Colorectal Cancer, TRK 1,2,3

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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 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 TRK 1,2,3  in Colorectal Cancer
The Neurotrophic Tyrosine Kinase (NTRK) 1, 2 and 3 genes encode Tropomyosin receptor kinase (Trk) A, B and C respectively, which are normally found on the cell surface of neuronal cells. In a percentage of colorectal cancers (CRCs), chromosomal rearrangements have been found leading to expression of a Trk fusion protein. This fusion is made up of only part of the Trk protein that has undergone a genetic alteration, and as a result of that event has become joined to part of another protein. The TrkA fusions that have been observed in CRCs include LMNA-NTRK1 and TPM3-NTRK1, as well as some involving TrkC: ETV6-NTRK3. Other fusion proteins may be discovered in CRC tumors. Clinical trials are currently underway at MGH and other cancer centers testing new Trk inhibitor drugs in patients with CRC tumors harboring NTRK fusion proteins.

The Neurotrophic Tyrosine Kinase (NTRK) 1, 2 and 3 genes encode Tropomyosin receptor kinase (Trk) A, B and C respectively, which are normally found on the cell surface of neuronal cells. In a percentage of colorectal cancers (CRCs), chromosomal rearrangements have been found leading to expression of a Trk fusion protein. This fusion is made up of only part of the Trk protein that has undergone a genetic alteration, and as a result of that event has become joined to part of another protein. The TrkA fusions that have been observed in CRCs include LMNA-NTRK1 and TPM3-NTRK1, as well as some involving TrkC: ETV6-NTRK3. Other fusion proteins may be discovered in CRC tumors. Clinical trials are currently underway at MGH and other cancer centers testing new Trk inhibitor drugs in patients with CRC tumors harboring NTRK fusion proteins.

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.
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene
Trial Status: Showing Results: 1-10 of 41 Per Page:
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Protocol # Title Location Status Match
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 (Larotrectinib) in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE) Study of LOXO-101 (Larotrectinib) in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE) MGH Open DG
NCT03192345 A First-in-human Study of the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR439459 Monotherapy and Combination of SAR439459 and REGN2810 in Patients With Advanced Solid Tumors A First-in-human Study of the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR439459 Monotherapy and Combination of SAR439459 and REGN2810 in Patients With Advanced 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
NCT02817633 A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors A Phase 1 Study of TSR-022, an Anti-TIM-3 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
NCT03144804 A Phase 2 Study of Lamivudine in Patients With p53 Mutant Metastatic Colorectal Cancer A Phase 2 Study of Lamivudine in Patients With p53 Mutant Metastatic Colorectal Cancer MGH Open D
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