[ad_1]
According to the Medical College of Georgia at Augusta University, about one-fifth of the often fatal head and neck cancers contain gene mutations in pathways important for normal cell proliferation, and scientists say these mutations that cause cancer cells to grow abnormally and can also make cancer vulnerable.
The findings of the research were published in the journal ‘npj Genomic Medicine’.
The study details keys to targeting that vulnerability including individualized genomic analysis to identify a patient’s specific mutation, and find the drugs that directly target it, investigations that should be given more attention in cancer therapy development.
ALSO READ: Study finds out how ovarian cancer begins in high-risk women
The MAPK pathway is a “signalling 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, said 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 tumour growth can also make it sensitive to drug therapy, said Lui. While a lot of discovery is still needed to find more mutations in the MAPK pathway and the drugs that target them, Lui said they are among the most logical treatment targets for this tough-to-treat cancer.
As she spoke, she was looking in her lab for drugs that kill head and neck primary tumours from patients, and at the genetics behind how they kill.
“It’s critical to the survival of cancer,” said 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 heterogeneous cancer, the scientists wrote.
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 noted.
Also, next on the horizon is combining this “precision medicine” approach with immunotherapy that better enables a patient’s immune system to also target cancer, she said.
Lui’s 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 the removal of the lymph nodes and the primary tumour 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 tumour’s 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 the signalling of this factor that was important to cancer’s 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 tumour cell growth, which also made tumour cells “addicted” to the signal from the mutated EGFR. The drug erlotinib could break the addiction and inhibit cancer cell growth.
Lui didn’t find an EGFR mutation in this young man’s pretreatment biopsy but reasoned the mutation had to have something to do with the receptor’s signalling 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 said 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 cancer.
Erlotinib had actually failed in clinical trials because it wasn’t given to the right patients, which is what precision medicine is, Lui noted. In fact, laboratory studies had indicated that activation of MAPK1 confers resistance to erlotinib, she said, while this patient’s response clearly counters that. Follow up work by Grandis indicated that in patients actually, the higher the MAPK1 activation, the better cancer responded to erlotinib.
To help move cancer treatment forward, Lui encouraged the physicians who come across these types of “exceptional responses” to report them, work with scientists to study them, and then pursue clinical trials when appropriate.
For patients, her message is not to give up because, with a more high-level analysis of tumours, there might be a certain mutation that makes their cancer vulnerable to a specific medication, she said of these “gene-drug responses” that are the focal point of her translational work.
“There are secrets that make cancer vulnerable,” Lui said. “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 signalling 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 was “futile,” and typically “failed miserably” in clinical trials, Lui and her colleagues wrote.
While the reasons may be uncertain, they likely include the wrong drug for that specific, problematic mutation, Lui said, 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 aren’t effective precision drugs for about 80 per cent of patients, Lui and her co-authors 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 signalling.
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 by about 52 per cent. In 2016 the Food and Drug Administration modified its approval of erlotinib to treat non-small cell lung cancer patients with 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 tumours 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 said.
This story has been published from a wire agency feed without modifications to the text.
[ad_2]
Source link
states, cannabis has been touted as a potential treatment for everything from anxiety and nausea to HIV and cancer buy cialis cheap serevent cyclobenzaprine with ibuprofen versus ibuprofen alone I know he will comply with all the rules, a crying Hamilton told ABC News last week, before she learned that doctors had reversed their decision and would put Anthony on the transplant list
s own testimony, that Rodriguez committed multiple violations of the joint drug agreement, including acquiring performance enhancing drugs from Bosch for several years buying cialis online reviews Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting
cialis order online Today s scientific press conference highlighted six studies selected from thousands of abstracts being presented over the next week in Montreal and virtually
ladygra tylenol rhume et sinus posologie Lopez, 13, went to Cook for seventh grade and had attended the Sebastopol Road school until Friday generic cialis 20mg B 9 4 2009; 96 3 216 222
Looks like I actually ovulate sometimes now but can t seem to hold a pregnancy best site to buy cialis online Since a dilator effect was not seen in arterioles dissected from NKCC1 deficient mice, relaxation appears to be due to inhibition of the widely expressed NKCC1 isoform of the cotransporter
major brand allergy pills prescription medication for severe allergies allergy pills non drowsy
order deltasone 10mg online prednisone 5mg us
over counter nausea medicine cefadroxil 500mg usa
best acne pills prescription aczone oral order acne pills
acid reducing medications buy generic quinapril 10mg
isotretinoin 10mg over the counter accutane 40mg pill isotretinoin 40mg without prescription
sleeping tablets prescribed by doctors phenergan 10mg sale
order amoxicillin 250mg online amoxil 1000mg tablet amoxil generic
buy zithromax 500mg for sale order zithromax 500mg without prescription order azithromycin 500mg pill
oral azipro azithromycin brand buy azipro online cheap
order furosemide 40mg pills buy lasix 100mg
deltasone 20mg pill order prednisone 40mg pill
buy amoxil without prescription cheap generic amoxicillin brand amoxil 500mg
order monodox online purchase acticlate online cheap
order amoxiclav without prescription buy amoxiclav generic
order levothroid online cheap purchase levothroid pill order levoxyl without prescription
buy levitra 10mg online cheap levitra canada
clomid online buy buy clomiphene pills for sale serophene brand
tizanidine without prescription buy tizanidine pill buy tizanidine without a prescription
order semaglutide 14 mg pill order rybelsus online cheap buy semaglutide tablets
buy deltasone 10mg pills prednisone 20mg drug order prednisone 40mg pills
semaglutide 14mg for sale buy rybelsus 14 mg order semaglutide 14mg pill
purchase accutane online cheap accutane for sale accutane order
brand ventolin 4mg albuterol for sale online albuterol 4mg for sale
buy amoxil 250mg generic buy amoxil 250mg generic order amoxicillin for sale
buy augmentin tablets amoxiclav online buy augmentin 1000mg brand
zithromax pills zithromax 250mg sale azithromycin price
order synthroid for sale buy levothyroxine tablets synthroid usa
how to buy prednisolone omnacortil 5mg price omnacortil 5mg cheap
order clomid 100mg pills buy cheap clomiphene clomid pills
purchase gabapentin pill where to buy neurontin without a prescription neurontin for sale online
order sildenafil 100mg pills viagra mail order us buy sildenafil 50mg pills
rybelsus 14 mg drug buy rybelsus medication buy rybelsus 14 mg pills
free online slot machines best casino online spins real money online
where to buy vardenafil without a prescription buy vardenafil without prescription order levitra 20mg without prescription
order plaquenil 400mg online order hydroxychloroquine for sale buy hydroxychloroquine 200mg without prescription
aristocort price aristocort tablet buy generic aristocort
cialis 40mg for sale cialis generic purchasing cialis on the internet
cost clarinex buy clarinex 5mg sale clarinex brand
cenforce 100mg price cheap cenforce 50mg how to buy cenforce
buy claritin pills for sale claritin online order cost claritin
aralen 250mg drug buy chloroquine 250mg sale buy chloroquine medication
order priligy 90mg sale order generic cytotec purchase cytotec pills
glycomet 500mg us metformin 1000mg for sale buy metformin online cheap
order atorvastatin 80mg online order atorvastatin 80mg for sale buy atorvastatin 10mg pill
zovirax 800mg cheap zyloprim without prescription buy zyloprim online
how to get amlodipine without a prescription amlodipine online order norvasc order
zestril 10mg pill buy lisinopril 10mg for sale order prinivil without prescription
crestor 20mg canada order crestor 20mg generic ezetimibe 10mg price
cost omeprazole 10mg prilosec medication prilosec price
domperidone tablet sumycin 500mg pills tetracycline price
buy generic metoprolol online buy lopressor 50mg online metoprolol for sale
cost cyclobenzaprine 15mg order cyclobenzaprine 15mg for sale how to buy lioresal
toradol 10mg uk buy cheap colchicine buy colcrys tablets
order tenormin sale order tenormin 100mg for sale buy atenolol 100mg pill
buy medrol 16mg online buy methylprednisolone tablets medrol 4 mg for sale
buy generic propranolol inderal 10mg generic buy plavix pills
edit my paper practice essay writing online cheap paper writing services
purchase methotrexate generic methotrexate 2.5mg pills purchase medex pills
mobic price order meloxicam 7.5mg generic celecoxib cheap
buy metoclopramide without prescription order maxolon pills losartan 25mg ca
order tamsulosin 0.2mg without prescription cheap flomax buy celecoxib
buy esomeprazole online topamax ca cost topiramate 100mg
imitrex uk imitrex for sale purchase levaquin without prescription
order avodart sale order avodart without prescription oral zantac
order cipro 1000mg online cheap – keflex 250mg for sale brand clavulanate
flagyl for sale – cefaclor sale zithromax 500mg usa
stromectol 12mg online – purchase amoxiclav pills tetracycline for sale online
cheap valacyclovir 500mg – nemasole online order acyclovir 800mg sale
buy flagyl 400mg without prescription – cleocin brand oral azithromycin
acillin pills ampicillin where to buy amoxicillin order online
buy glucophage pills – oral bactrim 480mg buy lincocin 500 mg
retrovir 300 mg cost – order allopurinol 300mg without prescription
clozapine brand – frumil 5mg tablet buy cheap generic pepcid