Lung cancer: How a drug combination may help reduce tumors
There are two types of lung cancer.
ISLAMABAD, (Online) - Lung cancer is the second most common type of cancer among adults in the United States, with almost a quarter of a million new diagnoses each year.
There are two types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
NSCLC is generally less aggressive but is the most prevalent, accounting for around 80% of cases.
New research, conducted at the Salk Institute of Biological Studies and published today in the journal Science Advances, has highlighted a potential new targeted therapy for NSCLCs.
Researchers said a combination of two drugs was effective in significantly reducing tumor size during tests conducted on mice.
What the lung tumor study involved
The researchers at Salk wanted to explore a new targeted therapy option for NSCLCs comprising the LKB1 genetic mutation.
Targeted therapies are drugs designed for specific molecular subtypes of NSCLCs, explained Dr. Andrew McKenzie, the vice president of personalized medicine at Sarah Cannon Research Institute in Tennessee as well as the scientific director at Genospace.
“As these therapies are ‘tailored’, “if you test a patient and see a mutation, it’s better to give the targeted therapy than immunotherapy or immunotherapy and chemotherapy,” he told Healthline.
First, the Salk team established that histone deacetylase 3 (HDAC3), a type of protein in the body, is critical in the growth of NSCLCs with the LKB1 mutation.
In a statement, Lillian Eichner, PhD, a professor at Northwestern University in Illinois and the co-lead of the study who was a postdoctoral fellow at Salk during the research, said that this came as a surprise.
“We thought the whole HDAC enzyme class was directly linked to the cause of LKB1 mutant lung cancer,” she stated.
However, Eichner continued, “we didn’t know the specific role of HDAC3 in lung tumor growth.”
From here, she and the team turned to two medications.
The potent drug combination
The first drug was entinostatTrusted Source. While this drug is not currently approved by the Food and Drug Administration (FDA), it has been shown in clinical studies to target HDACs.
The second drug was trametinib, which is designed to stop cancer cells from multiplying.
“Trametinib is FDA-approved in the treatment of NSCLCs but only in combination with a partner drug called dabrafenib,” noted McKenzie.
“These two drugs together are only approved in one specific subtype of NSCLC; cancers which have the BRAF V600E mutation,” he added.
“Trametinib on its own has not been very efficacious and needs to be combined with dabrafenib to see the clinical outcomes associated with FDA approval,” McKenzie said.
Tumors are known to become resistant to trametinib, which is why it’s used in combination with dabrafenib.
The researchers wanted to see if combining trametinib with HDAC3-targeting entinostat would have the same effect on reducing resistance.
The drug combination was given to mice with LKB1-mutated NSCLC for 42 days, after which their tumors were reassessed.
Compared to mice not given the drug treatment, tumors in recipient mice had reduced in size by 79%. The treated mice also had 63% fewer lung tumors, the researchers reported.
The importance of the lung tumor study
As the research was conducted in mice, what does this mean for human patients?
Alexandre Chan,PharmD, a professor of clinical pharmacy and founding chair at University of California, Irvine – School of Pharmacy & Pharmaceutical Sciences, stated that the results are “encouraging.”
However, he noted, “clinical trials [in humans] will need to be done” before the treatment can be considered.
These trials will establish “whether this combination is efficacious in patients with lung cancer,” Chan told Healthline.
Furthermore, he said they will also determine “whether the toxicity profiles of the two drugs are safe to be administered together.”
McKenzie asserted the new findings are “exciting” — and that “this type of study is really important for us to build that knowledge base of how we might overcome resistant targeted therapies in NSCLCs.”
However, he added, while many will get excited about the prospect of a new targeted therapy to overcome resistant NSCLC, it’s important to “temper hope.”
“The reality [is] that these experiments and [results] we see in mice don’t always pan out in humans,” he stated.
“But even when that is the case,” McKenzie continued, “the scientific community still learns an awful lot.”
Dr. Ranee Mehra, a professor of medicine at the University of Maryland School of Medicine and a medical oncologist at the University of Maryland Greenebaum Comprehensive Cancer Center, agreed with taking a cautious approach.
“For patients, we hope a reduction in tumors will help them to live longer,” she told Healthline. “But we cannot make that assumption from laboratory studies done in mice.”
Ultimately, though, “this data does provide more justification for considering further studies,” Mehra noted.
What to know about gene mutations
“NSCLCs can have mutations associated with them that drive the growth of the cancer,” stated Mehra.
Up to 30% of NSCLCs involve driver mutations of the LKB1 gene — which plays a vital role in suppressing tumor growth.
So what does driver mutation do? “[It] supports the growth of cancer cells, enabling cells to quickly duplicate, survive, and spread,” explained Chan.
While scientists now better understand driver mutations, added McKenzie, “we’re still trying to figure out exactly where these come from and what brings them about.”
For instance, factors such as smoking — which you might expect to lead to more severe lung cancer — don’t seem to play a role.
“In people who have never smoked, we see a high prevalence of these very actionable mutations,” McKenzie noted.
According to Chan, treatment approaches and their efficacy can vary depending on the genetic mutation (if present).
“During the initial diagnosis, a number of diagnostic procedures will be performed, including CT scans and PET, as well as biopsies,” he explained.
The test results are then used to determine which treatment approach(es) is best suited to the patient.
Unfortunately, NSCLCs with LKB1 mutations are often less responsiveTrusted Source to traditional treatments, such as immunotherapy alone or immunotherapy and chemotherapy combined.
While these can still be beneficial, McKenzie shared, “they’re not as effective as targeted therapies — because these take advantage of what’s driving the tumor to be so aggressive.”
Either way, it’s crucial to appreciate that lung cancer outcomes have made notable strides in recent years.
“[They’re] much better than 10 years ago,” revealed McKenzie. “And that’s thanks to the advent of novel immunotherapies and targeted therapies that are now part of standard care.”