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Gall Bladder and Bile Duct Cancers, ATR, no-mutation in ATR

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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 ATR  - General Description
CLICK IMAGE FOR MORE INFORMATION
The protein encoded by ATR is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling and causing a pause in the cell cycle following DNA replication stress or damage. The activated protein can phosphorylate and activate several important proteins that are involved in the inhibition of DNA replication and cell division, which are critical for DNA repair.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate or damaged DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair if you select PKcs from the gene list when you sign on to this page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which in turn acts upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, germline or inherited BRCA1 and BRCA2 were identified a while ago as proteins that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway. Mutations in HR pathway members include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations in proteins involved in the DNA repair pathway found in cancer highlights how important the HR DSB DNA repair pathway is in cells. The mutations in HR pathway proteins result in proteins that do not function properly in their role in DNA repair. Without proper function of the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

ATR is only rarely mutated in cancer, however, the frequent mutations in ATM result in cells that are completely reliant on the ATR pathway to repair DSB's in the DNA. This has therapeutic implications for treatment of tumors that have mutations in the HR DNA repair pathway.

Testing for mutations in the many genes/proteins involved in DNA repair discussed above is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in these proteins-including ATR- are available at the MGH Cancer Center.

The protein encoded by ATR is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling and causing a pause in the cell cycle following DNA replication stress or damage. The activated protein can phosphorylate and activate several important proteins that are involved in the inhibition of DNA replication and cell division, which are critical for DNA repair.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate or damaged DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair if you select PKcs from the gene list when you sign on to this page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which in turn acts upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, germline or inherited BRCA1 and BRCA2 were identified a while ago as proteins that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway. Mutations in HR pathway members include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations in proteins involved in the DNA repair pathway found in cancer highlights how important the HR DSB DNA repair pathway is in cells. The mutations in HR pathway proteins result in proteins that do not function properly in their role in DNA repair. Without proper function of the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

ATR is only rarely mutated in cancer, however, the frequent mutations in ATM result in cells that are completely reliant on the ATR pathway to repair DSB's in the DNA. This has therapeutic implications for treatment of tumors that have mutations in the HR DNA repair pathway.

Testing for mutations in the many genes/proteins involved in DNA repair discussed above is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in these proteins-including ATR- are available at the MGH Cancer Center.



PubMed ID's
27617969, 24003211, PMC2988877
Expand Collapse no-mutation in ATR  in ATR
Mutations in the ATR gene are extremely rare in cancers. In fact, the ATR protein and its role in causing cell cycle delay through activating the protein CHK1 is a key pathway. Cell cycle delay induced by CHK1 gives the cell time to repair DSB's in the DNA, thereby acting as a tumor suppressor. When other proteins in the HR DNA pathway are mutated (see red proteins in the graphic above), ATR is the only option for DNA repair left to cells. This is why ATR inhibitors and other therapies can be effective treatments inducing death to tumor-cells.
Mutations in the ATR gene are extremely rare in cancers. In fact, the ATR protein and its role in causing cell cycle delay through activating the protein CHK1 is a key pathway. Cell cycle delay induced by CHK1 gives the cell time to repair DSB's in the DNA, thereby acting as a tumor suppressor. When other proteins in the HR DNA pathway are mutated (see red proteins in the graphic above), ATR is the only option for DNA repair left to cells. This is why ATR inhibitors and other therapies can be effective treatments inducing death to tumor-cells.

Alterations in the gene encoding ATR are not found in gall bladder and bile duct cancers. ATR is an important protein in the DNA repair pathway. ATR controls a signaling pathway in the cell by activating CHK1, which causes a delay in the cell cycle (see graphic above). Without this delay, cells would not have time to repair broken or damaged DNA. The accumulation of damaged DNA in the cell can lead to cancer.

ATR has become an important protein to inhibit with drugs in cancer. Cancer cells often have genetic alterations in other proteins in the DNA repair pathway (see red proteins in graphic above). If the ATM protein is mutated and unable to cause cell cycle arrest for DNA repair, then ATR is the only option for cancer cells to use to delay the cell cycle and repair DNA. Drugs targeting ATR block this pathway, leaving cancer cells no way to pause the cell cycle to achieve DNA repair. The tumor cells die as the result of accumulated damaged or broken DNA.

Alterations in the gene encoding ATR are not found in gall bladder and bile duct cancers. ATR is an important protein in the DNA repair pathway. ATR controls a signaling pathway in the cell by activating CHK1, which causes a delay in the cell cycle (see graphic above). Without this delay, cells would not have time to repair broken or damaged DNA. The accumulation of damaged DNA in the cell can lead to cancer.

ATR has become an important protein to inhibit with drugs in cancer. Cancer cells often have genetic alterations in other proteins in the DNA repair pathway (see red proteins in graphic above). If the ATM protein is mutated and unable to cause cell cycle arrest for DNA repair, then ATR is the only option for cancer cells to use to delay the cell cycle and repair DNA. Drugs targeting ATR block this pathway, leaving cancer cells no way to pause the cell cycle to achieve DNA repair. The tumor cells die as the result of accumulated damaged or broken DNA.

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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:
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 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
NCT03201458 Atezolizumab With or Without Cobimetinib in Treating Patients With Metastatic Bile Duct Cancer That Cannot Be Removed by Surgery or Gallbladder Cancer Atezolizumab With or Without Cobimetinib in Treating Patients With Metastatic Bile Duct Cancer That Cannot Be Removed by Surgery or Gallbladder 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
NCT02675946 CGX1321 in Subjects With Advanced Solid Tumors and CGX1321 With Pembrolizumab in Subjects With Advanced GI Tumors (Keynote 596) CGX1321 in Subjects With Advanced Solid Tumors and CGX1321 With Pembrolizumab in Subjects With Advanced GI Tumors (Keynote 596) MGH Open D
NCT03482102 Durvalumab (MEDI4736) and Tremelimumab and Radiation Therapy in Hepatocellular Carcinoma and Biliary Tract Cancer Durvalumab (MEDI4736) and Tremelimumab and Radiation Therapy in Hepatocellular Carcinoma and Biliary Tract Cancer 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
Trial Status: Showing Results: 1-10 of 15 Per Page:
12Next »

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