Prostate Cancer, FGFR 1, 2, 3 and 4, All Genetic Alterations

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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 FGFR 1, 2, 3 and 4  - General Description
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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 All Genetic Alterations  in FGFR 1, 2, 3 and 4
As explained above, specific types of tumors are associated with different genetic alterations. These include mutations, where a single nucleotide change in the gene can confer an altered FGFR protein that cannot be regulated normally. A second type of genetic alteration in FGFR family members involves insertions or deletions. In this case, a portion of the FGFR is missing, or, a portion of some other gene has been inserted in the FGFR gene, altering its normal function and regulation. A third type of genetic alteration in FGFR is translocation, where a whole portion of the FGFR gene has broken away from the rest of the gene, and attached iteself to another gene. These fusion proteins have part of FGFR, and part of another protein, and do not behave normally. Genetic testing of tumors identifies each of these genetic changes in a tumor, indicating specific treatment options.
As explained above, specific types of tumors are associated with different genetic alterations. These include mutations, where a single nucleotide change in the gene can confer an altered FGFR protein that cannot be regulated normally. A second type of genetic alteration in FGFR family members involves insertions or deletions. In this case, a portion of the FGFR is missing, or, a portion of some other gene has been inserted in the FGFR gene, altering its normal function and regulation. A third type of genetic alteration in FGFR is translocation, where a whole portion of the FGFR gene has broken away from the rest of the gene, and attached iteself to another gene. These fusion proteins have part of FGFR, and part of another protein, and do not behave normally. Genetic testing of tumors identifies each of these genetic changes in a tumor, indicating specific treatment options.

Genetic alterations in FGFR family members have been found in prostate cancers. FGFR1 is frequently amplified in prostate tumors. FGFR2 has been found rarely in metastatic prostate cancer. FGFR3 is found to be mutated infrequently in prostate cancers. FGFR4 is amplified in a significant number of prostate tumors, depending somewhat on the stage of the cancer.

Testing for genetic alterations in FGFR can be performed at the MGH Cancer Center. Clinical trials for treatment with FGFR inhibitors are also underway at the MGH Cancer Center.

Source N. Hallinan et al., Cancer Treatment Reviews 46 (2016) 51-62.

Genetic alterations in FGFR family members have been found in prostate cancers. FGFR1 is frequently amplified in prostate tumors. FGFR2 has been found rarely in metastatic prostate cancer. FGFR3 is found to be mutated infrequently in prostate cancers. FGFR4 is amplified in a significant number of prostate tumors, depending somewhat on the stage of the cancer.

Testing for genetic alterations in FGFR can be performed at the MGH Cancer Center. Clinical trials for treatment with FGFR inhibitors are also underway at the MGH Cancer Center.

Source N. Hallinan et al., Cancer Treatment Reviews 46 (2016) 51-62.

PubMed ID's
27109926
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing all 9 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
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 9 results Per Page:
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