image:Dr. Vivian Wai Yan Lui view more
Credit: Michael Holahan, Augusta University
AUGUSTA, Ga. (April 28, 2022) 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 patients 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 papers 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 kill.
Its critical to the survival of the cancer, says Lui, and every cancer type likely has one or more drug-sensitizing mutations that may vary in individuals depending on how they got cancer.
If these types of studies continue to find the methodology works, gene panels might need to be developed to expedite target discovery in this very heterogenous cancer, the scientists write.
More clinical trials around the globe at institutions like MCG and the Georgia Cancer Center are essential to identifying these specific mutations and drugs that target them in a precision manner, Lui notes.
Also, next on the horizon is combining this precision medicine approach with immunotherapy that better enables a patients immune system to also target the cancer, she says.
Luis interest in the MAPK pathway solidified almost a decade ago at the University of Pittsburgh where she did her postdoctoral studies and eventually joined the faculty. Her mentor was Dr. Jennifer R. Grandis (now at the University of California, San Francisco), who led the head and neck cancer program there. The patient in his 30s, a heavy smoker and drinker, had stage four head and neck squamous cell carcinoma that had metastasized to his lymph nodes. The patient went to Pittsburgh for removal of the lymph nodes and the primary tumor but was fortunate enough to be eligible for a window of opportunity trial there. Before starting any standard treatment, he received a trial drug for 13 days, in his case an epidermal growth factor receptor, or EGFR, blocker. The receptor is involved in cell growth, and is found on some normal cells, including in the head and neck area where there is a lot of natural cell turnover because of exposure to things like food and drink. However, in cancer cells, including head and neck cancer cells, EGFR is abundantly expressed for the rapid growth critical to a tumors spread and survival.
The patient was given the drug, erlotinib, which was not known to be particularly effective in these cancers but was being looked at to see if it would quieten signaling of this factor that was important to the cancers growth. When he went for surgery following the trial, the surgeon called to report there was no cancer on his tongue and studies of his 36 lymph nodes indicated they also now showed no evidence of cancer. The patient was still doing well by the time the Pittsburgh colleagues published the paper two years later in 2015 in JAMA Oncology.
His was rightly called an exceptional response, the first Lui and her colleagues had found in head and neck cancer, and she had to figure out the mutation the drug targeted to enable such a response. Exceptional responders are how the National Cancer Institute describes people who have more than a six-month response to a therapy when they are running out of treatment options.
An EGFR gene mutation was a logical choice for his mutation. Harvard investigators had previously found that in non-small cell lung cancer, EGFR activating mutations could activate tumor cell growth, which also made tumor cells addicted to the signal from the mutated EGFR. The drug erlotinib could break the addiction and inhibit cancer cell growth.
Lui didnt find an EGFR mutation in this young mans pretreatment biopsy but reasoned the mutation had to have something to do with the receptors signaling network. She was surprised and the first to find it was a MAPK1 gene mutation, MAPK1 p.E322K specifically, that could also be found in liver, breast and other cancers.
When they later engineered the mutation in head and neck cancer cells, the already aggressive cells grew even faster, Lui says of a mutation that can result from habits like heavy smoking and drinking. They would also find that the particular mutation was very common in the United States in patients with head and neck cancer, while there was a wider spectrum of mutations present in Asians with the cancer.
Erlotinib had actually failed in clinical trials because it wasnt given to the right patients, which is what precision medicine is, Lui notes. In fact, laboratory studies had indicated that activation of MAPK1 confers resistance to erlotinib, she says, while this patients response clearly counters that. Follow up work by Grandis indicated that in patients actually, the higher the MAPK1 activation, the better the cancer responded to erlotinib.
To help move cancer treatment forward, Lui encourages physicians who come across these types of exceptional responses to report them, work with scientists to study them, then pursue clinical trials when appropriate.
For patients, her message is not to give up because with more high-levelanalysis of tumors, there might be a certain mutation that makes their cancer vulnerable to a specific medication, she says of these gene-drug responses that are the focal point of her translational work.
There are secrets that make the cancer vulnerable, Lui says. When cancer cells have an important gene mutation that they are activating or that cancer cells are addicted to for survival, then when you hit that signaling pathway, the cancer cells will die or be really well controlled.
Prior to the era of genomic medicine, when scientists began to identify and target a specific gene mutation, non-precision drug treatment of the MAPK pathway in head and neck cancers as well as other cancers were futile, and typically failed miserably in clinical trials, Lui and her colleagues write.
While the reasons may be uncertain, they likely include the wrong drug for that specific, problematic mutation, Lui says, as well as the fact that some MAPK pathway mutations are known to convey drug resistance.
Either way, there is a lot of work to do. Today there are just a handful of drugs that target specific, cancer-causing mutations in head and neck cancer but there arent effective precision drugs for about 80% of patients, Lui and her coauthors write.
But there is mounting evidence that targeting specific MAPK pathway mutations in the pathway like MAPK1, HRAS, KRAS and BRAF can be very effective for these patients.
As an example, the RAS inhibitor tipifarnib received Breakthrough Therapy Designation by the Food and Drug Administration in February 2021 for patients with a specific recurrent or metastatic HRAS-mutant head and neck squamous cell cancer. HRAS is involved in cell growth signaling.
Also, studies indicate that EGFR targeted therapy in metastatic non-small cell lung cancer, increases progression-free survival to a median of 18.9 months and median overall survival beyond three years and reduces death rates about 52%. In 2016 the Food and Drug Administration modified its approval of erlotinib to treat non-small cell lung cancer patients with the specific EGFR mutations. In 2020, the FDA approved erlotinib in combination with ramucirumab, a monoclonal antibody that binds to a receptor for vascular endothelial growth factor, or VEGF, which tumors use to grow the blood vessels they need to thrive, as a frontline treatment for these cancers. The FDA granted Breakthrough Therapy Designation to tipifarnib, an inhibitor of a protein which has the downstream effect of interfering in this case with mutations of the gene HRAS, which is also involved in cell division and in the MAPK pathway. There are now more than 1.5 million people with non-small cell lung cancer on precision medicine because of investigators who continued to examine the initial few responders, Lui says.
Lui is a native of Hong Kong, who was on the faculty of The Chinese University of Hong Kong before joining the MCG faculty in October 2021. In 2020 Lui and her colleagues reported that MAPK pathway mutations are a factor in about one-fifth of head and neck cancer patients and that unexpectedly these mutations are associated with longer patient survival than other causes like human papillomavirus.
Head and neck cancer is typically aggressive and often both the disease and its treatment are painful and disfiguring. It carries a higher risk of suicide than many other cancer types. The incidence of head and neck cancer is going up across the world, with causes including tobacco and/or alcohol use, air pollutants, cancer causing viruses like the sexually transmitted HPV, and Epstein-Barr virus, one of the most common viruses that is primarily spread by saliva and can cause problems like infectious mononucleosis. Other causes include poor dental hygiene and chewing betel nut, a stimulant which comes from the Areca palm plant, and is used as a recreational drug and as a still-unproven treatment for problems like schizophrenia and glaucoma. Chewing betel nut is a common cultural practice in South and Southeast Asia and the Asian Pacific. Its often chewed with products like tobacco and has been associated with cancer and a host of other medical problems like a slow heart rate and stomach ulcers.
The carcinogens largely damage the lining of the head and neck region resulting in one or more mutations that can lead to cancer.
Read the full study.
npj Genomic Medicine
Precision drugging of the MAPK pathway in head and neck cancer
16-Mar-2022
Read the original post:
Gene mutations that contribute to head and neck cancer also provide precision treatment targets - EurekAlert
- Living with Lupus: Hematopoietic Stem Cell Therapy for Lupus [Last Updated On: September 24th, 2011] [Originally Added On: September 24th, 2011]
- Unlocking the Secrets of Blod Cell Therapy - Video [Last Updated On: October 14th, 2011] [Originally Added On: October 14th, 2011]
- Alzheimers Neurons Created from Pluripotent Stem Cells [Last Updated On: January 28th, 2012] [Originally Added On: January 28th, 2012]
- Verastem to Present at Molecular Medicine Tri-Conference Symposium “Targeting Cancer Stem Cells in Oncology” [Last Updated On: February 16th, 2012] [Originally Added On: February 16th, 2012]
- Plethora of New Products to be Showcased at 2012 Molecular Medicine Tri-Conference [Last Updated On: February 18th, 2012] [Originally Added On: February 18th, 2012]
- Leukaemia cells have a remembrance of things past [Last Updated On: April 26th, 2012] [Originally Added On: April 26th, 2012]
- Science Translational Medicine and the DMM Global Foundation Announce Days of Molecular Medicine 2012 "The ... [Last Updated On: July 13th, 2012] [Originally Added On: July 13th, 2012]
- Common RNA pathway found in ALS and dementia [Last Updated On: October 1st, 2012] [Originally Added On: October 1st, 2012]
- Culprits behind ALS and dementia share common pathway [Last Updated On: October 2nd, 2012] [Originally Added On: October 2nd, 2012]
- 22 Molecular Medicine—Cloning and Stem Cells - Video [Last Updated On: November 1st, 2012] [Originally Added On: November 1st, 2012]
- Stem Cells and the Future of Medicine - Larry Goldstein, Ph.D. at TEDxAmericasFinestCity - Video [Last Updated On: November 1st, 2012] [Originally Added On: November 1st, 2012]
- Program in Molecular Medicine - UMass Medical School ... [Last Updated On: September 26th, 2016] [Originally Added On: September 26th, 2016]
- Molecular medicine - Wikipedia, the free encyclopedia [Last Updated On: September 26th, 2016] [Originally Added On: September 26th, 2016]
- Department of Molecular Medicine - College of Veterinary ... [Last Updated On: September 26th, 2016] [Originally Added On: September 26th, 2016]
- Molecular Medicine - Graduate School of Biomedical ... [Last Updated On: September 26th, 2016] [Originally Added On: September 26th, 2016]
- Home - Weatherall Institute of Molecular Medicine [Last Updated On: October 20th, 2016] [Originally Added On: October 20th, 2016]
- Molecular Medicine - Wake Forest Baptist Health [Last Updated On: October 20th, 2016] [Originally Added On: October 20th, 2016]
- Cellular and Molecular Medicine Graduate Program [Last Updated On: October 20th, 2016] [Originally Added On: October 20th, 2016]
- International Masters Program Molecular Medicine ... [Last Updated On: October 20th, 2016] [Originally Added On: October 20th, 2016]
- LSUHSC School of Medicine - Biochemistry and Molecular Biology [Last Updated On: November 20th, 2016] [Originally Added On: November 20th, 2016]
- Molecular Medicine | Molecular Medicine Reports ... [Last Updated On: November 20th, 2016] [Originally Added On: November 20th, 2016]
- Precision medicine opens the door to scientific wellness preventive approaches to suicide - Medical Xpress [Last Updated On: August 15th, 2017] [Originally Added On: August 15th, 2017]
- New Hampshire biologist reacts to gene-editing discovery - The Union Leader [Last Updated On: August 15th, 2017] [Originally Added On: August 15th, 2017]
- The Human Heart May Have a Natural 'Backup Battery' - Healthline [Last Updated On: August 15th, 2017] [Originally Added On: August 15th, 2017]
- Georgia colleges gear up for new semester - AJC.com - Atlanta Journal Constitution [Last Updated On: August 15th, 2017] [Originally Added On: August 15th, 2017]
- Change in protein production essential to muscle function - Baylor College of Medicine News (press release) [Last Updated On: August 15th, 2017] [Originally Added On: August 15th, 2017]
- Clinical trial uses a genetically engineered virus to fight cancer - Medical Xpress [Last Updated On: August 15th, 2017] [Originally Added On: August 15th, 2017]
- A New Gene Editing Technique Could Finally Allow Us to Treat ALS - Futurism [Last Updated On: August 15th, 2017] [Originally Added On: August 15th, 2017]
- New Version of CRISPR Corrects RNA Defects Linked to ... - Technology Networks [Last Updated On: August 16th, 2017] [Originally Added On: August 16th, 2017]
- Circular RNA Linked to Brain Function - Technology Networks [Last Updated On: August 16th, 2017] [Originally Added On: August 16th, 2017]
- Yenepoya University to offer biotech skill enhancement programme - Hindu Business Line [Last Updated On: August 16th, 2017] [Originally Added On: August 16th, 2017]
- Spotlight Innovation Enters into Sponsored Research Agreement with Indiana University to Develop New Therapies for ... - PR Newswire (press release) [Last Updated On: August 16th, 2017] [Originally Added On: August 16th, 2017]
- Using barcodes to trace cell development - Medical Xpress [Last Updated On: August 16th, 2017] [Originally Added On: August 16th, 2017]
- What can genetic testing really tell you? - Popular Science [Last Updated On: August 17th, 2017] [Originally Added On: August 17th, 2017]
- Cancer Treatment Centers of America and Foundation Medicine Join Forces to Advance Precision Cancer Treatment - Markets Insider [Last Updated On: August 17th, 2017] [Originally Added On: August 17th, 2017]
- A New Method of 3D Printing Living Tissues - Technology Networks [Last Updated On: August 17th, 2017] [Originally Added On: August 17th, 2017]
- Spotlight Innovation Enters into Sponsored Research Agreement with Indiana University to Develop New Therapies for ... - Markets Insider [Last Updated On: August 17th, 2017] [Originally Added On: August 17th, 2017]
- MS in Molecular Medicine - Drexel University College of ... [Last Updated On: August 17th, 2017] [Originally Added On: August 17th, 2017]
- Master of Science (MSc) in Molecular Medicine - NTNU [Last Updated On: August 17th, 2017] [Originally Added On: August 17th, 2017]
- Molecular Medicine Research - Wake Forest School of Medicine [Last Updated On: August 17th, 2017] [Originally Added On: August 17th, 2017]
- New method for the 3D printing of living tissues - Scientist Live [Last Updated On: August 22nd, 2017] [Originally Added On: August 22nd, 2017]
- Bio-inspired Materials Give Boost to Regenerative Medicine - Bioscience Technology [Last Updated On: August 22nd, 2017] [Originally Added On: August 22nd, 2017]
- MSU Expanding Medical Research In Grand Rapids | WKAR - WKAR [Last Updated On: August 30th, 2017] [Originally Added On: August 30th, 2017]
- Stabilizing TREM2 a potential strategy to combat Alzheimer's disease - Medical Xpress [Last Updated On: August 30th, 2017] [Originally Added On: August 30th, 2017]
- TCI woman fell 31 floors, due to work in molecular medicine in Malaysia - Magnetic Media (press release) [Last Updated On: August 30th, 2017] [Originally Added On: August 30th, 2017]
- Molecular Medicine | University of Maryland School of Medicine [Last Updated On: August 30th, 2017] [Originally Added On: August 30th, 2017]
- Reconstructing life at its beginning, cell by cell - Phys.Org [Last Updated On: August 31st, 2017] [Originally Added On: August 31st, 2017]
- Dr. Pawel Muranski to Head New Cellular Immunotherapy Laboratory at NewYork-Presbyterian/Columbia University ... - Newswise (press release) [Last Updated On: August 31st, 2017] [Originally Added On: August 31st, 2017]
- Hofstra and Northwell rename medical school following $61 million donation - The Island Now [Last Updated On: August 31st, 2017] [Originally Added On: August 31st, 2017]
- TREM2 Cleavage Site Pinpointed: A Gateway to New Therapies? - Alzforum [Last Updated On: August 31st, 2017] [Originally Added On: August 31st, 2017]
- The Secret Ingredient That Stops Honeybees From Becoming Queens - New York Times [Last Updated On: August 31st, 2017] [Originally Added On: August 31st, 2017]
- What happened to precision medicine? - Phoenix Business Journal [Last Updated On: September 4th, 2017] [Originally Added On: September 4th, 2017]
- Fetal genes can increase the risk of illness during pregnancy - Medical Xpress [Last Updated On: September 4th, 2017] [Originally Added On: September 4th, 2017]
- Society of Nuclear Medicine and Molecular Imaging (SNMMI) [Last Updated On: October 1st, 2017] [Originally Added On: October 1st, 2017]
- For Authors - Molecular Medicine [Last Updated On: October 1st, 2017] [Originally Added On: October 1st, 2017]
- Center for Applied Proteomics and Molecular Medicine [Last Updated On: October 15th, 2017] [Originally Added On: October 15th, 2017]
- Nuclear Medicine - Molecular Imaging - Nuclear Medicine ... [Last Updated On: August 3rd, 2018] [Originally Added On: August 3rd, 2018]
- Proteomics Conferences 2018 | Molecular Medicine Congress ... [Last Updated On: August 21st, 2018] [Originally Added On: August 21st, 2018]
- Section of Molecular Medicine | Wake Forest School of Medicine [Last Updated On: November 9th, 2018] [Originally Added On: November 9th, 2018]
- Faculty Research - Department of Molecular Medicine ... [Last Updated On: February 14th, 2019] [Originally Added On: February 14th, 2019]
- Goethe-Universitt Molecular Medicine (Master of Science) [Last Updated On: March 5th, 2019] [Originally Added On: March 5th, 2019]
- Biochemistry and Molecular Biology at Miller School of ... [Last Updated On: March 30th, 2019] [Originally Added On: March 30th, 2019]
- Molecular Medicine Research - Mayo Clinic Research [Last Updated On: April 27th, 2019] [Originally Added On: April 27th, 2019]
- Molecular Medicine (MolMed) | Duke School of Medicine [Last Updated On: April 27th, 2019] [Originally Added On: April 27th, 2019]
- Molecular Medicine | Molecular, Cellular and Developmental ... [Last Updated On: April 27th, 2019] [Originally Added On: April 27th, 2019]
- Home | EMBO Molecular Medicine [Last Updated On: May 5th, 2019] [Originally Added On: May 5th, 2019]
- Molecular Medicine (formerly Molecular & Cellular Biology) [Last Updated On: June 3rd, 2019] [Originally Added On: June 3rd, 2019]
- The world's first psilocybin research center is opening in Jamaica - Big Think [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- Synthetic networks with tunable responsiveness, biodegradation, and molecular recognition for precision medicine applications - Science Advances [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- No place for racism: an open letter from University of Auckland staff - The Spinoff [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality - Beyond the Abstract - UroToday [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- Tulane researcher is editor of journal issue honoring 40th anniversary of key cancer discovery - News from Tulane [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- New insights into heart's healing capacity - Baylor College of Medicine News [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- Giving a Speed Boost to Nerve Regrowth - Technology Networks [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- Exploring the stress-mood-appetite connection - Baylor College of Medicine News [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- What's in the cards for this year's Nobel Prizes? - STAT [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- Treatment for Incurable Breast Cancer, Melanoma Improved by Adding Local Anesthetics - Newswise [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- DNA Nanomachines Are Opening Medicine to the World of Physics - Singularity Hub [Last Updated On: October 3rd, 2019] [Originally Added On: October 3rd, 2019]
- Institute of Human Virology Hosts 21st Annual International Meeting of Top Scientists on Ending the HIV/AIDS Epidemic in America and the Intersection... [Last Updated On: October 5th, 2019] [Originally Added On: October 5th, 2019]
- Digital Biopsies: Radiomics and Pathomics Are Important Stops on the Path to Precision Medicine - Cancer Therapy Advisor [Last Updated On: October 5th, 2019] [Originally Added On: October 5th, 2019]