Gall Bladder and Bile Duct Cancers, IDH1

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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 IDH1  - General Description
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The IDH1 gene encodes an enzyme called isocitrate dehydrogenase 1, found in the compartment of cells called the cytoplasm. This enzyme is normally involved in the transfer of energy from one molecule to another during certain biochemical reactions within the cell.

Mutations involving the IDH1 gene have been found in various cancers, including Acute Myeloid Leukemia (AML), intrahepatic bile duct cancers (Cholangiomas), Chondrosarcomas, and specific brain tumors (gliomas and glioblastomas). These alterations cause the amino acid (protein building block) arginine to be replaced by a different amino acid at a key position in the long chain of amino acids that make up this protein. The change in amino acid sequence alters the structure of the protein, resulting in loss of its normal function. Instead of its' normal metabolic product, the mutated IDH1 produces a new metabolite, R (-)-2-hydroxyglutarate, also called 2-HG. 2HG inhibits Tet and KGM enzymes, which alter the organization of DNA and disrupt normal gene expression patterns. These changes contribute directly to the development of cancer.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of IDH1 mutations in brain tumors called gliomas (50-60%) and glioblastomas (~10%), cholangiocarcinomas (18-25%), chondrosarcomas, and Acute Myeloid Leukemia (5-10%).
The IDH1 gene encodes for the metabolic enzyme isocitrate dehydrogenase 1. This enzyme is located in the cytoplasm and peroxisomes of cells, and normally functions to catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, with the production of NADPH.

Recurrent mutations in IDH1 occur primarily at codon 132. These mutations result in decreased normal enzymatic activity, while conferring neomorphic activity that produces the oncometabolite R(-)-2-hydroxyglutarate (2HG) as the end-product. Levels of 2HG can accumulate dramatically in IDH1-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.

Tumor genotype testing performed clinically at the MGH Cancer Center has identified the highest incidence of IDH1 mutations in low-grade gliomas (50-60%), glioblastomas (~10%), cholangiocarcinomas (18-25%), chondrosarcomas, and acute myeloid leukemias (5-10%).
PubMed ID's
22234630, 22180306
Expand Collapse IDH1  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) 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) 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 6 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
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
NCT02375880 Study of DKN-01 and Gemcitabine/Cisplatin in Patients With Carcinoma to Primary to the Intra- or Extra-Hepatic Biliary System or Gallbladder Study of DKN-01 and Gemcitabine/Cisplatin in Patients With Carcinoma to Primary to the Intra- or Extra-Hepatic Biliary System or Gallbladder 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 6 results Per Page:

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