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Expand Collapse Colorectal Cancer  - General Description Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
PubMed ID's
2188735,
Expand Collapse FGFR 1, 2, 3 and 4  - General Description
CLICK IMAGE FOR MORE INFORMATION
Fibroblast growth factors (FGF’s) are ligands that bind to FGF cell surface receptors (FGFR’s) and activate them. Once activated, FGFR’s on normal cells transmit a growth signal inside the cell. This growth signal is transmitted via two important pathways inside cells; the RAS-dependent MAP kinase pathway, and a second signal pathway that involves PI3K and AKT. There are four different FGFR’s that make up a family of FGFR tyrosine kinase cell surface receptors, each having an extracellular domain that binds FGF ligands, a second domain that goes through the cell outer membrane, and a third domain that is inside the cell cytoplasm (see diagram above). FGFR signaling in normal cells stimulates proliferation, differentiation, embryonic development, cell migration, survival, angiogenesis (vascularization), and organogenesis (organ development).

Recently, FGFR genetic abnormalities have been found in several types of cancer. There are four FGFR family members, FGFR1, FGFR2, FGFR3, and FGFR4. Alterations in FGFR genes result in dysregulated FGF receptors and can promote cancer growth and metastasis. In a recent study of almost 5000 tumors, alterations in FGFR were found in 7% of of tumors. Among these tumors, alterations were identified in all 4 FGFR’s including FGFR1 (49%), FGFR2 (19%), FGFR3 (23%), and FGFR4 (7%). A small number of the tumors had genetic alterations in more than one type of FGFR. Clearly cancers have found a way to take advantage of FGF/FGFR signaling pathway in cells to cause uncontrolled growth leading to tumors.

While the FGFR genetic abnormalities may vary in frequency depending on the group of tumor types tested, there are clearly some patterns emerging in terms of which tumor types are likely to have specific kinds of genetic alterations in FGFR 1, 2, 3 or 4. Genetic alterations in the FGFR receptors can include point mutations, insertions/deletions, gene amplification, or translocations. The sensitivity of various gene alterations to FGFR inhibition is currently under investigation. Drugs targeting the FGF/FGFR pathway include small molecule tyrosine kinases inhibitors and ligand traps.

Several pharmaceutical companies have developed drugs that target and inhibit FGFR in tumors. Some of these are designed to target multiple members of the FGFR family. At MGH and other major cancer centers, clinical trials are available to patients whose tumors have been tested and found to have genetically altered FGFR. Treatment for these patients can be available on clinical studies testing these FGFR inhibitors, including FGFR inhibitors called TAS120 and Debio 1347. Other agents such as FGF401 and BLU554 are specific for inhibiting FGFR4 and are being tested in liver cancer. Contact the MGH Cancer Center to find out more about having genetic testing performed on a tumor, or for more information about these clinical trials.

Fibroblast growth factors (FGF’s) are ligands that bind to FGF cell surface receptors (FGFR’s) and activate them. Once activated, FGFR’s on normal cells transmit a growth signal inside the cell. This growth signal is transmitted via two important pathways inside cells; the RAS-dependent MAP kinase pathway, and a second signal pathway that involves PI3K and AKT. There are four different FGFR’s that make up a family of FGFR tyrosine kinase cell surface receptors, each having an extracellular domain that binds FGF ligands, a second domain that goes through the cell outer membrane, and a third domain that is inside the cell cytoplasm (see diagram above). FGFR signaling in normal cells stimulates proliferation, differentiation, embryonic development, cell migration, survival, angiogenesis (vascularization), and organogenesis (organ development).

Recently, FGFR genetic abnormalities have been found in several types of cancer. There are four FGFR family members, FGFR1, FGFR2, FGFR3, and FGFR4. Alterations in FGFR genes result in dysregulated FGF receptors and can promote cancer growth and metastasis. In a recent study of almost 5000 tumors, alterations in FGFR were found in 7% of of tumors. Among these tumors, alterations were identified in all 4 FGFR’s including FGFR1 (49%), FGFR2 (19%), FGFR3 (23%), and FGFR4 (7%). A small number of the tumors had genetic alterations in more than one type of FGFR. Clearly cancers have found a way to take advantage of FGF/FGFR signaling pathway in cells to cause uncontrolled growth leading to tumors.

While the FGFR genetic abnormalities may vary in frequency depending on the group of tumor types tested, there are clearly some patterns emerging in terms of which tumor types are likely to have specific kinds of genetic alterations in FGFR 1, 2, 3 or 4. Genetic alterations in the FGFR receptors can include point mutations, insertions/deletions, gene amplification, or translocations. The sensitivity of various gene alterations to FGFR inhibition is currently under investigation. Drugs targeting the FGF/FGFR pathway include small molecule tyrosine kinases inhibitors and ligand traps.

Several pharmaceutical companies have developed drugs that target and inhibit FGFR in tumors. Some of these are designed to target multiple members of the FGFR family. At MGH and other major cancer centers, clinical trials are available to patients whose tumors have been tested and found to have genetically altered FGFR. Treatment for these patients can be available on clinical studies testing these FGFR inhibitors, including FGFR inhibitors called TAS120 and Debio 1347. Other agents such as FGF401 and BLU554 are specific for inhibiting FGFR4 and are being tested in liver cancer. Contact the MGH Cancer Center to find out more about having genetic testing performed on a tumor, or for more information about these clinical trials.

PubMed ID's
9212826, 24265351
Expand Collapse FGFR 1, 2, 3 and 4  in Colorectal Cancer
Genetic alterations in FGFR family members have been found in colorectal cancers. In rare cases, FGF4 has been found to be amplified.

Testing for FGFR genetic alterations can be performed at the MGH cancer center, or other major centers.

Genetic alterations in FGFR family members have been found in colorectal cancers. In rare cases, FGF4 has been found to be amplified.

Testing for FGFR genetic alterations can be performed at the MGH cancer center, or other major centers.

PubMed ID's
24265351
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.
Our Colorectal Cancer Team

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene
Trial Status: Showing Results: 1-10 of 30 Per Page:
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Protocol # Title Location Status Match
NCT01948297 Debio 1347-101 Phase I Trial in Advanced Solid Tumours With Fibroblast Growth Factor Receptor (FGFR) Alterations Debio 1347-101 Phase I Trial in Advanced Solid Tumours With Fibroblast Growth Factor Receptor (FGFR) Alterations MGH Open DG
NCT02335918 A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors MGH Open D
NCT02279433 A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b MGH Open D
NCT02715284 A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors MGH Open D
NCT02099058 A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors MGH Open D
NCT02327169 A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies MGH Open D
NCT01714739 A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors MGH Open D
NCT01633970 A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors MGH Open D
NCT02467361 A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers MGH Open D
NCT02228811 A Study of DCC-2701 in Participants With Advanced Solid Tumors A Study of DCC-2701 in Participants With Advanced Solid Tumors MGH Open D
Trial Status: Showing Results: 1-10 of 30 Per Page:
123Next »
Our Colorectal Cancer Team

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