Brain Tumors, TRK 1,2,3, mutation

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Expand Collapse Brain Tumors  - General Description Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Data summarized by the CBTRUS (the Central Brain Tumor Registry of the United States) Statistical Report: Primary Brain and Central Nervous System Tumors diagnosed in the U.S. between 2008 and 2012 was analyzed and published in 2015. It includes malignant and non-malignant tumors in brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity. In the 2015 published report, the final number of all newly diagnosed tumors including all of the above was 356,858 in the U.S. between 2008 and 2012. The most commonly diagnosed CNS tumors are meningiomas (36.4% for this time period), followed by tumors of the pituitary (15.5% for this time period). Gliomas are tumors that arise from glial or precursor cells in the CNS, and include glioblastoma (15.1% for this time period), astrocytoma, oligodendroglioma, ependymoma, mixed glioma and malignant glioma, and a few other rare histologies. Of the 356,858 tumors included in the CBTRUS 2015 analysis, 239,835 (67.2%) were non-malignant tumors, while 117,023 of the CNS tumors for this time period were malignant.
Few definitive observations on environmental or occupational causes of primary Central Nervous System (CNS) tumors have been made. The following risk factors have been considered: Exposure to vinyl chloride may be a risk factor for glioma. Radiation exposure is a risk factor for meningioma. Epstein-Barr virus infection has been implicated in the etiology of primary CNS lymphoma. Transplant recipients and patients with the acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma.
Familial tumor syndromes and related chromosomal abnormalities that are associated with CNS neoplasms include the following: Neurofibromatosis type I (17q11), neurofibromatosis type II (22q12), von Hippel-Lindau disease (3p25-26), tuberous sclerosis complex (9q34, 16p13), Li-Fraumeni syndrome (17p13), Turcot syndrome type 1 (3p21, 7p22), Turcot syndrome type 2 (5q21), nevoid basal cell carcinoma syndrome (9q22.3) and multiple endocrine neoplasia type 1 (11q13).

Sources: National Cancer Institute, 2016
CBTRUS Statistical Report: Primary Brain and CNS Tumors Diagnosed in the US in 2008-2012; Neuro Oncol; 2015


Expand Collapse TRK 1,2,3  - General Description
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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 mutation  in TRK 1,2,3
Mutations in genes occur when there is a nucleotide that changes in the normal DNA sequence that encodes the gene. This genetic alteration results in a change in the amino acid sequence of the resulting protein, which can have a significant impact on the function or regulation of the protein.
Mutations in genes occur when there is a nucleotide that changes in the normal DNA sequence that encodes the gene. This genetic alteration results in a change in the amino acid sequence of the resulting protein, which can have a significant impact on the function or regulation of the protein.

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 15 Per Page:
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Protocol # Title Location Status Match
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
NCT02523014 A Study Looking at Targeted Therapy According to Tumor Markers for People With Meningiomas A Study Looking at Targeted Therapy According to Tumor Markers for People With Meningiomas MGH Open D
NCT02573324 A Study of ABT-414 in Subjects With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification A Study of ABT-414 in Subjects With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification MGH Open D
NCT02927340 A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions A Study of Lorlatinib in Advanced ALK and ROS1 Rearranged Lung Cancer With CNS Metastasis in the Absence of Measurable Extracranial Lesions MGH Open D
NCT01987830 Bevacizumab w / Temozolomide PET & Vascular MRI For GBM Bevacizumab w / Temozolomide PET & Vascular MRI For GBM MGH Open D
NCT01295944 Carboplatin and Bevacizumab for Recurrent Ependymoma Carboplatin and Bevacizumab for Recurrent Ependymoma MGH Open D
NCT02764151 First in Patient Study for PF-06840003 in Malignant Gliomas First in Patient Study for PF-06840003 in Malignant Gliomas MGH Open D
NCT02525692 Oral ONC201 in Adult Recurrent Glioblastoma Oral ONC201 in Adult Recurrent Glioblastoma MGH Open D
NCT02709889 Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors MGH Open D
Trial Status: Showing Results: 1-10 of 15 Per Page:
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