Searching On:

Disease:

Gene:

Colorectal Cancer, TRK 1,2,3, in-frame deletion

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 TRK 1,2,3  - General Description
CLICK IMAGE FOR MORE INFORMATION
The Tropomyosin receptor kinase (Trk) family has three members, Trk A, Trk B, and Trk C. They are encoded by three separate genes, NTRK1, NTRK2, and NTRK 3, respectively. Each has an external domain outside the cell membrane that can bind ligand, a transmembrane domain that traverses the cell membrane, and an intracellular domain that transmits the signal if ligand-binding occurs. The normal function of these tyrosine kinase cell surface receptors is on neuronal cells, where they have important roles in the development and activity of the nervous system.
TrkA, TrkB and TrkC are each activated by a different neurotrophin (NT) ligand, and when stimulated by the appropriate NT ligand, multiple single receptors cluster together and phosphates are added to the intracellular domain of the receptors. This activates a specific signal cascade inside the cell, resulting in cell differentiation, cell survival, and/or cell proliferation. As can be seen in the graphic above, the TrkA receptor is activated by Nerve Growth Factor (NGF), the TrkB receptor is activated by Brain-Derived Growth Factor (BDNF) or NT4/5, and the TrkC receptor is activated by NT3.
In development under normal conditions, when the Trk receptor binds to its specific NT ligand, different signal pathways within the cell are activated (see graphic above). When TrkA binds NGF, the Ras/MAP kinase pathway is activated, along with PLC gamma and PI3K, which leads to cell proliferation. When TrkB binds BDNF, the Ras-ERK pathway is activated, as well as activating the PI3K and PLC gamma pathways, leading to neuronal cell differentiation and survival. When TrkC binds NT3, the PI3 and AKT pathways are activated, insuring cell survival. The regulation of each of these receptors is critical to normal neuronal development.
In cancer, Trk receptors are dysregulated due to one of several genetic alterations that prevent the normal regulation of the signals controlled by the receptors. The most clinically relevant genetic alteration that has been found in the Trk receptors in cancer is called a gene fusion, where a portion of the NTRK gene encoding the Trk receptor has broken from the rest of the gene, and has become attached to a portion of another gene. In the case of gene fusions with Trk receptors, the fusion Trk proteins no longer require their specific ligand to activate signal pathways within the cell, but instead are continually activated. They have lost their normal negative regulation, and send constant proliferation signals to the cell, promoting cancer growth and survival. Other genetic alterations in NTRK genes that have been found in cancers include mutations, in-frame deletions of the gene, and alternative splicing. Both in-frame deletions and alternative splicing result in a Trk receptor that is missing specific regions of the protein.
Many different NTRK gene fusions have been identified in tumors. Recently, drug companies have developed multiple Trk inhibitors as possible treatments for aberrant Trk proteins in cancer. Some of these Trk inhibitors are currently in clinical trials at MGH and at other cancer centers. Additional Trk inhibitors are also under development by pharmaceutical companies, and will soon be in patient clinical trials. More studies are needed to determine which Trk inhibitors are the most effective against specific NTRK genetic alterations in specific tumors.
Graphic was adapted from the article, NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. Authors: Alessio Amatu, Andrea Sartore-Bianchi, and Salvatore Siena. ESMO Open 2016:1e000023.
The Tropomyosin receptor kinase (Trk) family has three members, Trk A, Trk B, and Trk C. They are encoded by three separate genes, NTRK1, NTRK2, and NTRK 3, respectively. Each has an external domain outside the cell membrane that can bind ligand, a transmembrane domain that traverses the cell membrane, and an intracellular domain that transmits the signal if ligand-binding occurs. The normal function of these tyrosine kinase cell surface receptors is on neuronal cells, where they have important roles in the development and activity of the nervous system.
TrkA, TrkB and TrkC are each activated by a different neurotrophin (NT) ligand, and when stimulated by the appropriate NT ligand, multiple single receptors cluster together and phosphates are added to the intracellular domain of the receptors. This activates a specific signal cascade inside the cell, resulting in cell differentiation, cell survival, and/or cell proliferation. As can be seen in the graphic above, the TrkA receptor is activated by Nerve Growth Factor (NGF), the TrkB receptor is activated by Brain-Derived Growth Factor (BDNF) or NT4/5, and the TrkC receptor is activated by NT3.
In development under normal conditions, when the Trk receptor binds to its specific NT ligand, different signal pathways within the cell are activated (see graphic above). When TrkA binds NGF, the Ras/MAP kinase pathway is activated, along with PLC gamma and PI3K, which leads to cell proliferation. When TrkB binds BDNF, the Ras-ERK pathway is activated, as well as activating the PI3K and PLC gamma pathways, leading to neuronal cell differentiation and survival. When TrkC binds NT3, the PI3 and AKT pathways are activated, insuring cell survival. The regulation of each of these receptors is critical to normal neuronal development.
In cancer, Trk receptors are dysregulated due to one of several genetic alterations that prevent the normal regulation of the signals controlled by the receptors. The most clinically relevant genetic alteration that has been found in the Trk receptors in cancer is called a gene fusion, where a portion of the NTRK gene encoding the Trk receptor has broken from the rest of the gene, and has become attached to a portion of another gene. In the case of gene fusions with Trk receptors, the fusion Trk proteins no longer require their specific ligand to activate signal pathways within the cell, but instead are continually activated. They have lost their normal negative regulation, and send constant proliferation signals to the cell, promoting cancer growth and survival. Other genetic alterations in NTRK genes that have been found in cancers include mutations, in-frame deletions of the gene, and alternative splicing. Both in-frame deletions and alternative splicing result in a Trk receptor that is missing specific regions of the protein.
Many different NTRK gene fusions have been identified in tumors. Recently, drug companies have developed multiple Trk inhibitors as possible treatments for aberrant Trk proteins in cancer. Some of these Trk inhibitors are currently in clinical trials at MGH and at other cancer centers. Additional Trk inhibitors are also under development by pharmaceutical companies, and will soon be in patient clinical trials. More studies are needed to determine which Trk inhibitors are the most effective against specific NTRK genetic alterations in specific tumors.
Graphic was adapted from the article, NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. Authors: Alessio Amatu, Andrea Sartore-Bianchi, and Salvatore Siena. ESMO Open 2016:1e000023.
Expand Collapse in-frame deletion  in TRK 1,2,3
In-frame deletions are genetic alterations of genes that result in segments of the gene being missing. This results in the translation of an abnormal protein that is not correct structurally, and cannot be regulated normally in cells.
In-frame deletions are genetic alterations of genes that result in segments of the gene being missing. This results in the translation of an abnormal protein that is not correct structurally, and cannot be regulated normally in cells.

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, (M) - Mutation
Trial Status: Showing Results: 1-10 of 30 Per Page:
123Next »
Protocol # Title Location Status Match
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 DGM
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 DG
NCT02568267 Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) MGH Open DG
NCT02576431 Study of LOXO-101 in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE) Study of LOXO-101 in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE) 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
NCT02715284 A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors 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
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
Trial Status: Showing Results: 1-10 of 30 Per Page:
123Next »
Our Colorectal Cancer Team

Share with your Physican

Print information for your Physician.

Print information