Head & Neck Cancers, FGFR 1, 2, 3 and 4

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Expand Collapse Head & Neck Cancers  - General Description This year about 52,000 people in the U.S. will be told by a doctor that they have cancer of the head and neck. Approximately 70% of these new patients will be men. However, about 265,000 Americans remain alive today after having been diagnosed with head & neck cancer.

Head and neck cancers develop inside the mouth (in the oral cavity), nose (nasal cavity), or the tube (pharynx) that runs from the back of the nose to the top of the windpipe (trachea) and the top of the tube that goes to the stomach (esophagus). Cancers that begins in the lips, salivary glands, throat or voice box (larynx) are also classified as head and neck cancer. However, cancers of the esophagus, eye, brain, and thyroid gland usually aren't regarded as head and neck cancers, and neither are cancers of the skin, muscles, or bones of the head and neck. Head and neck cancers usually begin in squamous cells and therefore are called squamous cell carcinomas. The FDA has approved the targeted therapy cetuximab (Erbitux) for treatment of patients with squamous cell carcinoma of the head and neck.

Head and neck 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. 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 can also be performed to determine if the cancer has spread. These include MRI and CT scans.

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

Source: National Cancer Institute, 2012
An estimated 644,000 new cases of head and neck cancer are diagnosed each year worldwide, posing the sixth leading cause of cancer death. The American Cancer Society projected 39,400 new head and neck cancer diagnoses and 7,900 cancer deaths in the U.S. in 2009. In Europe, the projected incidence for 2008 was 132,300 and the mortality was 62,800. The estimated annual incidence of head and neck cancers is 2-4-fold higher among men than women.

More than 95% of head and neck cancers are of squamous cell histology (SCCHN) and originate in the mucosal lining of the upper aerodigestive tract. Anatomic sites include the lip/oral cavity, nasopharynx, oropharynx, hypopharynx and larynx. Common risk factors include tobacco use (smoking and/or chewing) and alcohol consumption, with a suggested synergistic effect. Less common risk factors include chewing of betel nuts (a common practice in some parts of Asia) and occupational exposures. Infection with the oncogenic human papillomavirus (HPV) has been identified as a distinct and rising risk factor, particularly among patients with squamous cell carcinoma of the oropharynx, specifically tonsils and the base of tongue. The incidence of SCCHN has increased steadily during the last several decades, whereas the incidence of tobacco-associated SCCHN has decreased, to the point where the incidence of HPV-associated and non-HPV-associated cancers is nearly equivalent. HPV status has been shown to strongly predict outcomes in patients with locally or regionally advanced oropharynx squamous cell carcinoma, but the prognostic impact of HPV in recurrent/metastatic SCCHN is currently less well understood.

Molecular hallmarks of SCCHN that have been identified as key drivers over the past decade include gene mutations in TP53, CDKN2A, PIK3CA, PTEN and HRAS. Recent investigations using high-throughput gene sequencing also found mutations in other cell differentiation-related genes, such as NOTCH1, NOTCH2, NOTCH3 and TP63, suggesting that deregulation of the terminal differentiation program is critical for squamous cancer development.

The epidermal growth factor receptor (EGFR) and its downstream molecular pathways are of particular importance in SCCHN. EGFR is overexpressed in up to 90% of all SCCHN. High expression levels of EGFR and transforming growth factor (TGF, a ligand of EGFR), as well as EGFR gene amplification, has been associated with increased resistance to treatment and poorer clinical outcome, including decreased disease-free and overall survival.

Therapeutic options and treatment decisions at first diagnosis are dependent on disease stage. For early-stage and locally advanced disease (the majority of new
cases), therapy is tailored to the primary site of disease, feasibility of organ preservation and prognosis and functional outcomes following therapy. Despite aggressive treatment, only 35% to 55% of patients who present with locally advanced SCCHN remain alive and free of disease 3 years after standard curative treatment. Between 30-40% of patients develop loco-regional recurrences, with distant metastases occurring in 20-30% of cases. The majority of recurrences appear within 2 years of initial treatment. An additional 10-20% of patients have evidence of distant metastases at the time of first diagnosis.

For patients with recurrent/metastatic SCCHN who are considered incurable with surgery or radiotherapy, first-line palliative treatment options include platinum agents, taxanes, methotrexate, 5-fluorouracil and cetuximab. Even with combination regimens, objective radiographic responses are achieved in fewer than 40% of patients in most large studies. Patients with disease progression on platinum-based therapy have limited treatment options and a poor prognosis. In these patients, overall response to second-line cytotoxic therapy has been 3%. Poor survival at this stage is related to the development of metastases and poor local disease control.

Source: National Cancer Institute, 2012
This year about 52,000 people in the U.S. will be told by a doctor that they have cancer of the head and neck. Approximately 70% of these new patients will be men. However, about 265,000 Americans remain alive today after having been diagnosed with head & neck cancer.

Head and neck cancers develop inside the mouth (in the oral cavity), nose (nasal cavity), or the tube (pharynx) that runs from the back of the nose to the top of the windpipe (trachea) and the top of the tube that goes to the stomach (esophagus). Cancers that begins in the lips, salivary glands, throat or voice box (larynx) are also classified as head and neck cancer. However, cancers of the esophagus, eye, brain, and thyroid gland usually aren't regarded as head and neck cancers, and neither are cancers of the skin, muscles, or bones of the head and neck. Head and neck cancers usually begin in squamous cells and therefore are called squamous cell carcinomas. The FDA has approved the targeted therapy cetuximab (Erbitux) for treatment of patients with squamous cell carcinoma of the head and neck.

Head and neck 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. 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 can also be performed to determine if the cancer has spread. These include MRI and CT scans.

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

Source: National Cancer Institute, 2012
An estimated 644,000 new cases of head and neck cancer are diagnosed each year worldwide, posing the sixth leading cause of cancer death. The American Cancer Society projected 39,400 new head and neck cancer diagnoses and 7,900 cancer deaths in the U.S. in 2009. In Europe, the projected incidence for 2008 was 132,300 and the mortality was 62,800. The estimated annual incidence of head and neck cancers is 2-4-fold higher among men than women.

More than 95% of head and neck cancers are of squamous cell histology (SCCHN) and originate in the mucosal lining of the upper aerodigestive tract. Anatomic sites include the lip/oral cavity, nasopharynx, oropharynx, hypopharynx and larynx. Common risk factors include tobacco use (smoking and/or chewing) and alcohol consumption, with a suggested synergistic effect. Less common risk factors include chewing of betel nuts (a common practice in some parts of Asia) and occupational exposures. Infection with the oncogenic human papillomavirus (HPV) has been identified as a distinct and rising risk factor, particularly among patients with squamous cell carcinoma of the oropharynx, specifically tonsils and the base of tongue. The incidence of SCCHN has increased steadily during the last several decades, whereas the incidence of tobacco-associated SCCHN has decreased, to the point where the incidence of HPV-associated and non-HPV-associated cancers is nearly equivalent. HPV status has been shown to strongly predict outcomes in patients with locally or regionally advanced oropharynx squamous cell carcinoma, but the prognostic impact of HPV in recurrent/metastatic SCCHN is currently less well understood.

Molecular hallmarks of SCCHN that have been identified as key drivers over the past decade include gene mutations in TP53, CDKN2A, PIK3CA, PTEN and HRAS. Recent investigations using high-throughput gene sequencing also found mutations in other cell differentiation-related genes, such as NOTCH1, NOTCH2, NOTCH3 and TP63, suggesting that deregulation of the terminal differentiation program is critical for squamous cancer development.

The epidermal growth factor receptor (EGFR) and its downstream molecular pathways are of particular importance in SCCHN. EGFR is overexpressed in up to 90% of all SCCHN. High expression levels of EGFR and transforming growth factor (TGF, a ligand of EGFR), as well as EGFR gene amplification, has been associated with increased resistance to treatment and poorer clinical outcome, including decreased disease-free and overall survival.

Therapeutic options and treatment decisions at first diagnosis are dependent on disease stage. For early-stage and locally advanced disease (the majority of new
cases), therapy is tailored to the primary site of disease, feasibility of organ preservation and prognosis and functional outcomes following therapy. Despite aggressive treatment, only 35% to 55% of patients who present with locally advanced SCCHN remain alive and free of disease 3 years after standard curative treatment. Between 30-40% of patients develop loco-regional recurrences, with distant metastases occurring in 20-30% of cases. The majority of recurrences appear within 2 years of initial treatment. An additional 10-20% of patients have evidence of distant metastases at the time of first diagnosis.

For patients with recurrent/metastatic SCCHN who are considered incurable with surgery or radiotherapy, first-line palliative treatment options include platinum agents, taxanes, methotrexate, 5-fluorouracil and cetuximab. Even with combination regimens, objective radiographic responses are achieved in fewer than 40% of patients in most large studies. Patients with disease progression on platinum-based therapy have limited treatment options and a poor prognosis. In these patients, overall response to second-line cytotoxic therapy has been 3%. Poor survival at this stage is related to the development of metastases and poor local disease control.

Source: National Cancer Institute, 2012
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 Head & Neck Cancers
Genetic alterations have been found in FGFR family members in Head and Neck cancers. Amplification of FGFR1 occurs in some head and neck tumors.

Testing for genetic alterations in FGFR genes is performed at MGH or at other major centers.

Genetic alterations have been found in FGFR family members in Head and Neck cancers. Amplification of FGFR1 occurs in some head and neck tumors.

Testing for genetic alterations in FGFR genes is performed at MGH or at other major centers.

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 20 Per Page:
12Next »
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
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
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
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
NCT00585195 A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer MGH Open D
NCT02834247 A Study of TAK-659 in Combination With Nivolumab in Participants With Advanced Solid Tumors A Study of TAK-659 in Combination With Nivolumab in Participants With Advanced Solid Tumors MGH Open D
NCT02488759 A Study to Investigate the Safety and Efficacy of Nivolumab and Nivolumab Plus Ipilimumab in Virus-associated Tumors A Study to Investigate the Safety and Efficacy of Nivolumab and Nivolumab Plus Ipilimumab in Virus-associated Tumors MGH Open D
NCT02551185 ACY 241 in Combination With Paclitaxel in Patients With Advanced Solid Tumors ACY 241 in Combination With Paclitaxel in Patients With Advanced Solid Tumors MGH Open D
NCT01953926 An Open-label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR Gene Amplification An Open-label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR Gene Amplification MGH Open D
Trial Status: Showing Results: 1-10 of 20 Per Page:
12Next »
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