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A new study, done in part at the UK Markey Cancer Center, shed light on why lung cancer cells can resist therapeutic cancer treatment.

Markey research sheds light on lung cancer formation and treatment

A new study co-authored by a researcher starting her laboratory at the UK Markey Cancer Center shows that in certain genetic situations, one non-small cell lung cancer subtype can change into another subtype.

This lung cancer “lineage switching” could explain why some cancers are resistant to therapeutics, and this research examines exactly how the lineage switch can happen. The work was a collaborative effort between laboratories in Kentucky, New York and Boston.

“Now that we have a glimpse into the molecular mechanism of lineage switching, we can begin to learn how to manipulate this phenomenon for better therapeutic outcomes,” said study co-author Christine Fillmore Brainson, assistant professor in the UK Toxicology and Cancer Biology department.

Previously, it was unclear which cells in the adult lung can be the “cells-of-origin” of the two major subtypes of non-small cell lung cancer, namely adenocarcinoma and squamous cell carcinoma. Likewise, it was unclear what differences in DNA organization define the two distinct lung cancer subtypes. The existence of adenosquamous lung tumors, clinically defined by the presence of both glandular adenocarcinoma lesions and fully stratified squamous lesions within the same tumor, suggested that both adenocarcinomas and squamous cell carcinomas could come from the same cells in the lung, but clear evidence for this theory was lacking.

Published in Nature Communications, the study showed that adenocarcinoma cells can change to squamous cells due to reorganization of their DNA in specific ways. Beginning with a mouse model of adenosquamous lung tumors, researchers validated the genetics by comparing it to human adenosquamous lung tumor – the genetics are often the same, including activation of the oncogene KRAS and the deletion of the tumor suppressor Lkb1. The team then used transplant assays to demonstrate that established adenocarcinoma tumors could transition to squamous cell carcinomas in the mouse lung.

Lastly, the group isolated different lung cells, and demonstrated that only certain lung cells could give rise to tumors capable of undergoing the lineage switch.

“This data is exciting because it shows which cells in the lung can give rise to adenosquamous tumors,” Brainson said.  “And the technique we used to transform the isolated cells can be applied to many lung cancer models.”

Oncologists have observed this “lineage switching” after the failure of EGFR tyrosine kinase inhibitor treatment, when it is clinically justifiable to take a second biopsy. However, second biopsies are not normally done after chemotherapy, a practice that Brainson thinks could be revised to understand the exact mechanisms of therapy resistance.

In addition to Brainson, the manuscript was co-authored by Haikuo Zhang of the Dana-Farber Cancer Institute in Boston. The research was a collaborative effort between the laboratories of Carla Kim at Boston Children’s Hospital, where Brainson was based for her post-doctoral studies; Hideo Watanabe at Icahn School of Medicine in New York; and Dr. Kwok-Kin Wong at Pearlmutter Cancer Center in New York.

This work was funded in part by the American Cancer Society, the Lung Cancer Research Foundation, the V Foundation for Cancer Research, the March of Dimes, the National Cancer Institute, the Gross-Loh Family Fund for Lung Cancer Research and Susan Spooner Family Lung Cancer Research Fund at the Dana-Farber Cancer Institute


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Dr. Timothy Mullett accepting the Lane W. Adams Quality of Life Award at the ACS summit in January.

Markey’s Dr. Timothy Mullett honored for exceptional patient care

The American Cancer Society (ACS) recently honored UK Markey Cancer Center surgeon Dr. Timothy Mullett with the Lane W. Adams Quality of Life Award. He was one of six recipients chosen for the national honor for his leadership in serving the complex needs of cancer patients and their families.

The ACS Quality of Life Award honors providers who routinely excel in providing care to their patients experiencing cancer, going beyond the bounds of their duties. Lane W. Adams emphasized the importance of a “warm hand of service” during his vice presidency of the American Cancer Society. This award represents Adams’ credence to serve and enhance others’ well-being.

Mullett has committed his time to lung screening and education by chartering the Lung Screening Excellence Project in Kentucky and serving as co-investigator at Kentucky Lung Cancer Education, Awareness, Detection and Survivorship, or LEADS. As a stage-4 liver cancer survivor, Mullett has a unique and personal perspective in providing care to his patients. He is known for his devotion to providing high-quality care for underrepresented citizens in Kentucky by working with nonprofit, government and medical groups.

Mullett currently serves as medical director for the Markey Cancer Center Research Network. He has also served as a colonel in the Army Reserves, with deployments in 2004 and 2012.


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Making the Rounds with Dr. Timothy Mullett

Meet Dr. Timothy Mullett, cancer surgeon – and cancer survivor

Making the RoundsGet to know Dr. Timothy Mullett, a cardiothoracic surgeon at the UK Markey Cancer Center, in our latest installment of Making the Rounds, a blog series where you’ll meet the providers at UK HealthCare.

Dr. Mullett specializes in surgical treatment for patients with lung cancer. He’s also the medical director of Markey’s Research and Affiliate networks. In addition to treating patients with cancer, Dr. Mullett is a cancer survivor himself. In 2014, he was diagnosed with liver cancer and was successfully treated at Markey.

When did you know you wanted to be a doctor?

It was one of those decisions I had made early on. I got sick when I was around 14 and I got used to being around doctors. I ended up getting better, but that left me with something that said, ‘This looks like a pretty cool place to spend some time.’

Who’s your favorite musical artist?

I’m a fan of country music. I’ve been listening to that for a long time. I’m a fan of modern country music: Tim McGraw, Faith Hill and now into Chris Stapleton.

My favorite part about music is that I put together this playlist. We have some friends that gather at the lake and I started to put together a playlist for when we’re on our boat. We’ve got my kids, some others folks and several families that are our age. Everyone contributes to this playlist that has now grown to about 780 songs. Everything from Meghan Trainor back to Eric Clapton. I love to put it on shuffle and let it go.

Describe your ideal weekend. Would it involve being on the lake?

Yeah, something on the water. Any time that I can gather with family and friends on a lake and get some water skiing in in the morning and some conversation and relaxation in in the evening. And I enjoy grilling something on the house boat.

What excites you most about working at UK HealthCare?

It’s the people we work with. The friends and contacts I’ve made here at UK are like a family, and we’re taking care of other people. We come together as a team and work together to say, ‘This is how we want to attack this problem.’ It’s great.


Check out our video interview with Dr. Mullett below. He tells us more about his work at Markey and how his own cancer diagnosis has impacted the way he cares for his patients.


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This one test could save your life

It’s a sad fact that Kentucky leads the U.S. in lung cancer incidence and mortality. If you smoke, live with a smoker or have smoked in the past, consider getting screened. Early detection is your strongest weapon against the disease.

What is lung cancer screening?

At the UK Markey Cancer Center, we use a low-dose CT scan to take many images of your chest and lungs. This allows a radiologist to look inside your lungs and identify suspicious spots that may be potential cancers.

Only low-dose CT scans – not chest X-rays – are recommended for lung cancer screening.

A suspicious or positive result means that the CT scan shows something that is abnormal. Additional tests will be done to determine whether this is cancer.

A negative result means that there were no abnormal findings at the time of the CT scan. It does not mean that you will never get lung cancer.

Who is qualified for lung cancer screening?

Lung cancer screening is recommended for patients who are at high risk for lung cancer, including those who:

  • Are ages 55-80, and
  • Currently smoke or have quit within the past 15 years, and
  • Have a 30 pack-year smoking history, which means smoking one pack a day for 30 years or two packs a day for 15 years, and
  • Have no current symptoms of lung cancer.

A lung cancer screening does not prevent lung cancer, but it can detect cancer at an early stage, before you develop symptoms of the disease.

Lung cancer screening has been shown to decrease the risk of lung cancer death in patients who are high risk for developing cancer. When lung cancer is found early, many treatment options are available, which greatly improves the likelihood of survival.


Next steps:

  • To make an appointment with the UK Lung Cancer Screening Program, call us at 844-SCN-LUNG (844-726-5864). You must have a primary care physician to participate in a lung cancer screening.
  • If you’re a smoker, you probably already know it’s not a healthy habit. Check out our “Take action to stop smoking” blog post with tips to help you quit.
Lung cancer in Kentucky

We’re fighting back against lung cancer in Kentucky

There’s a No. 1 ranking we’re not proud of in Kentucky: leading the nation in lung cancer incidence and mortality. November is Lung Cancer Awareness Month and the perfect time to learn more about the disease and what UK HealthCare is doing to fight back.

At the UK Markey Cancer Center, we’re working hard to reduce the burden of lung cancer in Kentucky through screening and prevention, state-of-the-art treatment and research, and compassion for patients and their families.

Markey’s Multidisciplinary Lung Cancer Program  brings together a team of health care providers with expertise in all areas of lung cancer. We treat small cell lung cancer, non-small cell lung cancer, mesothelioma and other cancers of the chest and lungs.

Screening and diagnosis

Survival rates for lung cancer are much lower than other common types of cancer, with less than 18 percent of people with lung cancer surviving five years. That’s why it’s so important to catch the disease at its earliest. When we detect early-stage lung cancer, a patient’s chances of survival can be as high as 70 percent.

The UK Lung Cancer Screening Program is available for patients who might be at risk for lung cancer, including smokers and former smokers, and can help identify lung cancer early on, before symptoms are noticeable.

Treating lung cancer

When a patient is diagnosed with lung cancer, we act fast to find a course of treatment that’s best for that person. Each treatment plan is based on the individual’s unique needs and the specifics of their cancer.

Surgery, radiation and chemotherapy treatments at Markey are state-of-the-art and are supplemented by national research studies as well as treatments with promising new drugs.

To make an appointment at the Multidisciplinary Lung Cancer Program, call 859-257-4488 or use our secure online appointment form.


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A recent study by UK researchers shows a new way tobacco smoke may cause lung cancer: stopping a DNA repair process called nucleotide excision repair (NER).

UK researchers find a new way tobacco smoke can cause cancer

A recent study led by UK researchers illuminates a new way that tobacco smoke may promote the development of lung cancer: inhibiting a DNA repair process called nucleotide excision repair (NER). The results of the study were published in the journal PLoS ONE.

Tobacco smoke damages our DNA

Many components of tobacco smoke are carcinogens that can damage DNA. This damage must be removed by DNA repair processes to prevent the development of genetic mutations. In this way, DNA repair processes such as NER are crucial for blocking the accumulation of the DNA mutations that ultimately drive lung cancer development.

“It is well established that the carcinogens in tobacco smoke can produce mutations,” said Isabel Mellon, an associate professor in the Department of Toxicology and Cancer Biology at UK and the principal investigator of the study. “But relatively few researchers have investigated the effects of tobacco smoke on DNA repair pathways.”

Smoking also stops DNA from fixing itself

Mellon and her research team examined the effects of cigarette smoke condensate (CSC) – a commonly-used surrogate for tobacco smoke – on the function of the NER process in cultured human lung cells. They found that exposure of these cells to CSC significantly reduces NER efficiency. Additionally, the researchers showed that CSC exposure stimulates the destruction of a key NER protein known as XPC. The reduced abundance of XPC that follows might explain how CSC suppresses NER.

The study’s results point to a twofold effect of tobacco smoke on DNA integrity: it not only damages DNA, but it also suppresses a key process that repairs DNA damage.

“Inhibition of NER would likely increase the production of mutations and cancer incidence, particularly in cases of chronic DNA damage induction, as occurs in the lung issue of smokers,” Mellon explained.

Research that points toward the future

If this is the case, then the capacity of cells within the lung of a given person to repair damaged DNA could be used to predict that person’s risk of developing lung cancer as a result of tobacco smoke exposure.

“In the future, we hope to determine how the efficiency of the NER pathway differs among different people,” said Mellon. “We are also continuing to evaluate how the efficiency of DNA repair in people is negatively impacted by exposure to environmental agents. Whether due to genetic or environmental factors, reduced DNA repair could increase a person’s risk for developing cancer.”


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Dr. Douglas Andres

UK lung cancer study picks up after 15 years

In the late 1990s, University of Kentucky Professor Douglas Andres found that mutations in a protein known as RIT1 could initiate cancer development in laboratory models.

RIT1 works as a molecular switch. In response to signals from outside the cell, it turns on fundamental cellular activities, and then turns them off again to ensure they don’t continue unchecked.

“Proteins like RIT1 control everything from how cells differentiate to how they grow,” Andres said. “In a disease like cancer, they often get broken in the ‘on’ position. The cells that have RIT1 mutations constantly grow, even though they don’t receive the necessary signals from the environment.”

When Andres applied for funding to follow up on his findings, his application was declined. The reviewers of his grant wanted evidence that RIT1 mutations might actually promote cancer development in people. Unfortunately, searching for RIT1 mutations in human tumors was, at that time, a difficult undertaking. The technological advances required to successfully complete this mission would not be made until several years later.

But Andres didn’t lose hope.

“I never really give up on anything,” he said.

Just over a year ago, his patience was rewarded – Alice Berger, a postdoctoral researcher in the laboratory of Professor Matthew Meyerson at the Broad Institute of MIT and Harvard, provided the evidence he needed. Working collaboratively, the research teams led by Andres and Meyerson showed what Andres had hypothesized all along: RIT1 mutations present in human lung cancers can transform non-cancerous cells into cancerous ones.

Now, after waiting more than 15 years, Andres has finally been awarded the funds to expand upon his initial discovery. Specifically, the breakthroughs gained from his collaboration with Meyerson helped him secure a two-year, $150,000 grant from the Kentucky Lung Cancer Research Program.

“With the grant we received, we will push the work forward,” Andres said. “We hope this will lead to greater understanding of RIT1 mutations and how tumors containing them may differ from other lung tumors.”

Ultimately, Andres hopes to use the insight obtained from these efforts to develop new tests that can diagnose RIT1-mutant lung cancers in patients. The awareness gained from such efforts could potentially lead to the development of therapies that specifically kill cancer cells containing RIT1 mutations.

“Each time that we gain fundamental insight into a problem – that is an exhilaration,” Andres said. “Sometimes it happens in six months of work, or, in this case, it’s taken 15 years between our initial discovery and our ideas actually coming to fruition.”


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Immunotherapy offers new hope for cancer treatment

Back in December, former U.S. President Jimmy Carter surprised the nation by announcing that he no longer had any traces of cancer in his system, just a few months after announcing a frightening stage IV melanoma diagnosis.

So what led to his surprising good news? A specific type of cancer treatment called immunotherapy.