Gene mutations that contribute to head and neck cancer also provide ‘precision’ treatment targets

Source: www.sciencedaily.com Author: Medical College of Georgia at Augusta University About one-fifth of often deadly head and neck cancers harbor genetic mutations in a pathway that is key to normal cell growth, and scientists report those mutations, which enable abnormal cancer cell growth, can also make the cancer vulnerable. Keys to targeting that vulnerability include individualized genomic analysis to identify a patient's specific mutation, and finding the drugs that directly target it, investigations that should be given more attention in cancer therapy development, they report in a review article in the journal NPJ Genomic Medicine. The MAPK pathway is a "signaling hub" for cells important to the usual development of the head and neck region, and activating key pathway constituents, like the genes MAPK1 and HRAS, is known to drive the growth of a variety of cancers, says Dr. Vivian Wai Yan Lui, molecular pharmacologist and translational scientist at the Georgia Cancer Center and Medical College of Georgia and the paper's corresponding author. But the mutations in the genes in the MAPK pathway that enable tumor growth can also make it sensitive to drug therapy, says Lui. While a lot of discovery is still needed to find more mutations in the MAPK pathway and the drugs that target them, Lui says they are among the most logical treatment targets for this tough-to-treat cancer. As she speaks, she is looking in her lab for drugs that kill head and neck primary tumors from patients, and at the genetics behind how they [...]

A better understanding of how genetics influences responses to mouth cancer drugs could lead to improved treatment

Source: medicalxpress.com Author: provided by Agency for Science, Technology and Research (A*STAR) A single letter DNA mutation is a big determinant of whether patients with advanced oral cancer respond to treatments. Researchers from the National Cancer Centre Singapore (NCCS) and A*STAR who uncovered the mechanisms behind this effect hope their findings will help doctors target treatment more effectively. Oral squamous cell carcinoma (OSCC) is characterized by the uncontrolled growth of thin, scale-like squamous cells in the outer layer of the mouth. Only around 50 per cent of patients who are treated through surgery or radiotherapy are cured, and the average duration of survival of those with advanced OSCC that recurs following treatment is just 6 to 9 months. Epidermal growth factor receptors (EGFRs) play important roles in driving the progression of some OSCCs. Drugs that target them, however, only work in a small number of patients. A 2012 clinical trial led by Daniel Tan at NCCS and A*STAR's Genome Institute of Singapore had found that the EGFR-blocking drug gefitinib worked well in two patients with two copies of the EGFR coding gene with an adenine (A) nucleobase in place of the more common guanine (G) at a particular location. More recently, tests by Gopal Iyer, also at NCCS, and Tan showed that OSCC patient-derived cells with the above A/A genotype were sensitive to gefitinib and erlotinib, another EGFR blocker. Those with the G/G or G/A variants exhibited resistance to the drugs. Editing the DNA of the G/G genotype cells to [...]

Targeted Drugs No Help in Head and Neck Cancer

Source: medpagetoday.comAuthor: Charles Bankhead, Staff Writer, MedPage TodayDate: March 05, 2013    The addition of targeted agents to standard chemotherapy failed to improve efficacy in two different trials of advanced head and neck cancer. In one trial, patients given gefitinib (Iressa) in addition to docetaxel lived about a month longer than those who received docetaxel plus placebo. In the other trial, adding erlotinib (Tarceva) to cisplatin-based chemoradiation did not improve response rate or progression-free survival. However, neither regimen was associated with increased toxicity compared with standard chemotherapy, investigators reported online in the Journal of Clinical Oncology. Noting the lack of useful biomarkers to guide the use of targeted agents, the authors of an accompanying editorial said that experience to date suggests current strategies amount to "skimming the surface of a problem that is exceedingly complex." "It is unlikely that genomic sequencing alone will represent a panacea to the therapeutic challenges in squamous cell carcinoma of the head and neck," said Aaron R. Hansen, MBBS, and Lillian L. Siu, MD, of Princess Margaret Cancer Center in Toronto. "Comprehensive characterization that encompasses a broader omics-based molecular evaluation, as well as immune function assessments, is urgently needed." The rationale for the gefitinib and erlotinib trials came from evidence that the drugs targeting epidermal growth factor receptors (EGFR) have synergism with conventional chemotherapeutic agents, have radiosensitizing properties, and have demonstrated modest activity as monotherapy in some clinical studies. Cetuximab (Erbitux), another EGFR inhibitor, has been approved for use with radiation therapy or as monotherapy [...]

2013-03-07T14:25:20-07:00March, 2013|Oral Cancer News|

New drug combination could prevent head and neck cancer in high-risk patients

Source: www.sciencedaily.com Author: staff A new drug combination shows promise in reducing the risk for patients with advanced oral precancerous lesions to develop squamous cell carcinoma of the head and neck. The results of the study, which included preclinical and clinical analyses, were published in Clinical Cancer Research, a journal of the American Association for Cancer Research. "Squamous cell carcinoma of the head and neck (SCCHN) is the most common type of head and neck cancer," said Dong Moon Shin, M.D., professor of hematology, medical oncology and otolaryngology at Emory University School of Medicine, and director of the Cancer Chemoprevention Program at Winship Cancer Institute at Emory University in Atlanta, Ga. "The survival rate for patients with SCCHN is very poor. An effective prevention approach is desperately needed, especially since we can identify patients who are at extremely high risk: those with advanced oral precancerous lesions." Based on prior research suggesting a role for epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in promoting SCCHN, Shin and colleagues believed combining an EGFR inhibitor and a COX-2 inhibitor could provide an effective chemopreventive approach. They found that the combination of the EGFR inhibitor erlotinib and the COX-2 inhibitor celecoxib was more effective for inhibiting the growth of human SCCHN cell lines compared with either drug alone. In addition, treating mice with the drug combination prior to transplanting them with human SCCHN cells more effectively suppressed cancer cell growth than did pretreating the mice with either drug alone. Based on these preclinical [...]

2013-02-20T07:38:26-07:00February, 2013|Oral Cancer News|

Erlotinib dose doubled for smokers with head/neck cancer

Source: www.oncologyreport.com Author: Miriam E. Tucker Giving smokers a higher, short-course dose of erlotinib before definitive surgery for squamous cell carcinoma of the head and neck resulted in favorable responses for the first patients evaluated in a small pilot study. Investigators gave 300 mg of erlotinib (Tarceva) to smokers daily and 150 mg daily to nonsmokers who had a waiting period of more than 14 days before scheduled surgery for head and neck cancer. Seven of the 10 patients evaluated so far had partial responses and 3 had stable disease, according to a poster presented at a head and neck cancer symposium sponsored by the American Society for Radiation Oncology. The study was based on recent data in non–small cell lung cancer (NSCLC) patients showing that smokers metabolize erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, twice as quickly as do nonsmokers (J. Clin. Oncol. 2009;27:1220-6), said lead author Dr. Mercedes Porosnicu of Wake Forest Baptist Medical Center in Winston Salem, N.C. That study established the maximum tolerated dose of erlotinib at 300 mg daily in NSCLC patients who smoke. Dr. Poroniscu’s presentation included the case study of a smoker with a very large oral cavity tumor protruding through his lips. He was described as being in significant pain and unable to eat or chew. The first CT scan showed a tumor of at least 8 cm and there was "significant metabolic activity" on PET scan. "At 6 days of erlotinib treatment, his tumor was obviously smaller and he could [...]

‘Synthetic lethality’ strategy improves molecularly targeted cancer therapy

Source: www.physorg.com Author: Fox Chase Cancer Center Molecularly targeted therapies can reduce tumors rapidly. However, not all tumors respond to the drugs, and even those that do often develop resistance over time. Looking for a way to combat the problem of resistance, researchers at Fox Chase Cancer Center hypothesized that hitting already weakened cancer cells with a second targeted agent could kill them—but only if it was the right second agent. One well-validated molecular target for anti-cancer drugs is the epidermal growth factor receptor, or EGFR. Using a novel screening approach, investigators in the Fox Chase Developmental Therapeutics Program identified over 60 additional proteins that are necessary for cells to survive in the presence of an EGFR inhibitor. When they simultaneously blocked the EGFR inhibitors and any one of these other proteins, more of the cancer cells died. The researchers say this screening strategy to identify targets for effective combinations of cancer drugs will open the door for future therapies. Already, two clinical trials are under way to test innovative drug combinations suggested by the new tactic. "We found that knocking out one or the other target doesn't have a major effect, but knocking out both increases tumor cell death," says Igor Astsaturov, M.D., Ph.D., an assistant professor and medical oncologist at Fox Chase. Astsaturov led the study, which will be published in the September 21, 2010 issue of Science Signaling. To identify additional targets that would boost the effectiveness of EGFR inhibitors against cancer, Astsaturov and colleagues screened only [...]

2010-09-21T12:40:30-07:00September, 2010|Oral Cancer News|

Emory couples cancer drug with green tea extract to help fight cancers of the head and neck

Source: www.examiner.com Author: Kristina Bjoran Clinical researchers at the Emory University Winship Cancer Institute have discovered that pairing a popular cancer-fighting drug with green tea extract may help reduce the risks for neck and head cancers. The lead investigator in the trial is Dr. Dong Moon Shin, and he and his team have been working to combine the drug Erlotinib with an extract of green tea to observe the effects. Elrotinib is a drug that has been long used as an effective way to treat certain types of lung and pancreatic cancers. Neck and head cancers are more common than many know. The American Cancer Society touts that almost 50,000 Americans will be diagnosed with one of the two cancers this year alone, so this new trial at Emory may provide hope for those with pre-cancerous lesions related to the cancers. The chemical of interest in the green tea extract is called polyphenon E (PPE), and the lab experiments show that combing PPE with Elrontinib can potentially prevent the development of the cancers by targeting specific cellular activity in the pre-cancerous areas. Shin and his team are focusing on the lesions of the head and neck. Cancers of the head and neck have relatively low survival rates, and have not seen much of an increase over the past few decades. As the sixth most common type of cancer, this new study provides hope to those in need of a new, effective treatment.

2009-12-25T11:02:51-07:00December, 2009|Oral Cancer News|

DNA therapy for head and neck cancer

Source: Nature Reviews Clinical Oncology 6, 302 (June 2009) Author: Mandy Aujla Researchers have developed an antisense EGFR sequence to target EGFR, and found that this approach was safe and effective in patients with advanced squamous-cell carcinoma of the head and neck. Standard treatment for this type of cancer is suboptimal. Various drugs have been developed to block this increased signaling, such as cetuximab and erlotinib. These agents, however, have had limited success when used as monotherapy in treating squamous-cell carcinoma of the head and neck. Despite encouraging preclinical data these agents produce low response rates and are associated with toxic effects. Therefore, alternative approaches that target EGFR are needed. In this phase I trial, Lai and colleagues evaluated the safety and toxicity of EGFR antisense DNA therapy in 20 patients with advanced squamous-cell carcinoma of the head and neck. All patients included in the study had advanced disease that was unresponsive to standard therapies. The researchers tested six levels of the antisense EGFR at doses ranging from 60 to 1,920 g per injection, with three patients in each dose tier. The antisense EGFR was injected into the most accessible single tumor lesion once a week for 4 weeks. A biopsy was performed within 2 weeks of the final injection. A total of 17 patients completed the treatment course and were available for assessment. Of the five patients who achieved a clinical response, two had a complete response and three achieved a partial response. Two other patients had stable disease. [...]

Tarceva® and Avastin® safe and effective for patients with squamous-cell head and neck carcinoma

Source: professional.cancerconsultants.com Author: staff Researchers from the National Cancer Institute and the University of Chicago have reported that the combination of Tarceva® (erlotinib) and Avastin® (bevacizumab) is well tolerated and produces sustained responses in some patients with recurrent or metastatic squamous-cell head and neck carcinoma. The details of this study appeared in the March 2009 issue of Lancet Oncology.[1] Tarceva is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. EGFRs are small proteins that are found on the surface of all cells. EGFR binds exclusively to small growth factor proteins circulating in the blood. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote growth of a cell in a strictly controlled manner. However, in many cancer cells, EGFR is either abundantly over-expressed or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell. Tarceva is approved by the U.S. Food and Drug Administration (FDA) for the treatment of non–small cell lung cancer and has significant activity in a variety of tumors, including hepatocellular carcinoma, pancreatic cancer, colorectal cancer, and renal cell cancer. Avastin is a humanized monoclonal antibody that is targeted against the vascular endothelial growth factor (VEGF). Avastin is approved by the FDA for the initial treatment of advanced colorectal cancer in combination with 5-fluorouracil-based therapy and has demonstrated an improvement in survival when combined with Camptosar® (irinotecan)-based chemotherapy in the treatment of this disease. Avastin was also [...]

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