The second most frequent type of cancer in the world is lung cancer. Around 2 million people are given a lung cancer diagnosis each year, and 1.8 million people pass away from the condition.
Small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are the two forms of lung cancer, with NSCLC accounting for the majority of instances. Surgery, radiation, and chemotherapy are all effective treatments for NSCLC, although it is rarely curable.
Today, studies have discovered that a combination of two medications reduces the size and quantity of tumours in mice with NSCLC, a finding that could result in human clinical trials.
Lung cancer is the second most prevalent cancer diagnosed in the United States, according to the American Cancer Society. Moreover, it is the main cause of cancer mortality, accounting for one in five cancer-related deaths, more than colon, breast, and prostate cancers put together.
The typical age of diagnosis for lung cancer is 70 years old, with most cases being found in older patients. The good news is that cases are declining as fewer individuals smoke tobacco, which is responsible for more than 80% of lung cancer cases. A diagnosis of lung cancer is still given to over 2 million people annually worldwide.
Lung tumours other than small cell comprise 85% of cases (NSCLCs). There is an urgent need for novel therapies because immunotherapy and chemotherapy are not very successful against this kind of lung cancer.
Now, researchers from the Salk Institute and Northwestern University have discovered that treating NSCLC-affected mice with a cocktail of two drugs—one of which is already approved by the Food and Drug Administration (FDA) and the other is undergoing clinical trials—reduced the size and frequency of the tumours.
Need for new treatments
According to Dr. Lillian Eichner, a principal author of the study and an assistant professor of biochemistry and molecular genetics at Northwestern University, “This medication might be helpful for patients with KRAS/LKB1 mutant lung adenocarcinoma.”
About 20,000 new cases of this disease’s molecular subtype are reported each year in the United States, she said. “Patients with this terrible disease currently have an average survival duration of 10 months after diagnosis, and improved therapeutic techniques are desperately needed.”
Histone deacetylase (HDAC) inhibitors have been suggested as a possible therapy for this particular form of lung cancer by the researchers. Animal tumour growth has been demonstrated to be slowed by HDAC inhibitors, which are epigenetic regulators.
After proving that HDAC3 was essential for the development of difficult-to-treat LKB1-mutant cancers, the study’s authors investigated if pharmacologically inhibiting HDAC3 may have an impact on tumour growth.
In this study, they treated KRAS/LKB1 mutant NSCLC in mice with two different medications: the FDA-approved MEK inhibitor trametinib and the HDAC1/HDAC3 inhibitor entinostat, which is currently in clinical development.
Lung tumor study
The LKB1 genetic mutation is present in NSCLCs, and Salk researchers were interested in investigating a novel targeted therapeutic option.
According to Dr. Andrew McKenzie, vice president of personalised medicine at Tennessee’s Sarah Cannon Research Institute and scientific director at Genospace, targeted therapies are medicines created for certain molecular subtypes of NSCLCs.
Since that these treatments are “tailored,” he explained, “it is preferable to administer a targeted therapy rather than immunotherapy or immunotherapy and chemotherapy if you test a patient and discover a mutation.
Initially, the Salk team demonstrated that the body’s histone deacetylase 3 (HDAC3) protein is essential for the development of NSCLCs with the LKB1 mutation.
This was unexpected, according to co-lead of the study Lillian Eichner, PhD, a professor at Northwestern University in Illinois who was a postdoctoral researcher at Salk during the research.
She said, “We believed the entire HDAC enzyme class was intimately related to the origin of LKB1 mutant lung cancer.
“We didn’t know the exact involvement of HDAC3 in lung tumour formation,” Eichner stated. She then moved to two drugs with the assistance of the team.
The potent drug combination
Entinostat was the first medication. Although the Food and Drug Administration (FDA) has not yet approved this medication, clinical tests have demonstrated that it targets HDACs.
Trametinib was the second medication and it works by preventing the growth of cancer cells. Trametinib is FDA-approved for the treatment of NSCLCs, but it must be used in conjunction with the medication dabrafenib, McKenzie added.
These two medications are only permitted for use in NSCLCs with the BRAF V600E mutation, the author continued.
According to McKenzie, “Trametinib on its own has not been very effective and requires to be paired with dabrafenib to see the clinical outcomes associated with FDA approval.” Because trametinib might cause tumours to become resistant, dabrafenib is often used in conjunction with it.
The goal of the study was to determine whether trametinib and the HDAC3-targeting drug entinostat would reduce resistance in the same way. Mice with LKB1-mutated NSCLC were treated with the medication cocktail for 42 days, and then the tumours were examined again.
Tumors in recipient mice have shrunk by 79% in size compared to mice not receiving the medication treatment. The researchers also noted a 63% decrease in lung cancers in the treated animals.
Human trials needed
Cancers are already being treated with these medications. For the first time, the FDA approved trametinib in 2013 to treat metastatic malignant melanoma. In 2017, it received approval for the treatment of NSCLC.
Entinostat has undergone phase 1 and phase 2 clinical trials but has not yet received FDA approval for clinical usage. Phase 3 trials in people with breast cancer are also still being conducted. People have typically tolerated the medication well during the studies.
The medications have not yet been combined in human subjects. The following stages in evaluating the combined therapy were described by Dr. Eichner.
She said that in order to determine the safety of this combined therapeutic method, a phase 1 clinical research would be conducted first.
“Based on the known safety profiles of both medications, we are hoping that this would also be the case in people,” said Dr. Eichner. “Our preclinical investigations were extremely encouraging with regard to the safety of this pharmacological combination.”
A phase 2 research would then determine whether this combination inhibits tumour growth and lengthens the patients’ lives, she continued.
New hope for cancer patients
On average $1.3 billion is spent to bring a new treatment to market, according to a recent study, making drug development a time-consuming and expensive process.
Also, it often takes 6 to 12 years for new cancer medications to be approved. So, it is quicker and more cost-effective to identify new ways to use existing medications.
According to our research, cancer treatments that were previously unsuccessful might be successful if they are modified. In some cases, understanding basic tumour biology can result in novel cancer therapy strategies without the need to first create new medications, which can be a lengthy process, according to Dr. Lillian Eichner.
Although it is still early, their discoveries might result in new lung cancer medicines for this difficult-to-treat disease. Dr. Eichner is upbeat, but more study is required to validate the results.
According to “our findings,” treating patients concurrently with both of these already-approved medications “may significantly limit the growth of lung tumours for this set of patients.”
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