Bone and Soft Tissue Sarcoma, ATR

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Expand Collapse Bone and Soft Tissue Sarcoma  - General Description This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
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 ATR  in Bone and Soft Tissue Sarcoma
Alterations in the gene encoding ATR are not found in sarcomas. 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 sarcomas. 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.

Expand Collapse No mutation selected
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 27 Per Page:
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Protocol # Title Location Status Match
NCT03092323 A Randomized Trial of Pembrolizumab & Radiotherapy Versus Radiotherapy in High-Risk Soft Tissue Sarcoma of the Extremity A Randomized Trial of Pembrolizumab & Radiotherapy Versus Radiotherapy in High-Risk Soft Tissue Sarcoma of the Extremity MGH Open D
NCT02659020 A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma MGH Open D
NCT03126591 A Study of Olaratumab (LY3012207) Plus Pembrolizumab in Participants With Advanced or Metastatic Soft Tissue Sarcoma A Study of Olaratumab (LY3012207) Plus Pembrolizumab in Participants With Advanced or Metastatic Soft Tissue Sarcoma MGH Open D
NCT00585195 A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer MGH Open D
NCT02748135 A Two-Part Study of TB-403 in Pediatric Subjects With Relapsed or Refractory Medulloblastoma A Two-Part Study of TB-403 in Pediatric Subjects With Relapsed or Refractory Medulloblastoma MGH Open D
NCT02278250 An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-803/M4344 as a Single Agent and in Combination With Cytotoxic Chemotherapy in Subjects With Advanced Solid Tumors An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-803/M4344 as a Single Agent and in Combination With Cytotoxic Chemotherapy in Subjects With Advanced Solid Tumors 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
NCT02867592 Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors MGH Open D
NCT03002805 CBT-1® in Combination With Doxorubicin in Patients With Metastatic, Unresectable Sarcomas Who Previously Progressed on Doxorubicin CBT-1® in Combination With Doxorubicin in Patients With Metastatic, Unresectable Sarcomas Who Previously Progressed on Doxorubicin MGH Open D
NCT02454972 Clinical Trial of Lurbinectedin (PM01183) in Selected Advanced Solid Tumors Clinical Trial of Lurbinectedin (PM01183) in Selected Advanced Solid Tumors MGH Open D
Trial Status: Showing Results: 1-10 of 27 Per Page:
123Next »

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