Gall Bladder and Bile Duct Cancers, IDH2

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Expand Collapse Gall Bladder and Bile Duct Cancers  - General Description Gallbladder cancer and bile duct cancer arise in specific areas of the biliary tract. As a group, they are fairly rare, accounting for only 3% of gastrointestinal malignancies. Standard therapy involving surgery and/or chemotherapy can be effective if the disease is detected early. However, recurrent or advanced disease has been challenging to treat.

There have been significant advances in our understanding of the underlying mechanisms of cancer development in biliary tract cancers, particularly those arising in the bile duct. Cholangiocarcinoma is the more common name for bile duct cancer and can occur either inside the liver (intrahepatic cholangiocarcinoma) or in the part of the bile duct that lies outside the liver (extrahapatic cholangiocarcinoma). The incidence of cholangiocarcinoma is rising worldwide, possibly due to an increasing incidence of hepatitis B and hepatitis C infection that can cause cirrhosis of the liver.

Ongoing research has identified new potential directions for targeted therapy in cholangiocarcinoma. Researchers at the MGH discovered a subset of patients with intrahepatic cholangiocarcinoma that have a mutation in a gene called IDH (isocitrate dehydrogenase). This mutation alters the normal activity of the enzyme encoded by this gene, with the resulting production of a new metabolite (2-hydroxyglutarate, or 2-HG). This 2-HG metabolite accumulates to very high levels in the tumor cells and alters how the tumor cell reads a subset of important genes in the DNA (epigenetic regulation). Furthermore, in a different subset of cholangiocarcinoma patients, a chromosomal abnormality in the gene FGFR2 has been identified. This abnormality is a fusion between part of the FGFR2 gene to part of another gene. The result is a cancer protein that constantly activates oncogenic FGFR2 signaling. The clinical utility of therapeutically targeting these tumor alterations are topics of current clinical trial investigations.

Gallbladder cancer and bile duct cancer arise in specific areas of the biliary tract. As a group, they are fairly rare, accounting for only 3% of gastrointestinal malignancies. Standard therapy involving surgery and/or chemotherapy can be effective if the disease is detected early. However, recurrent or advanced disease has been challenging to treat.

There have been significant advances in our understanding of the underlying mechanisms of carcinogenesis in biliary tract cancers, particularly those arising in the bile duct. Cholangiocarcinoma is the more common name for bile duct cancer and can occur either inside the liver (intrahepatic cholangiocarcinoma) or in the part of the bile duct that lies outside the liver (extrahapatic cholangiocarcinoma). The incidence of cholangiocarcinoma is rising worldwide, possibly due to an increasing incidence of hepatitis B and hepatitis C infection that can cause cirrhosis of the liver.

Ongoing research has identified new potential directions for targeted therapy in cholangiocarcinoma. Researchers at the MGH discovered a subset of patients with intrahepatic cholangiocarcinoma that harbor a mutation in a gene called IDH (isocitrate dehydrogenase). This alters the normal activity of the enzyme encoded by this gene, thereby producing a new metabolite (2-hydroxyglutarate, or 2-HG). This metabolite accumulates to very high levels in the tumor cells and alters how the tumor cell reads a subset of important genes (epigenetic regulation). Furthermore, a chromosomal abnormality in the gene FGFR2 has been identified in a subset of cholangiocarcinoma patients. This abnormality is a fusion between part of the FGFR2 gene to part of one of several other genes. The result is a cancer protein that constantly activates oncogenic FGFR2 signaling. The clinical utility of therapeutically targeting these tumor alterations are topics of current clinical trial investigations.

Gallbladder cancer and bile duct cancer arise in specific areas of the biliary tract. As a group, they are fairly rare, accounting for only 3% of gastrointestinal malignancies. Standard therapy involving surgery and/or chemotherapy can be effective if the disease is detected early. However, recurrent or advanced disease has been challenging to treat.

There have been significant advances in our understanding of the underlying mechanisms of cancer development in biliary tract cancers, particularly those arising in the bile duct. Cholangiocarcinoma is the more common name for bile duct cancer and can occur either inside the liver (intrahepatic cholangiocarcinoma) or in the part of the bile duct that lies outside the liver (extrahapatic cholangiocarcinoma). The incidence of cholangiocarcinoma is rising worldwide, possibly due to an increasing incidence of hepatitis B and hepatitis C infection that can cause cirrhosis of the liver.

Ongoing research has identified new potential directions for targeted therapy in cholangiocarcinoma. Researchers at the MGH discovered a subset of patients with intrahepatic cholangiocarcinoma that have a mutation in a gene called IDH (isocitrate dehydrogenase). This mutation alters the normal activity of the enzyme encoded by this gene, with the resulting production of a new metabolite (2-hydroxyglutarate, or 2-HG). This 2-HG metabolite accumulates to very high levels in the tumor cells and alters how the tumor cell reads a subset of important genes in the DNA (epigenetic regulation). Furthermore, in a different subset of cholangiocarcinoma patients, a chromosomal abnormality in the gene FGFR2 has been identified. This abnormality is a fusion between part of the FGFR2 gene to part of another gene. The result is a cancer protein that constantly activates oncogenic FGFR2 signaling. The clinical utility of therapeutically targeting these tumor alterations are topics of current clinical trial investigations.

Gallbladder cancer and bile duct cancer arise in specific areas of the biliary tract. As a group, they are fairly rare, accounting for only 3% of gastrointestinal malignancies. Standard therapy involving surgery and/or chemotherapy can be effective if the disease is detected early. However, recurrent or advanced disease has been challenging to treat.

There have been significant advances in our understanding of the underlying mechanisms of carcinogenesis in biliary tract cancers, particularly those arising in the bile duct. Cholangiocarcinoma is the more common name for bile duct cancer and can occur either inside the liver (intrahepatic cholangiocarcinoma) or in the part of the bile duct that lies outside the liver (extrahapatic cholangiocarcinoma). The incidence of cholangiocarcinoma is rising worldwide, possibly due to an increasing incidence of hepatitis B and hepatitis C infection that can cause cirrhosis of the liver.

Ongoing research has identified new potential directions for targeted therapy in cholangiocarcinoma. Researchers at the MGH discovered a subset of patients with intrahepatic cholangiocarcinoma that harbor a mutation in a gene called IDH (isocitrate dehydrogenase). This alters the normal activity of the enzyme encoded by this gene, thereby producing a new metabolite (2-hydroxyglutarate, or 2-HG). This metabolite accumulates to very high levels in the tumor cells and alters how the tumor cell reads a subset of important genes (epigenetic regulation). Furthermore, a chromosomal abnormality in the gene FGFR2 has been identified in a subset of cholangiocarcinoma patients. This abnormality is a fusion between part of the FGFR2 gene to part of one of several other genes. The result is a cancer protein that constantly activates oncogenic FGFR2 signaling. The clinical utility of therapeutically targeting these tumor alterations are topics of current clinical trial investigations.

PubMed ID's
2083573, 20375404, 23558953, 25384085, 25608663
Expand Collapse IDH2  - General Description
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Isocitrate dehydrogenase 2, encoded by the IDH2 gene, is an enzyme found in the powerhouse of the cells, known as mitochondria. This enzyme is similar to IDH1 in that it is involved in the transfer of energy from one molecule to another during certain biochemical reactions.

Mutations in IDH2 are predominately found in patients with acute myeloid leukemia, cancer of the bile duct (cholangiocarcinoma) and certain soft tissue tumors (sarcoma), and are found less frequently in patients with cancers of the central nervous system. Cancer mutations in the IDH2 gene primarily cause the amino acid arginine to be replaced by a different amino acid at the 140th or 172nd position in this protein. The change in sequence alters the structure of the protein, which results in loss of the normal enzymatic function of IDH2. Instead of producing its normal end-product (alpha-ketoglutarate), it produces the new metabolite R(-)-2-hydroxyglutarate (2HG), which is thought to contribute directly to the tumorigenic process by altering the activity of a number of proteins. The net effect is the inability to express a number of genes and the ability to activate signaling pathways involved in metabolism, and growth of new tumor vasculature.

The highest incidence of IDH2 gene mutations have been reported in acute myeloid leukemia (5-20%), cholangiocarcinoma (4-6%), and central cartilaginous tumors (~5%).
The IDH2 gene encodes for the metabolic enzyme isocitrate dehydrogenase 2. Unlike IDH1, IDH2 is localized within the mitochondria. While IDH2 functions similarly to IDH1 by catalyzing the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, NAD+ is the final electron acceptor, thereby producing NADH.

Somatic mutations in IDH2 are found most frequently in acute myeloid leukemia, bile duct tumors (cholangiocarcinoma) and certain sarcomas, and to a much lesser extent in low-grade gliomas and secondary glioblastomas. These mutations result in decreased normal enzymatic activity and result in the neomorphic activity of producing the oncometabolite R(-)-2-hydroxyglutarate (2HG) as the end-product. Levels of 2HG can accumulate dramatically in IDH2-mutant tumors and this is thought to promote tumorigenesis by competitively inhibiting the activity of a number of dioxygenases. The net effect appears to involve the promotion of gene silencing through hypermethylation of DNA and histones, as well as the activation of the hypoxia-inducible factor signaling pathway.

The highest incidence of IDH2 gene mutations have been reported in acute myeloid leukemia (5-20%), cholangiocarcinoma (4-6%), and central cartilaginous tumors (~5%).
PubMed ID's
22234630, 22180306, 20884716, 21598255
Expand Collapse IDH2  in Gall Bladder and Bile Duct Cancers
In 2011, a group at the MGH were the first to discover alterations in the coding sequence for two genes that encode the enzymes IDH1 and IDH2. These altered metabolic enzymes produce a new metabolite (called 2-hydroxyglutarate, or 2HG) that ultimately impacts the expression of many genes involved in carcinogenesis. Since this altered enzyme is expressed only in tumor cells and not in normal cells, it is ideal for targeted therapy intervention. Together, this has provided one of the first true targeted therapy opportunity for cholangiocarcinoma patients and has allowed the inclusion of these patients into some of our most anticipated phase I clinical trials.

In 2011, a group at the MGH were the first to discover alterations in the coding sequence for two genes that encode the enzymes IDH1 and IDH2. These altered metabolic enzymes produce a new metabolite (called 2-hydroxyglutarate, or 2HG) that ultimately impacts the expression of many genes involved in carcinogenesis. Since this altered enzyme is expressed only in tumor cells and not in normal cells, it is ideal for targeted therapy intervention. Together, this has provided one of the first true targeted therapy opportunity for cholangiocarcinoma patients and has allowed the inclusion of these patients into some of our most anticipated phase I clinical trials.

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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 all 7 results Per Page:
Protocol # Title Location Status Match
NCT02481154 Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation MGH Open DG
NCT02508467 A Phase 1 Study of BLU-554 in Patients With Hepatocellular Carcinoma A Phase 1 Study of BLU-554 in Patients With Hepatocellular Carcinoma MGH Open D
NCT01658878 A Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab and the Combination Nivolumab Plus Ipilimumab in Patients With Advanced Liver Cancer A Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab and the Combination Nivolumab Plus Ipilimumab in Patients With Advanced Liver Cancer MGH Open D
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 D
NCT02325739 Safety and Efficacy of FGF401 in Patients With Solid Malignancies Safety and Efficacy of FGF401 in Patients With Solid Malignancies MGH Open D
NCT02540291 Study of E7046 in Subjects With Selected Advanced Malignancies Study of E7046 in Subjects With Selected Advanced Malignancies MGH Open D
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 D
MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

Additional clinical trials may be applicable to your search criteria, but they may not be available at MGH. These clinical trials can typically be found by searching the clinicaltrials.gov website.
Trial Status: Showing all 7 results Per Page:

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