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Research featuring UK scientists shows promise in treating cancer

A new study published in Nature Chemical Biology featuring UK research highlights a promising new way to address lung cancer and other deadly diseases.

Lung cancer accounts for 25 percent of cancer deaths in the U.S., and one out of every two patients diagnosed with lung cancer won’t survive more than one year. The problem is at its worst in Kentucky, where the state continues to lead the nation in lung cancer incidence and death.

The new research brings together scientists from the UK College of Pharmacy, Memorial Sloan Kettering Cancer Center and St. Jude Children’s Research Hospital and reveals a new way to treat lung cancer by blocking cancer-causing proteins on a cellular level. The study involves a compound developed by UK College of Pharmacy Dean Kip Guy’s lab.

The foundation for research

The groundwork for the study began more than 10 years ago when Dr. Bhuvanesh Singh, a physician-scientist at Memorial Sloan Kettering Cancer Center, identified that an increase of a protein called DCN1 led to more malignant lung cancers and shorter life spans for his patients. Of the patients he studied, those with high levels of DCN1 succumbed to the disease more quickly than those with normal levels.

Frustrated by their findings, Singh’s team set out to study the specifics of DCN1. While DCN1 is a normally occurring protein, his team found that too much of it leads directly to cancer formation. Simply put, a malignant tumor was formed when the amount of DCN1 in a cell was increased. Thus, patients with more DCN1 got sick more quickly and died faster than their counterparts.

Efforts in Brenda Schulman’s lab at St. Jude, led by biochemist Daniel Scott, established how DCN1 interacts with other proteins and controls cellular processes. Their key discovery used X-ray crystallography to show that a small modification of the partner protein to DCN1, known as UBE2M, was required for DCN1 to work. This common modification, N-terminal acetylation, had not previously been shown to be critical to controlling activity of this specific protein. Recognizing the potential for targeting this modification, Shulman reached out to form a collaboration between the three laboratories.

Their goal: to develop a way to stop DCN1 from killing patients.

‘Jamming the lock’

Understanding the behavior and function of DCN1 was far more ambitious than running simple tests. It was a significant step forward in understanding how proteins within a cell work.

Building upon the science from Shulman’s team, Jared Hammill from Guy’s lab and Danny Scott from Schulman’s lab worked to stop the interactions of DCN1 altogether. If DCN1’s activity depended on this interaction, then it stood to reason they could create a compound to intervene and stop the interaction from happening.

Guy describes the interaction as a “lock and key model.” Scientists have a blank key – which is UBE2M – and a lock, which is DCN1. The key wants to fit into the lock, so it’s modified until it fits. This modification process is N-terminal acetylation.

“What’s the significance?” Guy said. “Well, we’re the first people to show that protein interaction controlled by N-terminal acetylation can be blocked. We’re essentially jamming the lock with a compound so the key won’t fit.”

The items jamming that lock are a series of small molecules created in the lab. When the molecules were tested directly in cancer cells, they worked. They effectively blocked DCN1 from binding to UB2EM. After decades of collaborative research, there was finally a barrier between lock and key.

What it means for patients

The impact of these findings for healthcare and lung cancer patients specifically could be profound.

“We are excited about the implications of this research, which offer us a meaningful solution for addressing diseases like cancer, neurodegenerative disorders and infection,” Shulman said. “It’s exciting to collaborate with so many complementary groups of expertise and to watch how Dr. Scott and Dr. Hammill led the team. This research opens many new doors for us.”

The collaboration between these three labs could mean relief to many of those suffering from a variety of diseases.

“To have spent decades on this research and have such promising results is truly exhilarating,” Singh said. “At the end of the day, what matters most is improving health outcomes for our patients. This work represents a very important step towards developing a new approach to treat the most difficult of cancers and hopefully increase cure rates.”

This research was funded in part by National Institutes of Health, the Howard Hughes Medical Institute and American Lebanese Syrian Associated Charities.


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Meet the Researcher Day

UK cancer researchers welcome middle, high school students

Middle and high school students from across the region came to UK and UK HealthCare last week for an up-close look at what it’s like to be a cancer researcher.

“Meet the Researcher Day,” hosted by the UK Markey Cancer Center and the Leukemia & Lymphoma Society (LLS), is a field trip reward given to schools in the region that successfully raise more than $1,000 for the LLS’s Pennies for Patients campaign.

This year, students from Shelby County West Middle School, Mercer County Senior High School, Henry County Middle School and New Albany High School in Indiana won the opportunity to visit the Biomedical/Biological Sciences Research Building on UK’s campus and learn more about how the money they raised for Pennies for Patients will help further cancer research.

After an introduction by UK researchers Tianyan Gao and Craig Vander Kooi, the students received a tour of different cancer research labs and learned how to use basic lab equipment. The event also featured remarks from Dr. John D’Orazio, a pediatric oncologist and cancer researcher as well as LLS Honored Hero Brad Wilson, a UK chemical engineering student and two-time leukemia survivor. The students also heard a panel discussion about careers in science featuring D’Orazio and UK students Michael Gosky and Payton Stevens.

“I think it’s important that students get to see the lab spaces, meet the researchers and understand what the Leukemia & Lymphoma Society and Markey Cancer Center mission is: The cure for cancer,” said Shelia Gustafson, campaign director for the Kentucky and Southern Indiana Chapter of LLS.

Pennies for Patients is the annual fundraiser for the Student Series of the LLS. It encourages students to collect spare change during a three-week period early in the year. Funds raised support leukemia, lymphoma and myeloma research; patient and community service; public health education; and professional education.

For this year’s campaign, 485 schools across the region participated, raising more than $400,000 – a new record. The schools participating in Pennies for Patients had to raise a minimum of $1,000 to win the chance to attend Meet the Researchers Day. The four schools at Meet the Researchers Day this year were chosen in a random drawing, raising more than $10,000 combined for LLS.

Check out the video below for highlights from this year’s Meet the Research Day.


Next steps:

  • Learn more about clinical trials at Markey, which give patients access to the most up-to-date cancer research and innovations.
  • Markey is Kentucky’s only NCI-designated cancer center, providing world-class cancer care right here in the Commonwealth. Learn more about why patients choose Markey for their cancer treatment.
Kate Zaytseva, one of four project leaders on the COBRE grant for the Center for Cancer and Metabolism, and postdoc Naser Jafari are studying the importance of an enzyme called fatty acid synthase in controlling survival and spread of colorectal cancer.

UK wins $11.2 million NIH grant to study cancer-obesity link

UK has been awarded an $11.2 million grant from the National Institutes of Health to study the link between cancer and metabolic disorders, including obesity. The prestigious award will enable UK to launch the UK Center for Cancer and Metabolism (CCM).

The Centers of Biomedical Research Excellence (COBRE) grant to study the metabolism of cancer comes from the NIH’s National Institutes of General Medical Sciences and will fund the UK Center for Cancer and Metabolism over the next five years.

Kentucky has disproportionately high incidences of both cancer and metabolic disorders – our state leads the nation in cancer deaths and is in the top 10 for highest obesity rates in the country. While scientists have long known of a direct link between obesity and cancer, the need for further research into this field is a necessity for Kentuckians.

Senate Majority Leader Mitch McConnell of Kentucky, an advocate of the 21st Century Cures Act, contacted NIH Director Francis S. Collins on behalf of UK’s grant application.

“In an effort to improve healthcare access and outcomes for my constituents, UK has long made a priority of undertaking important research specific to Kentucky and the Appalachian region,” McConnell said.

“Over the years, UK and its Markey Cancer Center have developed one of the strongest cancer research, prevention and treatment programs in the country, as demonstrated by the center’s 2013 NIH National Cancer Institute designation, which I was proud to support. I was also pleased to assist UK in securing this competitive grant to advance and strengthen this critical health research for Kentucky by enabling advanced research focusing on the development of novel therapies for cancer treatment.”

Kentucky Representative Andy Barr echoed McConnell’s sentiments, noting that support and funding for innovative cancer research remains a priority.

“The awarding of this competitive grant is a recognition of the University of Kentucky as a national leader in biomedical research,” Barr said. “I have consistently supported the National Institutes of Health because these investments not only contribute to our local communities and institutions, they will improve and even save lives by advancing new treatments and cures. I am confident the healthcare services provided by the NCI-designated Markey Cancer Center and the research done by UK scientists funded by this grant will help us to find better ways to fight cancer, which will benefit patients and families in Kentucky and around the world.”

Linking metabolism and cancer

The UK Center for Cancer and Metabolism capitalizes on highly specialized institutional strengths in cancer and advanced metabolomics tools to focus on the underlying mechanisms that link dysfunctional metabolism to cancer. Recent studies have shown that the metabolic powerhouse of cells – the mitochondria – can influence how aggressive a cancer becomes.

UK has internationally renowned experts in the field of cancer and metabolism, and new state-of-the-art technology has improved the ability to understand how metabolism impacts cancer.

“As the University for Kentucky, we are uniquely positioned to conduct this level of sophisticated research thanks to the presence of a diverse array of biomedical researchers, clinicians and our leading academic medical center,” UK President Eli Capilouto said. “Research and development is at the core of economic and human development, and it is why UK is Kentucky’s most instrumental change agent, health provider and economic engine. The progress we make offers the brightest future and best hope for Kentucky.”

The CCM will bring together highly complementary disciplinary strengths at UK in cancer, metabolism and data sciences, coupled with sophisticated metabolomics tools and advanced cancer imaging capabilities, to strengthen the university’s cancer research enterprise by providing a thematically focused multidisciplinary infrastructure dedicated to defining the role of metabolism in the development and treatment of cancer.

“Research is at the heart of any progress we hope to make in bridging health gaps in the Commonwealth,” said Lisa Cassis, UK vice president for research. “Increased funding opportunities through the 21st Century Cures Act, and in particular this COBRE focused on cancer and metabolism, will enable the university to foster the development of the next generation of scientists who will lead our efforts in translating basic research findings into promising new therapies.”

Fighting back against cancer in Kentucky

The scientific discoveries achieved through the CCM will continue to help the UK Markey Cancer Center in its mission to conquer cancer in the Commonwealth. As Markey prepares to renew its National Cancer Institute Cancer Center designation, and simultaneously compete to become a Comprehensive Cancer Center later in 2017, Markey Director Dr. Mark Evers emphasizes the need for increased cancer research funding and continuing to push for new discoveries.

“Nowhere in the country is it more important to have this level of cancer research underway,” Evers said. “Kentuckians face a unique set of health issues, but we at the UK Markey Cancer Center are distinctly positioned to help solve the problem. Being an NCI-designated cancer center means being a leader in research as well as clinical care and outreach. This funding will allow us to translate our findings into potential new therapies for cancer patients from Kentucky and beyond.”

The CCM leverages expertise with mentors and collaborators from across multiple UK centers, disciplines and departments. The multidisciplinary collaboration is indicative of the type of work ongoing at UK and UK HealthCare every day.

“This new funding is another example of the vital importance to the people of Kentucky – and this region – in having an academic medical center at the University of Kentucky,” said Dr. Michael Karpf, UK executive vice president for health affairs. “The synergy and collaboration between researchers and clinicians to further studies in cancer can only be done at a place like this, where people are working together to make a difference in the lives of patients now and for generations to come.”

Promoting collaboration

COBRE grants also use this platform to develop promising early-stage investigators with enhanced skillsets in exciting new areas of cancer research and to enhance their success in competing for NIH grant support. The grant promotes collaborative, interactive efforts among researchers with complementary backgrounds, skills and expertise.

Four junior investigators, mentored by teams of clinicians and scientists from a variety of disciplines, departments, and colleges at UK, will lead major projects investigating an aspect of cancer metabolism:

  • “Role of vitamin D in protecting against cachexia in cancer patients,” led by Travis Thomas, Department of Clinical Sciences, UK College of Health Sciences
  • “Role of serine biosynthesis pathway in breast cancer,” led by Yadi Wu, Department of Pharmacology and Nutritional Sciences, UK College of Medicine
  • “Role of RORα in breast cancer metastasis,” led by Ren Xu, Department of Pharmacology and Nutritional Sciences, UK College of Medicine
  • “Role of fatty acid synthase in colorectal cancer,” led by Kate Zaytseva, Department of Toxicology and Cancer Biology, UK College of Medicine

The CCM is co-led by program directors Daret St. Clair, professor and James Graham Brown Foundation Endowed Chair in the UK Department of Toxicology and Cancer Biology, and Peter Zhou, professor in the UK Department of Molecular and Cellular Biochemistry.

“Having the kind of environment where learning and collaboration are placed at the forefront is why we were chosen for this grant, and we hope to continue that throughout the life of this center,” St. Clair said. “It will also enable us to reach out to new and talented researchers who want to come to UK to become new project leaders and continue the work we’re doing.”


Watch the video below to learn more about the Center for Cancer and Metabolism.


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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


Next steps:

Dr. Mark Evers

Video: Markey hosts inaugural Precision Medicine Symposium

The UK Markey Cancer Center on Wednesday hosted its inaugural Precision Medicine Symposium, aimed at teaching oncology healthcare providers how to implement precision medicine into their clinical practice.

Precision medicine in cancer treatment focuses on understanding genetic mutations and using those mutations to select the best therapy for patients. Precision medicine is one of the recommendations highlighted by the White House Cancer Moonshot’s Blue Ribbon Panel. Presentations at Wednesday’s symposium included discussions about oncogenomic testing, Markey’s new Molecular Tumor Board, clinical trials and more.

Attending the symposium were more than 190 providers, including oncologists, hematologists, pathologists, radiologists, oncology nurses, researchers, pharmacists, genetic counselors, and cancer center administrators and leaders representing more than 20 different medical centers and healthcare entities across the region.

Breakout sessions allowed providers to meet in smaller groups with presenters and ask questions about precision-medicine issues, such as payment and reimbursement for Molecular Tumor Board recommendations.

The symposium concluded with a keynote speech from Dr. Shridar Ganesan, chief of molecular oncology at the Rutgers Cancer Institute of New Jersey.

“This event is so important because we want to bring precision medicine to all patients with cancer in Kentucky,” said Jill Kolesar, PhD, co-director of the Markey’s Molecular Tumor Board. “We’re bringing together clinicians and scientists to bring initiatives from the Markey Cancer Center to the entire Commonwealth of Kentucky.”

Watch a video below for more highlights from this exciting event.


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Researchers are looking for exotic microorganisms, and they reported a unique bacterium found in a coal mine fire that's burned for nearly a decade.

Bacteria from Kentucky coal mine fire could make antibiotic drug more effective

Researchers looking in Appalachia for exotic microorganisms that could produce groundbreaking new medicines have reported a unique find from the smoldering remains of a coal mine fire that’s burned for nearly a decade in southeastern Kentucky.

In new findings published this week in the journal Nature Chemical Biology, a research team from UK, Rice University and the University of Oklahoma made new — and in some cases, more effective — versions of the antibiotic drug daptomycin by using an enzyme from soil bacteria found in smoke vents of the Ruth Mullins coal fire. The study’s authors said the enzyme, called PriB, could prove useful in drug development.

Study co-author Jon Thorson, PhD, director of the UK Center for Pharmaceutical Research and Innovation (CPRI), says the finding is part of the center’s efforts in “bioprospecting,” or the search for new organisms that could be useful for making drugs. Thorson and colleagues have isolated more than 750 microbial strains, including some that live miles below ground in coal mines. In addition, the team has isolated more than 250 corresponding microbial metabolites, more than half of which have never been previously documented.

“A major focus of the CPRI is the discovery of novel microbial natural products and corresponding biocatalysts that have synthetic applications,” Thorson said. “PriB is one of the first capable of modifying highly complex drugs like daptomycin.”

The organism that yielded PriB is Streptomyces species “RM-5-8.” The RM stands for Ruth Mullins, the name of the coal fire where RM-5-8 was found.

“We don’t know the mechanism for why it makes daptomycin work better,” said Rice structural biologist George Phillips, whose team determined the three-dimensional structure of the enzyme. “It may be that it just gets into membranes better because the enzyme’s specialty is adding a prenyl group, an organic molecule that typically comes into play when a molecule docks with the outer membrane of a cell. The target for the drug is associated with the membrane, so this might be the mechanism for the improvement.”

Phillips has collaborated closely with both Thorson and co-author Shanteri Singh, an assistant professor at the University of Oklahoma, for more than a decade. Phillips’ team specializes in using X-ray crystallography to determine the precise structure of enzymes like PriB.

“In the organism, the enzyme both makes prenyl groups and attaches them to the standard amino acid tryptophan,” Phillips said. “This is part of a much larger metabolic pathway, but the (UK) team isolated the gene that produces the enzyme, and they used that to create a form of E. coli that produced the enzyme in bulk.”

Phillips’ team crystallized the enzyme and determined its shape. Phillips said the enzyme has a pocket where it binds with tryptophan and attaches the prenyl group. Studies at UK found the enzyme readily prenylates more than a dozen other compounds and can also use “nonnative” prenyl donors that notably expand its synthetic utility. Phillips said his group is already looking for ways to modify PriB’s pocket to make it even more useful in biosynthesis.

“This prenylation reaction could be broadly useful in producing drugs and other chemicals through biotechnology,” Phillips said. “Because the enzyme is permissive, it is possible to think of using it to produce all sorts of drugs, including antibiotics and anti-cancer therapies.”


In the video below, Thorson explains how bioprospecting for microorganisms in Appalachia works.


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Dr. Doug Lowy, interim director of the National Cancer Institute, recently visited the Markey Cancer Center, continuing a dialogue on cancer in Kentucky.

NCI director meets Markey researchers, faculty on special visit

Dr. Doug Lowy, interim director of the National Cancer Institute, recently visited the UK Markey Cancer Center, continuing a dialogue on cancer in Kentucky following his visit to Hazard, Ky. last fall.

Kentucky is home to the highest cancer incidence and mortality rates in the country, a major health problem that Markey is dedicated to changing. In July 2013, Markey received a prestigious NCI designation, which allows the center access to more research funding, trials and treatments.

Much of Lowy’s visit focused on research. Nine UK faculty members gave presentations on major research initiatives and programs at Markey, ranging from efforts in cancer prevention and control to drug development and discovery. Major topics of discussion centered around the cancer types that affect Kentuckians the most: lung cancer, colon cancer, cervical cancer/HPV and the hepatitis C virus, which is linked to liver cancer.

After meeting with a group of Markey junior faculty members, Lowy learned more about the UK HealthCare enterprise and its support of Markey from Dr. Michael Karpf, executive vice president for health affairs at UK. Lowy finished the day with a tour of clinical space in UK Albert B. Chandler Hospital’s Pavilion A – future home to Markey’s Hematology and Blood & Marrow Transplantation inpatient floor – and a dedicated cancer research lab in the UK College of Pharmacy.

“We were honored to have Dr. Doug Lowy visit us today at the UK Markey Cancer Center to learn more about our patients and the research we do here,” said Dr. Mark Evers, director of Markey. “It was a wonderful opportunity to engage with the NCI and with Dr. Lowy, so that they better understand some of the difficulties we have in delivering care to our patient population.”

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Next steps:

  • Markey is Kentucky’s only NCI-designated cancer center, providing world-class cancer care right here in the Commonwealth. Learn more about why patients choose Markey for their cancer treatment.
  • Learn more about Markey’s NCI designation and what it means for our patients and their families.
A new study by UK Markey Cancer Center shows that chloroquine – an anti-malarial drug – may be useful in treating patients with metastatic cancers.

New study shows anti-malarial drugs may be able to treat cancer

A new study by UK Markey Cancer Center researchers shows that chloroquine – a drug currently used to treat malaria – may be useful in treating patients with metastatic cancers.

Published in Cell Reports, the study showed that chloroquine triggered the secretion of Par-4 – a protein that kills cancer cells and can limit metastasis – in both mouse models and in cancer patients in a clinical trial.

In order for Par-4 to be effective in stopping cancer cell growth, it requires the help of a protein called p53. P53 directly induces another protein called Rab8b, which is responsible for transporting Par-4. Unfortunately in many types of cancer, the p53 protein is often mutated or has its pathways disturbed, allowing metastasis to continue.

The study found that when chloroquine is introduced, it’s able to induce p53- and Rab8b-dependent Par-4 secretion from normal cells to help stop cancer metastasis in p-53 deficient tumors.

The study was led by the lab of Vivek M. Rangnekar, the Alfred Cohen endowed chair in oncology research at the UK Markey Cancer Center and a professor in the UK Department of Radiation Medicine. UK Researchers Ravshan Burikhanov and Nikhil Hebbar in Rangnekar’s group were co-first authors in the study.

“Because p53 is often mutated in tumors, it makes the tumors resistant to treatment,” said Rangnekar, also the co-leader of the Cancer Cell Biology and Signaling research program and associate director at Markey. “However, this study shows that the relatively safe, FDA-approved drug chloroquine empowered normal cells – which express wild type p53 – to secrete Par-4 and stop metastasis in p53-deficient tumors.”

At the UK Markey Cancer Center, one clinical trial using chloroquine for Par-4 induction in a variety of cancer patients is ongoing. Researchers are now planning a second clinical trial that would involve giving a maintenance dose of chloroquine to patients who are in remission, with the hopes of preventing cancer relapse.

This research was funded with grants from the National Institutes of Health and the UK Markey Cancer Center/Center for Clinical and Translational Science. Researchers from the University of Pittsburgh, Kansas University Cancer Center and Osaka University in Japan collaborated with UK scientists in this study.


Next steps:

The Molecular Tumor Board is codirected by Dr. Rachel Miller and Jill Kolesar, PharmD.

Molecular Tumor Board gives Markey patients expanded access to precision medicine

The UK Markey Cancer Center recently launched its own Molecular Tumor Board, an approach to cancer care that uses genetic analysis to help oncologists choose cancer therapies tailored to each patient’s individual needs. The Molecular Tumor Board is the latest precision medicine initiative to come online at Markey.

“Oncology is now more genetic-based, instead of being based upon tumor types,” said Dr. Mark Evers, director of the Markey Cancer Center. “By better understanding the genetic makeup of our patients and their tumors, we can help direct their therapy.”

The Molecular Tumor Board is co-directed by clinical pharmacologist Jill Kolesar, Pharm.D., who recently joined Markey and the UK College of Pharmacy after starting a similar initiative at the University of Wisconsin-Madison and Markey gynecologic oncologist Dr. Rachel Miller.

How the tumor board works

Currently, clinical trials often target tumors with certain molecular or genetic characteristics, then search for patients with tumors that matched those criteria ­– like looking for a needle in a haystack. The information gleaned by the Molecular Tumor Board will instead allow researchers to develop clinical trials targeted to the needs of the patients Markey treats; in other words, it means starting with the needle, rather than the haystack.

Here’s how the tumor board process will work at Markey: when a patient undergoes a biopsy, the physician may choose to request a Molecular Tumor Board review of that case. The patient’s tissue will then be sent to UK’s in-house pathology lab for genetic type testing. Using technology known as next-generation sequencing, pathologists will run tests to compare the patient’s genes against a panel of 198 gene mutations that are associated with all types of cancer – 94 are for blood cancers and an additional 104 are added for solid tumors.

Once the sequencing is complete, the final report ­– containing the findings of any possible gene mutations – is sent to Molecular Tumor Board members. The report will be evaluated for three types of potential care: FDA-approved therapies for that patient’s cancer type, FDA-approved therapies in another tumor type (also known as “off-label use”) and potential clinical trials.

For example: a lung cancer patient who undergoes genetic type testing may receive pathology results showing they have three gene mutations of the 198-gene panel that are associated with cancer. It is possible that any one of these mutations may have caused the cancer and there may be either FDA-approved drugs or clinical trials targeting each of these mutations.

It’s the job of the Molecular Tumor Board itself to evaluate all of these potential therapies to ultimately determine which of the therapies will yield the best possible outcome for the patient.

‘The essence of precision medicine’

The tumor board comprises a vast array of experts across both the UK medical and academic campuses, including oncologists, hematologists, surgeons, pharmacists, pathologists, biostatisticians, basic scientists and epidemiologists, who meet on a regular basis to discuss each individual case in person. Each member brings their own expertise to discuss the available options and ultimately make a recommendation for the best course of care for that patient.

“It’s the essence of precision medicine,” Miller said. “The Molecular Tumor Board provides not only an opportunity for our patients, but also an opportunity for a physician to gain a better understanding of these molecular characteristics while providing the latest in optimal care for our patients.”

Improving cancer care across Kentucky

By analyzing the molecular characteristics of cancer tumors on a case-by-case basis, the Molecular Tumor Board will also create a cache of information to direct the development of new therapies that target the types of cancers found at Markey and throughout Kentucky.

“The Molecular Tumor Board will bring a fuller understanding of the cancers faced by Kentuckians,” Kolesar said. “Going forward, this will guide us in developing clinical trials and novel therapies best matched to our patients in the Commonwealth.”

Across the country, only a few medical centers currently have a Molecular Tumor Board to help direct cancer care. This type of precision medicine was one of the key opportunities highlighted earlier in the year with the Cancer Moonshot initiative. Established by President Barack Obama during the 2016 State of the Union address and led by Vice President Joe Biden, the goal of the Cancer Moonshot is to double the rate of progress in cancer prevention, diagnosis, treatment and care over the next five years and to ultimately end cancer.

“As the state that leads the nation in cancer incidence and mortality, nowhere in the country is it more important for patients to have access to this type of personalized medicine,” Evers said. “This is an opportunity for us to make a direct impact on the dire cancer statistics here in Kentucky.”


Next steps:

  • Check out our infographic to see how a patient with lung cancer would benefit from the Molecular Tumor Board.
  • Clinical trials can give cancer patients access to the latest treatments and breakthroughs. Learn more about the clinical trials open right now at Markey.
A new study led by UK Markey Cancer researchers and published in the Journal of Cell Science establishes a novel link between cell polarity and cancer-associated inflammation.

Proposed clinical trial could change the game for triple-negative breast cancer

This is the first post in a two-part series about UK Markey Cancer Center researchers’ efforts to improve treatment for triple-negative breast cancer, a deadly form of the disease. Check out Part Two here.

UK Markey Cancer Center Oncologist Dr. Edward Romond spent his career at UK treating and studying breast cancer, even leading major Phase 3 clinical trials on the breast cancer drug trastuzumab in the early 2000s. Commonly known as Herceptin, this drug became a standard of care for patients with HER2-positive breast cancer.

Though he retired from practice last year, Romond continues to work part-time with the research team at Markey, this time pushing toward a cure for a different, more deadly, type of breast cancer.

“Breast cancer, we now recognize, is at least five different diseases that are completely different from each other,” Romond said. “And the hardest nut to crack is this one called triple-negative breast cancer.”

Treating triple-negative breast cancer

Triple-negative breast cancer is a moniker given to a particularly aggressive group of breast cancers that often affect younger women. Unlike the receptor-positive types of breast cancer, which have biomarkers that tell oncologists which treatment the patient should respond to, triple negative breast cancers have no definitive biomarkers. If the patient does not respond well to the current standard of care, it’s up to the oncologist to make an educated guess about which chemotherapy will do the job.

The good news is that triple-negative breast cancers do generally respond well to chemotherapy. However, because triple-negative breast cancers are not the same, and every single patient responds differently to various chemotherapies, it’s difficult to predict which chemotherapy will best treat each patient’s cancer.

But the researchers at Markey are working to change that paradox. Markey’s Breast Translational Group is currently developing a proposed clinical trial that could create a major shift in the way triple-negative breast cancers are treated.

Currently, after a patient is diagnosed with triple-negative breast cancer, she usually receives chemotherapy first to try and shrink the tumor (known as neoadjuvant therapy), followed by surgery to remove as much of the mass as possible. The patients are then monitored for signs of recurrence. If a patient has residual cancer despite getting neoadjuvant chemotherapy, they are at a high risk for recurrence.

Proposed clinical trial

There are currently at least six different types of chemotherapy that can be used as a possible therapy for patients, and each one may affect each individual patient in a different way. To tailor the treatment to each distinct patient, the investigators aim to test the tumors in a set of animal model “avatars” with these different therapies to gauge the response.

Here’s how the proposed trial would work: after the patient’s biopsy, her cancerous tissue would be transferred into a mouse that is bred to grow human tumors, then subsequently into three dozen mice: her “avatars.” While the patient undergoes neoadjuvant chemotherapy and then surgery – a process that can take up to six months – the avatars will be divided into groups, with each group receiving one of the six available chemotherapies.

When the researchers see which avatar group has the best result, they’ll know which chemotherapy should work best for that patient. Knowing this would provide additional options for women who have residual cancer after neoadjuvant chemotherapy, and may reduce their risk for disease recurrence.

“It would prevent us from having to experiment with each individual patient, and end up finding that they didn’t respond to that therapy,” said Kathleen O’Connor, director of Markey’s Breast Translational Group. “If we can do this, then the oncologists will no longer have to guess.”

Disrupting the standard of care

Dr. Aju Mathew, a medical oncologist who treats triple-negative breast cancer patients at Markey, compares his team’s game-changing proposition to the way Uber has altered the use of public and personal transportation.

“We often hear about disruptive technology — Uber being one, for example,” he said. “It disrupted the current paradigm of everyone driving a car on their own or hiring a cab. This trial is our way of disrupting the current standard of care, the current technology, and the current practice of medicine, to try to change the paradigm of ‘one size fits all’ approach for triple-negative breast cancer patients.”

Though the avatar model of research isn’t new, O’Connor notes that not many researchers are using them specifically for the treatment of an individual patient. Using a trial protocol to get the tissues directly from the patient’s biopsy is a key factor in making the research work.

“The important thing is that we need to get the tumor tissue before they’ve been exposed to chemotherapy,” O’Connor said. “This is one of the things that makes our trial unique.”

With the trial design in place, the team just needs to provide ample data showing that growing a patient’s tumor in the avatar from biopsy will work. But to gather that data, they need more funding. Initial pilot funds stemming from Markey’s National Cancer Institute (NCI) designation grant have enabled the team to establish their first set of avatars with tissues taken from patients’ surgeries. But a boost in funding would help them establish the preliminary data for the trial and allow the team to then apply for major federal funding.

“We have a large group of people who have freely given their time up to this point,” O’Connor said. “But we need to have money to protect the time of the researchers doing this work, and we need enough money to get the mice in order to do this.”

Check out the video below to see Markey researchers talk about their triple-negative breast cancer research.


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