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 Results: 1-10 of 14 Per Page:
12Next »
Protocol # Title Location Status Match
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
NCT02150967 A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma MGH Open D
NCT02519348 A Study of MEDI4736 With Tremelimumab, MEDI4736 or Tremelimumab Monotherapy in Unresectable Hepatocellular Carcinoma A Study of MEDI4736 With Tremelimumab, MEDI4736 or Tremelimumab Monotherapy in Unresectable Hepatocellular Carcinoma MGH Open D
NCT02428712 A Study of PLX8394 as a Single Agent in Patients With Advanced Unresectable Solid Tumors A Study of PLX8394 as a Single Agent in Patients With Advanced Unresectable Solid Tumors MGH Open D
NCT02715531 A Study of the Safety and Tolerability of Atezolizumab Administered in Combination With Bevacizumab and/or Other Treatments in Participants With Solid Tumors A Study of the Safety and Tolerability of Atezolizumab Administered in Combination With Bevacizumab and/or Other Treatments in Participants With Solid Tumors MGH Open D
NCT01658878 An Immuno-therapy Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab or Nivolumab in Combination With Other Agents in Patients With Advanced Liver Cancer An Immuno-therapy Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab or Nivolumab in Combination With Other Agents 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
NCT02034110 Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers MGH Open D
NCT02325739 FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression MGH Open D
NCT02200042 Gemcitabine Hydrochloride and Cisplatin With or Without Radiation Therapy in Treating Patients With Localized Liver Cancer That Cannot Be Removed by Surgery Gemcitabine Hydrochloride and Cisplatin With or Without Radiation Therapy in Treating Patients With Localized Liver Cancer That Cannot Be Removed by Surgery MGH Open D
Trial Status: Showing Results: 1-10 of 14 Per Page:
12Next »

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