Brain Tumors, FGFR 1, 2, 3 and 4, All Genetic Alterations

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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 FGFR 1, 2, 3 and 4  - General Description
CLICK IMAGE FOR MORE INFORMATION
Fibroblast growth factors (FGF’s) are ligands that bind to FGF cell surface receptors (FGFR’s) and activate them. Once activated, FGFR’s on normal cells transmit a growth signal inside the cell. This growth signal is transmitted via two important pathways inside cells; the RAS-dependent MAP kinase pathway, and a second signal pathway that involves PI3K and AKT. There are four different FGFR’s that make up a family of FGFR tyrosine kinase cell surface receptors, each having an extracellular domain that binds FGF ligands, a second domain that goes through the cell outer membrane, and a third domain that is inside the cell cytoplasm (see diagram above). FGFR signaling in normal cells stimulates proliferation, differentiation, embryonic development, cell migration, survival, angiogenesis (vascularization), and organogenesis (organ development).

Recently, FGFR genetic abnormalities have been found in several types of cancer. There are four FGFR family members, FGFR1, FGFR2, FGFR3, and FGFR4. Alterations in FGFR genes result in dysregulated FGF receptors and can promote cancer growth and metastasis. In a recent study of almost 5000 tumors, alterations in FGFR were found in 7% of of tumors. Among these tumors, alterations were identified in all 4 FGFR’s including FGFR1 (49%), FGFR2 (19%), FGFR3 (23%), and FGFR4 (7%). A small number of the tumors had genetic alterations in more than one type of FGFR. Clearly cancers have found a way to take advantage of FGF/FGFR signaling pathway in cells to cause uncontrolled growth leading to tumors.

While the FGFR genetic abnormalities may vary in frequency depending on the group of tumor types tested, there are clearly some patterns emerging in terms of which tumor types are likely to have specific kinds of genetic alterations in FGFR 1, 2, 3 or 4. Genetic alterations in the FGFR receptors can include point mutations, insertions/deletions, gene amplification, or translocations. The sensitivity of various gene alterations to FGFR inhibition is currently under investigation. Drugs targeting the FGF/FGFR pathway include small molecule tyrosine kinases inhibitors and ligand traps.

Several pharmaceutical companies have developed drugs that target and inhibit FGFR in tumors. Some of these are designed to target multiple members of the FGFR family. At MGH and other major cancer centers, clinical trials are available to patients whose tumors have been tested and found to have genetically altered FGFR. Treatment for these patients can be available on clinical studies testing these FGFR inhibitors, including FGFR inhibitors called TAS120 and Debio 1347. Other agents such as FGF401 and BLU554 are specific for inhibiting FGFR4 and are being tested in liver cancer. Contact the MGH Cancer Center to find out more about having genetic testing performed on a tumor, or for more information about these clinical trials.

Fibroblast growth factors (FGF’s) are ligands that bind to FGF cell surface receptors (FGFR’s) and activate them. Once activated, FGFR’s on normal cells transmit a growth signal inside the cell. This growth signal is transmitted via two important pathways inside cells; the RAS-dependent MAP kinase pathway, and a second signal pathway that involves PI3K and AKT. There are four different FGFR’s that make up a family of FGFR tyrosine kinase cell surface receptors, each having an extracellular domain that binds FGF ligands, a second domain that goes through the cell outer membrane, and a third domain that is inside the cell cytoplasm (see diagram above). FGFR signaling in normal cells stimulates proliferation, differentiation, embryonic development, cell migration, survival, angiogenesis (vascularization), and organogenesis (organ development).

Recently, FGFR genetic abnormalities have been found in several types of cancer. There are four FGFR family members, FGFR1, FGFR2, FGFR3, and FGFR4. Alterations in FGFR genes result in dysregulated FGF receptors and can promote cancer growth and metastasis. In a recent study of almost 5000 tumors, alterations in FGFR were found in 7% of of tumors. Among these tumors, alterations were identified in all 4 FGFR’s including FGFR1 (49%), FGFR2 (19%), FGFR3 (23%), and FGFR4 (7%). A small number of the tumors had genetic alterations in more than one type of FGFR. Clearly cancers have found a way to take advantage of FGF/FGFR signaling pathway in cells to cause uncontrolled growth leading to tumors.

While the FGFR genetic abnormalities may vary in frequency depending on the group of tumor types tested, there are clearly some patterns emerging in terms of which tumor types are likely to have specific kinds of genetic alterations in FGFR 1, 2, 3 or 4. Genetic alterations in the FGFR receptors can include point mutations, insertions/deletions, gene amplification, or translocations. The sensitivity of various gene alterations to FGFR inhibition is currently under investigation. Drugs targeting the FGF/FGFR pathway include small molecule tyrosine kinases inhibitors and ligand traps.

Several pharmaceutical companies have developed drugs that target and inhibit FGFR in tumors. Some of these are designed to target multiple members of the FGFR family. At MGH and other major cancer centers, clinical trials are available to patients whose tumors have been tested and found to have genetically altered FGFR. Treatment for these patients can be available on clinical studies testing these FGFR inhibitors, including FGFR inhibitors called TAS120 and Debio 1347. Other agents such as FGF401 and BLU554 are specific for inhibiting FGFR4 and are being tested in liver cancer. Contact the MGH Cancer Center to find out more about having genetic testing performed on a tumor, or for more information about these clinical trials.

PubMed ID's
9212826, 24265351
Expand Collapse All Genetic Alterations  in FGFR 1, 2, 3 and 4
As explained above, specific types of tumors are associated with different genetic alterations. These include mutations, where a single nucleotide change in the gene can confer an altered FGFR protein that cannot be regulated normally. A second type of genetic alteration in FGFR family members involves insertions or deletions. In this case, a portion of the FGFR is missing, or, a portion of some other gene has been inserted in the FGFR gene, altering its normal function and regulation. A third type of genetic alteration in FGFR is translocation, where a whole portion of the FGFR gene has broken away from the rest of the gene, and attached iteself to another gene. These fusion proteins have part of FGFR, and part of another protein, and do not behave normally. Genetic testing of tumors identifies each of these genetic changes in a tumor, indicating specific treatment options.
As explained above, specific types of tumors are associated with different genetic alterations. These include mutations, where a single nucleotide change in the gene can confer an altered FGFR protein that cannot be regulated normally. A second type of genetic alteration in FGFR family members involves insertions or deletions. In this case, a portion of the FGFR is missing, or, a portion of some other gene has been inserted in the FGFR gene, altering its normal function and regulation. A third type of genetic alteration in FGFR is translocation, where a whole portion of the FGFR gene has broken away from the rest of the gene, and attached iteself to another gene. These fusion proteins have part of FGFR, and part of another protein, and do not behave normally. Genetic testing of tumors identifies each of these genetic changes in a tumor, indicating specific treatment options.

Genetic alterations in different brain tumors have been found in FGFR family members. In rare cases, FGFR1 translocations have been found in glioblastoma multiforme. FGFR3 translocations have been identified in glioblastoma. FGF4 mutations have also been found in glioblastoma multiforme.

Testing for genetic alterations in FGFR can be performed at the MGH Cancer Center. Clinical trials for treatment with FGFR inhibitors are also underway at the MGH Cancer Center.

Source N. Hallinan et al., Cancer Treatment Reviews 46 (2016) 51-62.

Genetic alterations in different brain tumors have been found in FGFR family members. In rare cases, FGFR1 translocations have been found in glioblastoma multiforme. FGFR3 translocations have been identified in glioblastoma. FGF4 mutations have also been found in glioblastoma multiforme.

Testing for genetic alterations in FGFR can be performed at the MGH Cancer Center. Clinical trials for treatment with FGFR inhibitors are also underway at the MGH Cancer Center.

Source N. Hallinan et al., Cancer Treatment Reviews 46 (2016) 51-62.

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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
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
NCT01391143 Safety Study of MGA271 in Refractory Cancer Safety Study of MGA271 in Refractory Cancer MGH Open D
Trial Status: Showing Results: 1-10 of 15 Per Page:
12Next »
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