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Expand Collapse Prostate Cancer  - General Description This year about 220,800 men in the U.S. will be told by a doctor that they have prostate cancer. About half will be at least 67 years old. However, 10 times as many men (2.5 million) are alive today after having been diagnosed with prostate cancer.

The prostate is a walnut-sized gland located behind the rectum and under the bladder. It is the part of a man's reproductive system that produces some of the fluids that make up semen, which carries sperm out of the body. Nearly all primary prostate cancers are adenocarcinomas, which begin in cells that line certain internal organs and produce mucus or other fluids.

Prostate 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 prostate cancer spreads are the bones, lungs and liver. Some patients live a long time even after prostate cancer has spread to distant sites.

To find out whether prostate cancer has entered the lymph system, a surgeon may perform a pelvic lymphadenectomy to remove the lymph nodes in the pelvis. A pathologist looks at these lymph node tissues through a microscope to see if cancer cells are present. Several kinds of imaging technologies can also be performed to determine if prostate cancer has spread. These include bone scans, MRI and CT scans.

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

Source: National Cancer Institute, 2015
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients, especially those with localized tumors, may die of other illnesses without ever having suffered significant disability from the cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management. Controversy exists in regard to the value of screening, the most appropriate staging evaluation and the optimal treatment of each stage of the disease.

A complicating feature when evaluating survival after treatment, or when comparing the various treatment strategies, is that improved diagnostic methods can increasingly identify non-lethal tumors. Non-randomized comparisons of treatments may be confounded not only by patient-selection factors, but also by time trends. For example, a population-based study in Sweden showed that from 1960 to the late 1980s, before the use of prostate-specific antigen (PSA) for screening purposes, long-term relative survival rates after the diagnosis of prostate cancer improved substantially as more sensitive methods of diagnosis were introduced. This occurred despite the use of watchful waiting or palliative hormonal treatment as the most common treatment strategies for localized prostate cancer during the entire era (<150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that if all cancers diagnosed between 1960 and 1964 were of the lethal variety, then at least 33% of cancers diagnosed between 1980 and 1984 were of the non-lethal variety. With the advent of PSA screening, the ability to diagnose non-lethal prostate cancers may increase further.

Another issue complicating comparisons of outcomes among non-concurrent series of patients is the possibility of changes in criteria for histologic diagnosis of prostate cancer. This phenomenon creates a statistical artifact that can produce a false sense of therapeutic accomplishment and may also lead to more aggressive therapy. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004. The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval [CI], 0.79 0.91; P<0.001) than the same slides read in 1990 to 1992. As a result, Gleason score-standardized prostate cancer mortality for these men was artifactually improved from 2.08 to 1.50 deaths per 100 person years. This resulted in a 28% decrease, even though overall outcomes were unchanged.

Source: National Cancer Institute, 2012
This year about 220,800 men in the U.S. will be told by a doctor that they have prostate cancer. About half will be at least 67 years old. However, 10 times as many men (2.5 million) are alive today after having been diagnosed with prostate cancer.

The prostate is a walnut-sized gland located behind the rectum and under the bladder. It is the part of a man's reproductive system that produces some of the fluids that make up semen, which carries sperm out of the body. Nearly all primary prostate cancers are adenocarcinomas, which begin in cells that line certain internal organs and produce mucus or other fluids.

Prostate 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 prostate cancer spreads are the bones, lungs and liver. Some patients live a long time even after prostate cancer has spread to distant sites.

To find out whether prostate cancer has entered the lymph system, a surgeon may perform a pelvic lymphadenectomy to remove the lymph nodes in the pelvis. A pathologist looks at these lymph node tissues through a microscope to see if cancer cells are present. Several kinds of imaging technologies can also be performed to determine if prostate cancer has spread. These include bone scans, MRI and CT scans.

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

Source: National Cancer Institute, 2015
Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients, especially those with localized tumors, may die of other illnesses without ever having suffered significant disability from the cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management. Controversy exists in regard to the value of screening, the most appropriate staging evaluation and the optimal treatment of each stage of the disease.

A complicating feature when evaluating survival after treatment, or when comparing the various treatment strategies, is that improved diagnostic methods can increasingly identify non-lethal tumors. Non-randomized comparisons of treatments may be confounded not only by patient-selection factors, but also by time trends. For example, a population-based study in Sweden showed that from 1960 to the late 1980s, before the use of prostate-specific antigen (PSA) for screening purposes, long-term relative survival rates after the diagnosis of prostate cancer improved substantially as more sensitive methods of diagnosis were introduced. This occurred despite the use of watchful waiting or palliative hormonal treatment as the most common treatment strategies for localized prostate cancer during the entire era (<150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that if all cancers diagnosed between 1960 and 1964 were of the lethal variety, then at least 33% of cancers diagnosed between 1980 and 1984 were of the non-lethal variety. With the advent of PSA screening, the ability to diagnose non-lethal prostate cancers may increase further.

Another issue complicating comparisons of outcomes among non-concurrent series of patients is the possibility of changes in criteria for histologic diagnosis of prostate cancer. This phenomenon creates a statistical artifact that can produce a false sense of therapeutic accomplishment and may also lead to more aggressive therapy. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004. The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval [CI], 0.79 0.91; P<0.001) than the same slides read in 1990 to 1992. As a result, Gleason score-standardized prostate cancer mortality for these men was artifactually improved from 2.08 to 1.50 deaths per 100 person years. This resulted in a 28% decrease, even though overall outcomes were unchanged.

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 Prostate Cancer
A phase II clinical trial (RTOG 9202) has reported that prostate cancer patients with abnormal p53 status benefited from long-term hormone therapy, compared to short-term hormone therapy, when combined with radiation treatment.

Treatment strategies evaluating p53-activating drugs are beginning to enter phase I clinical evaluation (such as APR-246), and include patients with prostate cancer. The results are too preliminary to predict whether these p53-activating drugs will be effective in the treatment of TP53-mutant prostate cancer.

Results from two phase II clinical trials completed by the Radiation Therapy Oncology Group have reported that abnormalities in p53 (encoded by the TP53 gene) were found in ~20% of prostate cancer patients and were significantly associated with reduced survival and increased risk of distant metastasis.

A phase II clinical trial (RTOG 9202) has reported that prostate cancer patients with abnormal p53 status benefited from long-term hormone therapy, compared to short-term hormone therapy, when combined with radiation treatment.

Treatment strategies evaluating p53-activating drugs are beginning to enter phase I clinical evaluation (such as APR-246), and include patients with prostate cancer. The results are too preliminary to predict whether these p53-activating drugs will be effective in the treatment of TP53-mutant prostate cancer.

Results from two phase II clinical trials completed by the Radiation Therapy Oncology Group have reported that abnormalities in p53 (encoded by the TP53 gene) were found in ~20% of prostate cancer patients and were significantly associated with reduced survival and increased risk of distant metastasis.

PubMed ID's
17689883, 18059157, 22965953, 19544539
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 all 10 results Per Page:
Protocol # Title Location Status Match
NCT01999972 A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced Solid Tumors A Phase 1b Study Of Axitinib In Combination With Crizotinib In Patients With Advanced 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
NCT02082210 A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer MGH Open D
NCT02200614 Efficacy and Safety Study of BAY1841788 (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS) Efficacy and Safety Study of BAY1841788 (ODM-201) in Men With High-risk Non-metastatic Castration-resistant Prostate Cancer (ARAMIS) MGH Open D
NCT02219711 Phase 1/1b Study of MGCD516 in Patients With Advanced Cancer Phase 1/1b Study of MGCD516 in Patients With Advanced Cancer MGH Open D
NCT02655822 Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers MGH Open D
NCT01631552 Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers Phase I/II Study of IMMU-132 in Patients With Epithelial Cancers MGH Open D
NCT02709889 Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors MGH Open D
NCT01391143 Safety Study of MGA271 in Refractory Cancer Safety Study of MGA271 in Refractory Cancer MGH Open D
NCT02607228 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer MGH Open D
MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

Additional clinical trials may be applicable to your search criteria, but they may not be available at MGH. These clinical trials can typically be found by searching the clinicaltrials.gov website.
Trial Status: Showing all 10 results Per Page:
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