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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 TP53  - General Description
CLICK IMAGE FOR MORE INFORMATION
The p53 (TP53) gene produces a protein, P53 which has many complex functions within the cell. It has been called the “guardian of the genome” for reasons that have to do with these complex functions. Normal, non-cancerous cells have tightly regulated pathways that control cell growth, mediating cessation of growth or even cell death when circumstances warrant it. P53 is at the center of these pathways, acting as a “tumor suppressor” in responding to circumstances in the cell that require a cessation of growth. Perhaps for this reason, P53 is one of the most commonly mutated genes across all cancer types.

P53 itself regulates the expression of several genes that are involved in growth arrest or “cell cycle arrest”. Growth arrest is important for stopping the cell from normal growth and cell division so that if, for instance, there has been damage to the DNA from UV irradiation or some other insult causing DNA damage, the cessation of the cell cycle allows DNA repair to take place before the cell resumes growth. If the damage to the DNA is too extensive to repair, or if other factors such as oncogenic stress impact the cell, P53 then has roles in other processes that are part of the cell’s repertoire of responses. These include processes such as apoptosis (programmed cell death), senescence (irreversible cell cycle arrest), autophagy (regulated destruction of selected proteins within the cell, leading to cell death), and some important metabolic changes in the cell (see graphic above, adapted with permission).

P53 is itself acted upon by proteins in the cell that detect DNA damage or oncogenic stress (see graphic depicting P53 at the center of a number of cellular responses). In the case of DNA damage to the cell, P53 is acted upon by a protein called ATM and another designated CHK2 (see glossary for more information). These proteins activate P53 to regulate the changes that will cause growth arrest. Interestingly, these two genes themselves are found to be mutated and have altered function in certain cancers. The fact that both P53 and the genes that trigger P53’s response and initiation of growth arrest are mutated in some cancers highlights the importance of P53 to normal cell growth. P53 is found to be mutated in over half of cancers studied, including ovarian cancer, colon and esophageal cancer, and many other types of cancer. Because p53 plays so many complex roles in the cell, we do not depict it in a simple graphic as we have with other proteins on this web site in which genetic alterations have been found in specific tumors that lead to dysregulation of these proteins. Rather, P53 as a negative regulator of cell growth under important circumstances plays this role at the center of a complex network of pathways within the cell. Many of the proteins involved in the pathways that regulate P53 and its responses are also found to be genetically altered in some cancers.

As we have seen, the P53 protein has many functions in the cell, and because of these many roles, its location in the nucleus or cytoplasm varies, depending on the function and when it exerts its effect during the cell cycle. One important protein that regulates P53 is called HDM2/MDM2, depicted in the graphic above. The HDM2/MDM2 protein contains a p53 binding domain, and once bound to p53, it inhibits the activation of the P53 protein, and thereby prevents P53 from regulating growth arrest, even when there is damage to the DNA. Some cancers have been found to overexpress HDM2/MDM2, meaning there is an excess of the protein which binds to P53, preventing it from exerting its important role in regulating growth arrest. Cell division that occurs despite damage to the DNA can lead to cancer. Interestingly, those cancers that have been found to over-express HDM2/MDM2 typically are not found to have p53 mutations. This provides scientists with evidence that by whatever means, either through increasing the amount of the P53 inhibitor HDM2/MDM2, or, through mutations in P53 that prevent the normal activities of the protein, the normal function of P53 is important in preventing cancer. MDM2 was named after its discovery in studies on laboratory mice. The human version of the gene is designated HumanDM2, or HDM2. Genetic alterations leading to over-expression of MDM2 are observed most commonly in sarcomas, but have also been observed in endometrial cancer, colon cancer, and stomach cancer.

Source: Molecular Genetics of Cancer, Second Edition
Chapter No. 2, Section No. 12
Leif W. Ellisen, MD, PhD
The p53 (TP53) gene produces a protein, P53 which has many complex functions within the cell. It has been called the “guardian of the genome” for reasons that have to do with these complex functions. Normal, non-cancerous cells have tightly regulated pathways that control cell growth, mediating cessation of growth or even cell death when circumstances warrant it. P53 is at the center of these pathways, acting as a “tumor suppressor” in responding to circumstances in the cell that require a cessation of growth. Perhaps for this reason, P53 is one of the most commonly mutated genes across all cancer types.

P53 itself regulates the expression of several genes that are involved in growth arrest or “cell cycle arrest”. Growth arrest is important for stopping the cell from normal growth and cell division so that if, for instance, there has been damage to the DNA from UV irradiation or some other insult causing DNA damage, the cessation of the cell cycle allows DNA repair to take place before the cell resumes growth. If the damage to the DNA is too extensive to repair, or if other factors such as oncogenic stress impact the cell, P53 then has roles in other processes that are part of the cell’s repertoire of responses. These include processes such as apoptosis (programmed cell death), senescence (irreversible cell cycle arrest), autophagy (regulated destruction of selected proteins within the cell, leading to cell death), and some important metabolic changes in the cell (see graphic above, adapted with permission).

P53 is itself acted upon by proteins in the cell that detect DNA damage or oncogenic stress (see graphic depicting P53 at the center of a number of cellular responses). In the case of DNA damage to the cell, P53 is acted upon by a protein called ATM and another designated CHK2 (see glossary for more information). These proteins activate P53 to regulate the changes that will cause growth arrest. Interestingly, these two genes themselves are found to be mutated and have altered function in certain cancers. The fact that both P53 and the genes that trigger P53’s response and initiation of growth arrest are mutated in some cancers highlights the importance of P53 to normal cell growth. P53 is found to be mutated in over half of cancers studied, including ovarian cancer, colon and esophageal cancer, and many other types of cancer. Because p53 plays so many complex roles in the cell, we do not depict it in a simple graphic as we have with other proteins on this web site in which genetic alterations have been found in specific tumors that lead to dysregulation of these proteins. Rather, P53 as a negative regulator of cell growth under important circumstances plays this role at the center of a complex network of pathways within the cell. Many of the proteins involved in the pathways that regulate P53 and its responses are also found to be genetically altered in some cancers.

As we have seen, the P53 protein has many functions in the cell, and because of these many roles, its location in the nucleus or cytoplasm varies, depending on the function and when it exerts its effect during the cell cycle. One important protein that regulates P53 is called HDM2/MDM2, depicted in the graphic above. The HDM2/MDM2 protein contains a p53 binding domain, and once bound to p53, it inhibits the activation of the P53 protein, and thereby prevents P53 from regulating growth arrest, even when there is damage to the DNA. Some cancers have been found to overexpress HDM2/MDM2, meaning there is an excess of the protein which binds to P53, preventing it from exerting its important role in regulating growth arrest. Cell division that occurs despite damage to the DNA can lead to cancer. Interestingly, those cancers that have been found to over-express HDM2/MDM2 typically are not found to have p53 mutations. This provides scientists with evidence that by whatever means, either through increasing the amount of the P53 inhibitor HDM2/MDM2, or, through mutations in P53 that prevent the normal activities of the protein, the normal function of P53 is important in preventing cancer. MDM2 was named after its discovery in studies on laboratory mice. The human version of the gene is designated HumanDM2, or HDM2. Genetic alterations leading to over-expression of MDM2 are observed most commonly in sarcomas, but have also been observed in endometrial cancer, colon cancer, and stomach cancer.

Source: Molecular Genetics of Cancer, Second Edition
Chapter No. 2, Section No. 12
Leif W. Ellisen, MD, PhD
Expand Collapse TP53  in Lung Cancer
TP53 mutations are more prevalent in squamous cell lung carcinoma than in lung adenocarcinoma. G>T mutations in TP53 are significantly more common in smokers than in never-smokers with TP53-mutant squamous cell lung carcinoma (Mogi, 2010).

TP53 mutations in lung cancer are associated with resistance to chemotherapy.

TP53 mutations in lung carcinoma are modestly correlated with a negative prognosis, including enhanced malignancy and a diminished survival outlook. TP53 mutations usually occur prior to lymph node metastasis and persist throughout the course of disease progression and metastatic spread (Chang, 2011).

TP53 mutations are more prevalent in squamous cell lung carcinoma than in lung adenocarcinoma. G>T mutations in TP53 are significantly more common in smokers than in never-smokers with TP53-mutant squamous cell lung carcinoma (Mogi, 2010).

TP53 mutations in lung cancer are associated with resistance to chemotherapy.

TP53 mutations in lung carcinoma are modestly correlated with a negative prognosis, including enhanced malignancy and a diminished survival outlook. TP53 mutations usually occur prior to lymph node metastasis and persist throughout the course of disease progression and metastatic spread (Chang, 2011).

PubMed ID's
21331359, 20811949
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 45 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
NCT02219724 A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors 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
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 45 Per Page:
12345Next »
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