Gastric/Esophageal, FGFR 1, 2, 3 and 4, All Genetic Alterations

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Expand Collapse Gastric/Esophageal  - General Description Cancers of the stomach and esophagus, can also collectively be referred to as gastroesophageal or esophagogastric cancer. Gastric cancer incidence varies throughout the world, with a higher frequency in some countries-perhaps due to different diets or other factors. Esophageal cancers are more common in men than in women. Both alcohol use and tobacco use are associated with a higher risk of developing gastric or esophageal cancer. According to the National Cancer Institute (NCI) data, 16,940 men and 15,690 women were projected to be diagnosed with gastric cancer in the United States in 2017.

Most cancers involving the esophagus or stomach are either squamous cell cancer (SCC) or adenocarcinoma. Gastric and esophageal cancers tend to develop slowly over many years in the inner mucosal layer of the stomach or esophagus. These early changes rarely cause symptoms, and therefore frequently go undetected. As esophageal and gastric cancers become more advanced, symptoms become more apparent. Once symptoms bring a patient to a doctor for medical attention, the diagnosis can be made. Thorough diagnostics are available at the MGH, initially involving an endoscopic biopsy, which is used to definitively diagnose the cancer by experienced Pathologists. Subsequent to a confirmed diagnosis, it is important to stage the cancer which includes in-depth pathology analysis, as well as a radiographic imaging procedure such as CT or PET scan. Often lymph nodes near the cancer are analysed to insure the cancer has not spread.

There has been a growing interest in the molecular features of esophageal and gastric cancers, as genetic alterations in these cancers have been identified in patients. Some genes that have been found to be involved in these two cancer types are mutations or amplification of the genes that encode HER2, MET or EGFR. Other genetic alterations have also been identified. Testing for these genetic alterations is performed in the genetics lab of the MGH, enabling physicians to utilize targeted therapies tailored for individual tumors. Treatment options for esophageal and gastric cancers are available at the MGH Cancer Center, as well as Clinical Trials testing new treatments for patients with this diagnosis.

Source: National Cancer Institute, 2018
Cancers of the stomach and esophagus, can also collectively be referred to as gastroesophageal or esophagogastric cancer. Gastric cancer incidence varies throughout the world, with a higher frequency in some countries-perhaps due to different diets or other factors. Esophageal cancers are more common in men than in women. Both alcohol use and tobacco use are associated with a higher risk of developing gastric or esophageal cancer. According to the National Cancer Institute (NCI) data, 16,940 men and 15,690 women were projected to be diagnosed with gastric cancer in the United States in 2017.

Most cancers involving the esophagus or stomach are either squamous cell cancer (SCC) or adenocarcinoma. Gastric and esophageal cancers tend to develop slowly over many years in the inner mucosal layer of the stomach or esophagus. These early changes rarely cause symptoms, and therefore frequently go undetected. As esophageal and gastric cancers become more advanced, symptoms become more apparent. Once symptoms bring a patient to a doctor for medical attention, the diagnosis can be made. Thorough diagnostics are available at the MGH, initially involving an endoscopic biopsy, which is used to definitively diagnose the cancer by experienced Pathologists. Subsequent to a confirmed diagnosis, it is important to stage the cancer which includes in-depth pathology analysis, as well as a radiographic imaging procedure such as CT or PET scan. Often lymph nodes near the cancer are analysed to insure the cancer has not spread.

There has been a growing interest in the molecular features of esophageal and gastric cancers, as genetic alterations in these cancers have been identified in patients. Some genes that have been found to be involved in these two cancer types are mutations or amplification of the genes that encode HER2, MET or EGFR. Other genetic alterations have also been identified. Testing for these genetic alterations is performed in the genetics lab of the MGH, enabling physicians to utilize targeted therapies tailored for individual tumors. Treatment options for esophageal and gastric cancers are available at the MGH Cancer Center, as well as Clinical Trials testing new treatments for patients with this diagnosis.

Source: National Cancer Institute, 2018
Cancers of the stomach and esophagus, can also collectively be referred to as gastroesophageal or esophagogastric cancer. Gastric cancer incidence varies throughout the world, with a higher frequency in some countries-perhaps due to different diets or other factors. Esophageal cancers are more common in men than in women. Both alcohol use and tobacco use are associated with a higher risk of developing gastric or esophageal cancer. According to the National Cancer Institute (NCI) data, 16,940 men and 15,690 women were projected to be diagnosed with gastric cancer in the United States in 2017.

Most cancers involving the esophagus or stomach are either squamous cell cancer (SCC) or adenocarcinoma. Gastric and esophageal cancers tend to develop slowly over many years in the inner mucosal layer of the stomach or esophagus. These early changes rarely cause symptoms, and therefore frequently go undetected. As esophageal and gastric cancers become more advanced, symptoms become more apparent. Once symptoms bring a patient to a doctor for medical attention, the diagnosis can be made. Thorough diagnostics are available at the MGH, initially involving an endoscopic biopsy, which is used to definitively diagnose the cancer by experienced Pathologists. Subsequent to a confirmed diagnosis, it is important to stage the cancer which includes in-depth pathology analysis, as well as a radiographic imaging procedure such as CT or PET scan. Often lymph nodes near the cancer are analysed to insure the cancer has not spread.

There has been a growing interest in the molecular features of esophageal and gastric cancers, as genetic alterations in these cancers have been identified in patients. Some genes that have been found to be involved in these two cancer types are mutations or amplification of the genes that encode HER2, MET or EGFR. Other genetic alterations have also been identified. Testing for these genetic alterations is performed in the genetics lab of the MGH, enabling physicians to utilize targeted therapies tailored for individual tumors. Treatment options for esophageal and gastric cancers are available at the MGH Cancer Center, as well as Clinical Trials testing new treatments for patients with this diagnosis.

Source: National Cancer Institute, 2018
Cancers of the stomach and esophagus, can also collectively be referred to as gastroesophageal or esophagogastric cancer. Gastric cancer incidence varies throughout the world, with a higher frequency in some countries-perhaps due to different diets or other factors. Esophageal cancers are more common in men than in women. Both alcohol use and tobacco use are associated with a higher risk of developing gastric or esophageal cancer. According to the National Cancer Institute (NCI) data, 16,940 men and 15,690 women were projected to be diagnosed with gastric cancer in the United States in 2017.

Most cancers involving the esophagus or stomach are either squamous cell cancer (SCC) or adenocarcinoma. Gastric and esophageal cancers tend to develop slowly over many years in the inner mucosal layer of the stomach or esophagus. These early changes rarely cause symptoms, and therefore frequently go undetected. As esophageal and gastric cancers become more advanced, symptoms become more apparent. Once symptoms bring a patient to a doctor for medical attention, the diagnosis can be made. Thorough diagnostics are available at the MGH, initially involving an endoscopic biopsy, which is used to definitively diagnose the cancer by experienced Pathologists. Subsequent to a confirmed diagnosis, it is important to stage the cancer which includes in-depth pathology analysis, as well as a radiographic imaging procedure such as CT or PET scan. Often lymph nodes near the cancer are analysed to insure the cancer has not spread.

There has been a growing interest in the molecular features of esophageal and gastric cancers, as genetic alterations in these cancers have been identified in patients. Some genes that have been found to be involved in these two cancer types are mutations or amplification of the genes that encode HER2, MET or EGFR. Other genetic alterations have also been identified. Testing for these genetic alterations is performed in the genetics lab of the MGH, enabling physicians to utilize targeted therapies tailored for individual tumors. Treatment options for esophageal and gastric cancers are available at the MGH Cancer Center, as well as Clinical Trials testing new treatments for patients with this diagnosis.

Source: National Cancer Institute, 2018
Expand Collapse FGFR 1, 2, 3 and 4  - General Description
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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 FGFR family members have been found in gastric and esophageal cancers. Amplification of FGFR1 has been found in some esophageal tumors. Either mutation or amplification of FGFR2 have also been found in different gastric tumors. Any of these alterations results in abnormal FGFR receptors, which, instead of being activated by the binding of specific growth factors (ligands), are constantly activated. The receptor activation sends constant grow and replicate signals to the cell, contributing to the development of cancer.

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 FGFR family members have been found in gastric and esophageal cancers. Amplification of FGFR1 has been found in some esophageal tumors. Either mutation or amplification of FGFR2 have also been found in different gastric tumors. Any of these alterations results in abnormal FGFR receptors, which, instead of being activated by the binding of specific growth factors (ligands), are constantly activated. The receptor activation sends constant grow and replicate signals to the cell, contributing to the development of cancer.

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.

PubMed ID's
27109926

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 24 Per Page:
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Protocol # Title Location Status Match
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NCT02908451 A Study of AbGn-107 in Patients With Gastric, Colorectal, or Pancreatic Cancer A Study of AbGn-107 in Patients With Gastric, Colorectal, or Pancreatic Cancer MGH Open D
NCT03013218 A Study of ALX148 in Patients With Advanced Solid Tumors and Lymphoma A Study of ALX148 in Patients With Advanced Solid Tumors and Lymphoma MGH Open D
NCT02880371 A Study of ARRY-382 in Combination With Pembrolizumab for the Treatment of Patients With Advanced Solid Tumors A Study of ARRY-382 in Combination With Pembrolizumab for the Treatment of Patients With Advanced Solid Tumors MGH Open D
NCT01325441 A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies MGH Open D
NCT02013154 A Study of DKN-01 in Combination With Paclitaxel or Pembrolizumab A Study of DKN-01 in Combination With Paclitaxel or Pembrolizumab MGH Open D
NCT02715531 A Study of the Safety and Efficacy of Atezolizumab Administered in Combination With Bevacizumab and/or Other Treatments in Participants With Solid Tumors A Study of the Safety and Efficacy of Atezolizumab Administered in Combination With Bevacizumab and/or Other Treatments in Participants With Solid Tumors MGH Open D
NCT02743494 An Investigational Immuno-therapy Study of Nivolumab or Placebo in Patients With Resected Esophageal or Gastroesophageal Junction Cancer An Investigational Immuno-therapy Study of Nivolumab or Placebo in Patients With Resected Esophageal or Gastroesophageal Junction Cancer MGH Open D
NCT02488759 An Investigational Immuno-therapy Study to Investigate the Safety and Effectiveness of Nivolumab, and Nivolumab Combination Therapy in Virus-associated Tumors An Investigational Immuno-therapy Study to Investigate the Safety and Effectiveness of Nivolumab, and Nivolumab Combination Therapy in Virus-associated Tumors MGH Open D
NCT02903914 Arginase Inhibitor INCB001158 as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors Arginase Inhibitor INCB001158 as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors MGH Open D
Trial Status: Showing Results: 1-10 of 24 Per Page:
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