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Expand Collapse Lung Cancer  - General Description This year about 226,000 people in the U.S. will be told by a doctor that they have lung cancer. However, about 390,000 Americans remain alive today after having been diagnosed with this malignancy. Lung cancer includes tumors that begin in tissues lining air passages inside the lungs and bronchi. The bronchi are the 2 branches of the windpipe (trachea) that lead to the lungs. Based on how the cells look under a microscope, lung cancers are divided into 2 main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of these cases.

The main subtypes of NSCLC are squamous cell carcinoma (cancer beginning in thin, flat scaly-looking cells), adenocarcinoma (cancer beginning in cells that make mucus and other substances) and large cell carcinoma (cancer beginning in several types of large cells). The 2 main types of SCLC are small cell carcinoma (oat cell cancer) and combined small cell carcinoma.

Lung cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main sites to which lung cancer spreads are the adrenal gland, liver and lungs.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include MRI, bone scans and endoscopic ultrasound (EUS).

The FDA has approved several targeted therapies to treat patients with NSCLC. These include bevacizumab (Avastin), cetuximab (Erbitux), erlotinib (Tarceva), gefitnib (Iressa) and crizotinib (Xalkori). So far there are no FDA-approved targeted therapies for SCLC.

Despite significant improvements in the treatment of lung cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2012:

New cases: 226,160
Deaths: 160,340

Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional and distant stage disease, respectively.

NSCLC arises from the epithelial cells of the lung, from the central bronchi to the terminal alveoli. The histological type of NSCLC correlates with the site of origin, reflecting the variation in respiratory tract epithelium from the bronchi to the alveoli. Squamous cell carcinoma usually starts near a central bronchus while adenocarcinoma usually originates in peripheral lung tissue.

Tobacco smoking is the strongest risk factor for developing lung cancer, though it should be noted that the majority of patients diagnosed with lung cancer quit smoking years prior to diagnosis or were never-smokers (up to 15% of cases).

The identification of driver oncogene mutations in lung cancer has led to the development of targeted therapy that has vastly broadened treatment options and improved outcomes for subsets of patients with metastatic disease. It is now common practice to determine the genotype of a NSCLC patient early in the course of their diagnosis, to ensure that all possible treatment options are considered.

Source: National Cancer Institute, 2012
This year about 226,000 people in the U.S. will be told by a doctor that they have lung cancer. However, about 390,000 Americans remain alive today after having been diagnosed with this malignancy. Lung cancer includes tumors that begin in tissues lining air passages inside the lungs and bronchi. The bronchi are the 2 branches of the windpipe (trachea) that lead to the lungs. Based on how the cells look under a microscope, lung cancers are divided into 2 main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of these cases.

The main subtypes of NSCLC are squamous cell carcinoma (cancer beginning in thin, flat scaly-looking cells), adenocarcinoma (cancer beginning in cells that make mucus and other substances) and large cell carcinoma (cancer beginning in several types of large cells). The 2 main types of SCLC are small cell carcinoma (oat cell cancer) and combined small cell carcinoma.

Lung cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main sites to which lung cancer spreads are the adrenal gland, liver and lungs.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include MRI, bone scans and endoscopic ultrasound (EUS).

The FDA has approved several targeted therapies to treat patients with NSCLC. These include bevacizumab (Avastin), cetuximab (Erbitux), erlotinib (Tarceva), gefitnib (Iressa) and crizotinib (Xalkori). So far there are no FDA-approved targeted therapies for SCLC.

Despite significant improvements in the treatment of lung cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Estimated new cases and deaths from lung cancer (non-small cell and small cell combined) in the United States in 2012:

New cases: 226,160
Deaths: 160,340

Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional and distant stage disease, respectively.

NSCLC arises from the epithelial cells of the lung, from the central bronchi to the terminal alveoli. The histological type of NSCLC correlates with the site of origin, reflecting the variation in respiratory tract epithelium from the bronchi to the alveoli. Squamous cell carcinoma usually starts near a central bronchus while adenocarcinoma usually originates in peripheral lung tissue.

Tobacco smoking is the strongest risk factor for developing lung cancer, though it should be noted that the majority of patients diagnosed with lung cancer quit smoking years prior to diagnosis or were never-smokers (up to 15% of cases).

The identification of driver oncogene mutations in lung cancer has led to the development of targeted therapy that has vastly broadened treatment options and improved outcomes for subsets of patients with metastatic disease. It is now common practice to determine the genotype of a NSCLC patient early in the course of their diagnosis, to ensure that all possible treatment options are considered.

Source: National Cancer Institute, 2012
Expand Collapse APC  - General Description
CLICK IMAGE FOR MORE INFORMATION
Adenomatous Polyposis Coli (APC) is a regulator of several fundamental cellular processes, including cell division, cell attachment, cell migration, cell polarization, and chromosome segregation during division. In these complex functions, APC activity is essential for the prevention of cancer (in other words, APC acts as a tumor suppressor). APC is involved in these cellular functions through interactions with other cellular proteins. One of the most recognized functions of APC is in regulating levels of beta-catenin, which is part of the WNT signal pathway in cells.

The WNT signal pathway is important in a variety of cellular processes. In the left hand cell in the graphic above, one can see that when there is no WNT ligand to bind to the extracellular WNT receptor, APC exists in a complex with other proteins. The complex is known as the “destruction complex”, and acts to destroy beta-catenin in the cell cytoplasm. This keeps levels of beta-catenin in the cell very low. Beta-catenin also binds to E-cadherin at the cell membrane, and is involved in cell to cell contacts (see graphic).

When WNT ligand binds to the extracellular WNT receptor, as is depicted in the right hand cell in the graphic above, it activates the receptor to send a signal that causes the dissociation of the destruction complex including APC. Without the destruction complex, beta-catenin builds up in the cytoplasm of the cells. In the cytoplasm, beta-catenin binds to T-cell factor (TCF), and together they translocate into the nucleus. They then bind to DNA and activate the transcription of genes that promote cell growth, such as c-Myc and cyclin D1. In the presence of WNT ligand binding, normal cells proliferate and divide.

In some cancers, APC is genetically altered, either through mutation or actual loss of the gene. Mutations in APC have been found in most colon cancers, whether familial (inherited genetic alterations) or spontaneous (somatic gene mutation). Mutations in APC have also been found in other cancers, including in adenocarcinoma of the lung. When APC is missing or mutated it cannot function in the destruction complex, and beta-catenin builds up in the cytoplasm even in the absence of WNT signaling. This unregulated high level of beta-catenin binds to TCF, moves into the nucleus of cancer cells, and binds to DNA to stimulate transcription of c-Myc and cyclin D1, causing cells to grow and divide.

Another way that APC function can be disrupted is through changes in E-cadherin, a protein that binds to beta-catenin, and mediates cell to cell contact (see graphic above). In many cancers, E-cadherin expression is lost, and without E-cadherin interacting with beta-catenin, cell to cell contact becomes dysregulated. Other genetic changes in E-cadherin can be inherited. The gene that encodes E-cadherin is called CDH1. Inherited germline mutations in CDH1 result in an E-cadherin protein that does not function normally, and these inherited mutations in CDH1/E-cadherin have been found to be associated with Hereditary Diffuse Gastric cancer/Lobular Breast Cancer Syndrome. The fact that so many genetic alterations in the pathways associated with APC highlight the importance of the APC tumor suppressor in normally preventing cancer.


Sources:
Graphic adapted from slideshareecdn.com 02-cat-neoplasia-5081/95/02-cat-neoplasia-14-728.jpg?cb=124463107
Valeria Bugos, Camila Guezada, Nicolas Briceno
Text sources PMID#17881494 Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene

Adenomatous Polyposis Coli (APC) is a regulator of several fundamental cellular processes, including cell division, cell attachment, cell migration, cell polarization, and chromosome segregation during division. In these complex functions, APC activity is essential for the prevention of cancer (in other words, APC acts as a tumor suppressor). APC is involved in these cellular functions through interactions with other cellular proteins. One of the most recognized functions of APC is in regulating levels of beta-catenin, which is part of the WNT signal pathway in cells.

The WNT signal pathway is important in a variety of cellular processes. In the left hand cell in the graphic above, one can see that when there is no WNT ligand to bind to the extracellular WNT receptor, APC exists in a complex with other proteins. The complex is known as the “destruction complex”, and acts to destroy beta-catenin in the cell cytoplasm. This keeps levels of beta-catenin in the cell very low. Beta-catenin also binds to E-cadherin at the cell membrane, and is involved in cell to cell contacts (see graphic).

When WNT ligand binds to the extracellular WNT receptor, as is depicted in the right hand cell in the graphic above, it activates the receptor to send a signal that causes the dissociation of the destruction complex including APC. Without the destruction complex, beta-catenin builds up in the cytoplasm of the cells. In the cytoplasm, beta-catenin binds to T-cell factor (TCF), and together they translocate into the nucleus. They then bind to DNA and activate the transcription of genes that promote cell growth, such as c-Myc and cyclin D1. In the presence of WNT ligand binding, normal cells proliferate and divide.

In some cancers, APC is genetically altered, either through mutation or actual loss of the gene. Mutations in APC have been found in most colon cancers, whether familial (inherited genetic alterations) or spontaneous (somatic gene mutation). Mutations in APC have also been found in other cancers, including in adenocarcinoma of the lung. When APC is missing or mutated it cannot function in the destruction complex, and beta-catenin builds up in the cytoplasm even in the absence of WNT signaling. This unregulated high level of beta-catenin binds to TCF, moves into the nucleus of cancer cells, and binds to DNA to stimulate transcription of c-Myc and cyclin D1, causing cells to grow and divide.

Another way that APC function can be disrupted is through changes in E-cadherin, a protein that binds to beta-catenin, and mediates cell to cell contact (see graphic above). In many cancers, E-cadherin expression is lost, and without E-cadherin interacting with beta-catenin, cell to cell contact becomes dysregulated. Other genetic changes in E-cadherin can be inherited. The gene that encodes E-cadherin is called CDH1. Inherited germline mutations in CDH1 result in an E-cadherin protein that does not function normally, and these inherited mutations in CDH1/E-cadherin have been found to be associated with Hereditary Diffuse Gastric cancer/Lobular Breast Cancer Syndrome. The fact that so many genetic alterations in the pathways associated with APC highlight the importance of the APC tumor suppressor in normally preventing cancer.


Sources:
Graphic adapted from slideshareecdn.com 02-cat-neoplasia-5081/95/02-cat-neoplasia-14-728.jpg?cb=124463107
Valeria Bugos, Camila Guezada, Nicolas Briceno
Text sources PMID#17881494 Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene

PubMed ID's
1788494
Expand Collapse APC  in Lung Cancer
Mutations in APC have been found in lung adenocarcinoma with low frequency. These mutations occur in different areas of the gene, but affect the ability of APC to perform its normal function as a tumor suppressor.

Source: www.tumorportal.org

Mutations in APC have been found in lung adenocarcinoma with low frequency. These mutations occur in different areas of the gene, but affect the ability of APC to perform its normal function as a tumor suppressor.

Source: www.tumorportal.org

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 49 Per Page:
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Protocol # Title Location Status Match
NCT02052778 A Dose Finding Study Followed by a Safety and Efficacy Study in Patients With Advanced Solid Tumors or Multiple Myeloma With FGF/FGFR-Related Abnormalities A Dose Finding Study Followed by a Safety and Efficacy Study in Patients With Advanced Solid Tumors or Multiple Myeloma With FGF/FGFR-Related Abnormalities MGH Open D
NCT02637531 A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549 A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549 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
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
NCT02108964 A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies MGH Open D
NCT02365662 A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor 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
NCT02298153 A Study of Atezolizumab (MPDL3280A) in Combination With Epacadostat (INCB024360) in Subjects With Previously Treated Stage IIIB or Stage IV Non-Small Cell Lung Cancer and Previously Treated Stage IV Urothelial Carcinoma (INCB 24360-110 / ECHO-110) A Study of Atezolizumab (MPDL3280A) in Combination With Epacadostat (INCB024360) in Subjects With Previously Treated Stage IIIB or Stage IV Non-Small Cell Lung Cancer and Previously Treated Stage IV Urothelial Carcinoma (INCB 24360-110 / ECHO-110) MGH Open D
NCT01325441 A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies MGH Open D
Trial Status: Showing Results: 1-10 of 49 Per Page:
12345Next »
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