team

Share with your Physican

Print information for your Physician.

Print information

Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene
Trial Status: Showing Results: 1-10 of 28 Per Page:
123Next »
Protocol # Title Location Status Match
NCT02279433 A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b MGH Open D
NCT02099058 A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors MGH Open D
NCT02327169 A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies MGH Open D
NCT02219724 A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors MGH Open D
NCT02365662 A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor MGH Open D
NCT01714739 A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors MGH Open D
NCT01633970 A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors MGH Open D
NCT02467361 A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers MGH Open D
NCT02228811 A Study of DCC-2701 in Participants With Advanced Solid Tumors A Study of DCC-2701 in Participants With Advanced Solid Tumors MGH Open D
NCT02082210 A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer MGH Open D
Trial Status: Showing Results: 1-10 of 28 Per Page:
123Next »
Our Colorectal Cancer Team

Share with your Physican

Print information for your Physician.

Print information