Scientists at the University of California-San Diego report that an investigational drug candidate called tipifarnib showed promise in treating head and neck squamous cell carcinoma (HNSCC) tumors with mutations in the HRAS gene. Head and neck cancer is one of the leading causes of cancer-related deaths worldwide, and squamous cell carcinomas account for the majority of these cases.
The study Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas, published in Molecular Cancer Therapeutics, findings shed new light on the HRAS gene, a member of the RAS family of genes that produce proteins that regulate a variety of cellular processes, including growth, movement and differentiation. In 4 to 8 percent of HNSCC tumors, the HRAS gene is mutated.
Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FT substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS mutant tumors might be susceptible to tipifarnib-mediated inhibition of FT, write the investigators.
Here, we report the characterization of tipifarnib activity in a wide panel of HRAS mutant and wild type HNSCC xenograft models. Tipifarnib treatment displaced both mutant and wild type HRAS from membranes but only inhibited proliferation, survival and spheroid formation of HRAS mutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRAS mutant xenografts tested but displayed no activity in six HRAS wild type PDX models.
Mechanistically, drug treatment resulted in reduction of MAPK pathway signaling, inhibition of proliferation and induction of apoptosis and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FT inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDX.
These preclinical findings support that HRAS represents a druggable oncogene in HNSCC through FT inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.
This preclinical research has the potential to extend to the entire HNSCC patient community, whose overall survival rates are limited in recurrent or metastatic disease, and existing therapeutic options that are far from optimal, with response rates of roughly 10 to 20 percent, said senior co-author J. Silvio Gutkind, PhD, Distinguished Professor of Pharmacology and associate director of basic science at UC San Diego Moores Cancer Center.
These preclinical findings support the idea that HRAS represents a druggable oncogene in HNSCC through tipifarnibs inhibition of a key enzyme. It is a precision therapeutic option for HNSCCs harboring HRAS mutations.
In the study, UC San Diego researchers found that cell line- and patient-derived HNSCC models harboring HRAS mutations were highly sensitive to tipifarnib, which the authors said has demonstrated encouraging preliminary clinical activity in patients with relapsed or refractory HRAS-mutant HNSCC to date.
Currently, Kura Oncology, a San Diego-based biopharmaceutical company, is conducting a nationwide clinical trialto assess the safety and efficacy of tipifarnib in head and neck cancer with HRAS mutations. Employees of Kura are co-authors of the new paper. UC San Diego is not part of the trial.
Treatment with tipifarnib, wrote study authors, had a multifaceted effect on the biology of HRAS-mutant HNSCC tumors, reducing oncogenic signaling and proliferation, while increasing apoptosis, blocking angiogenesis, and driving squamous differentiation of tumors.
Head and neck cancer accounts for approximately 650,000 cases and 330,000 deaths annually worldwide. In the United States, approximately 4 percent of all cancers are head and neck, with an estimated 65,630 persons diagnosed each year, two-thirds of them men and 14,500 deaths, according to Cancer.Net.
Follow this link:
- Who are We? - November 7th, 2009 [November 7th, 2009]
- Vilsack targeted for his Pro-GMOs stand - November 7th, 2009 [November 7th, 2009]
- Call for technology to produce cellulosic ethanol - November 7th, 2009 [November 7th, 2009]
- Kenyan scientists weigh on GMOs - November 7th, 2009 [November 7th, 2009]
- Indian researcher makes a case for biotechnology - November 7th, 2009 [November 7th, 2009]
- Michigan smoothens the way for alternative energy investors - November 7th, 2009 [November 7th, 2009]
- Link of ethanol use to high food prices questioned - November 7th, 2009 [November 7th, 2009]
- EU challenges France on GM Maize - November 7th, 2009 [November 7th, 2009]
- POET rolls out cellulosic ethanol plant - November 7th, 2009 [November 7th, 2009]
- There’s a bright future for cellulosic ethanol investment - November 7th, 2009 [November 7th, 2009]
- Cellulosic ethanol can considerably reduce gasoline use by 2030 - November 7th, 2009 [November 7th, 2009]
- Human Genetic Engineering - Background - November 7th, 2009 [November 7th, 2009]
- Human Genetic Engineering - History - November 7th, 2009 [November 7th, 2009]
- Human Genetic Engineering - Methods - November 7th, 2009 [November 7th, 2009]
- Human Genetic Engineering - Uses - November 7th, 2009 [November 7th, 2009]
- Human Genetic Engineering - Controversy - November 7th, 2009 [November 7th, 2009]
- Human Genetic Engineering - In popular culture - November 7th, 2009 [November 7th, 2009]
- Human genetic engineering - An Introduction - November 7th, 2009 [November 7th, 2009]
- Human Genetic Engineering - A Very Hot Issue! - November 7th, 2009 [November 7th, 2009]
- What are the risks of genetic engineering in humans? (human genetic engineering) - November 7th, 2009 [November 7th, 2009]
- What are the benefits of human genetic engineering? (human genetic engineering) - November 7th, 2009 [November 7th, 2009]
- Genetic Engineering - Ethics and Controversy - November 7th, 2009 [November 7th, 2009]
- Genetic Engineering Ethics In Science Fiction - November 7th, 2009 [November 7th, 2009]
- Genetic Engineering Ethics - November 7th, 2009 [November 7th, 2009]
- Welcome to Pest Control Exterminator Network - December 13th, 2009 [December 13th, 2009]
- OMD - Genetic Engineering - August 27th, 2011 [August 27th, 2011]
- X-Ray Spex - Genetic Engineering - August 27th, 2011 [August 27th, 2011]
- Ancient Alien Nephilim, Giants, Mutants, Genetic Engineering, and Hybrids (2-6) - August 28th, 2011 [August 28th, 2011]
- Human-Plant Hybrid (Genetic Engineering at Home) - August 28th, 2011 [August 28th, 2011]
- Ancient Alien Nephilim, Giants, Mutants, Genetic Engineering, and Hybrids (1-6) - August 29th, 2011 [August 29th, 2011]
- 3. Genetic Engineering - August 29th, 2011 [August 29th, 2011]
- Genetic engineering nightmare - August 31st, 2011 [August 31st, 2011]
- Ancient Alien Nephilim, Giants, Mutants, Genetic Engineering, and Hybrids (3-6) - August 31st, 2011 [August 31st, 2011]
- Future of genetic engineering - by Futurist Dr Patrick Dixon. Genetic mutations and genetic disorders. Gene science by conference keynote speaker - September 2nd, 2011 [September 2nd, 2011]
- Genetic engineering: The world's greatest scam? - September 3rd, 2011 [September 3rd, 2011]
- Watch Fed Up! Genetic Engineering, Industrial Agriculture and Sustainable Alternatives Full Movie Online Part 1/15 - September 3rd, 2011 [September 3rd, 2011]
- Ancient Alien Nephilim, Giants, Mutants, Genetic Engineering, and Hybrids (5-6) - September 5th, 2011 [September 5th, 2011]
- Genetic Engineering, Humans with Animals. - September 6th, 2011 [September 6th, 2011]
- Is Genetic Engineering Good for the Environment? - September 7th, 2011 [September 7th, 2011]
- Open Source Food and Genetic Engineering - Michael Pollan - September 10th, 2011 [September 10th, 2011]
- Ancient Alien ( demons ) Nephilim Giants, Mutants Genetic Engineering and Hybrids.avi - September 11th, 2011 [September 11th, 2011]
- MUST SEE : Genetic Engineering Corn Grows in Sand ! For Those That Appreciate Nature ! - September 12th, 2011 [September 12th, 2011]
- Designing Humanity - Genetic Engineering - September 14th, 2011 [September 14th, 2011]
- Genetic Modification | QUEEN ANNE SCIENCE CAFE - September 14th, 2011 [September 14th, 2011]
- Genetic Engineering in California Agriculture - September 15th, 2011 [September 15th, 2011]
- Genetic Engineering Animation - September 15th, 2011 [September 15th, 2011]
- Proof Of Ancient Genetic Engineering - September 15th, 2011 [September 15th, 2011]
- Joad Cressbeckler Fears Genetic Modification Causes 'Wrath-Minded Taters' - September 16th, 2011 [September 16th, 2011]
- Ethical Concerns With Genetic Engineering - September 16th, 2011 [September 16th, 2011]
- Scientists under Attack - Genetic Engineering in the magnetic Field of Money TRAILER - September 17th, 2011 [September 17th, 2011]
- Genetic Modification - September 18th, 2011 [September 18th, 2011]
- Genetic Engineering Not a New Science - Pamela Ronald - September 23rd, 2011 [September 23rd, 2011]
- The Island of Dr. Moreau prt. IV - September 28th, 2011 [September 28th, 2011]
- Ancient Alien Nephilim, Giants, Mutants, Genetic Engineering, and Hybrids (4-6) - September 30th, 2011 [September 30th, 2011]
- 4. Genetic Engineering (cont.) - October 2nd, 2011 [October 2nd, 2011]
- Ancient Alien Nephilim, Giants, Mutants, Genetic Engineering, and Hybrids (6-6) - October 4th, 2011 [October 4th, 2011]
- Islands at Risk (Part 3) - Genetic Engineering in Hawai'i - October 4th, 2011 [October 4th, 2011]
- Morgellons Is Genetic Engineering , A Silent Superbug - October 4th, 2011 [October 4th, 2011]
- Islands at Risk (Part 2) - Genetic Engineering in Hawai'i - October 4th, 2011 [October 4th, 2011]
- The Ethics of Genetically Engineering Children - Arthur Caplan - October 4th, 2011 [October 4th, 2011]
- Disney Geneticists Debut New Child Stars - October 4th, 2011 [October 4th, 2011]
- Genetic Engineering and Society, Lecture 1a, Honors Collegium 70A, UCLA - October 4th, 2011 [October 4th, 2011]
- OMD - Genetic Engineering (312mm Version) (Audio Only) - October 4th, 2011 [October 4th, 2011]
- The difference between normal and genetically modified food - October 4th, 2011 [October 4th, 2011]
- Bioethics Of Human Genetic Engineering - Documentary Video - October 6th, 2011 [October 6th, 2011]
- Islands at Risk (Part 1) - Genetic Engineering in Hawai'i - October 6th, 2011 [October 6th, 2011]
- Coast To Coast AM: Genetic Engineering 3-24-2011 Download Link - October 6th, 2011 [October 6th, 2011]
- Lloyd Pye - Ancient Genetic Engineering - October 13th, 2011 [October 13th, 2011]
- X RAY SPEX - ROUNDHOUSE LONDON GENETIC ENGINEERING - Video - October 13th, 2011 [October 13th, 2011]
- OMD - Genetic Engineering 1983 - Video - October 14th, 2011 [October 14th, 2011]
- OMD - GENETIC ENGINEERING - Video - October 14th, 2011 [October 14th, 2011]
- Mechanism of Recombination - Video - October 15th, 2011 [October 15th, 2011]
- Harvard Prof. Michael Sandel on Human Genetic Modification, Berkeley, CA, 7 May 2007 - Video - October 15th, 2011 [October 15th, 2011]
- Genetic Engineering [Medical Ethics Series] - (excerpt) - Video - October 15th, 2011 [October 15th, 2011]
- Genetic Engineering and Society, Lecture 1b, Honors Collegium 70A, UCLA - Video - October 24th, 2011 [October 24th, 2011]
- Genomics: genetic modification (genetic engineering) and the human gene project - Video - October 26th, 2011 [October 26th, 2011]
- Genetically Engineering Intelligent Babies - Horizon: Are We Still Evolving? Preview - BBC Two - Video - October 27th, 2011 [October 27th, 2011]
- "GENETIC ENGINEERING" GERMAN REGIME feat THIRSTIN HOWL THE3RD - Video - October 28th, 2011 [October 28th, 2011]
- Science 360: Genetic Engineering - Video - October 31st, 2011 [October 31st, 2011]
- UFOTV Presents... - Bad Seed: Danger of Genetically Modified Food - Video - November 8th, 2011 [November 8th, 2011]