Support from the James Graham Brown Foundation, Kosair Charities, the Louisville community and the University of Louisville’s President Dr. James Ramsey have fostered the emergence of a leading Cancer Center that is making critical contributions to clinical care in the region and, through pioneering research, to cancer patients throughout the world. Much of the research that has been performed in our laboratories over the past 15 years under leadership is reaching clinical trials in humans, where new cancer drugs and diagnostics are being tested.
The goals of our groundbreaking translational research programs are to bring laboratory discoveries to patients in the clinic.
To achieve this, we are:
- Identifying, developing, and rigorously evaluating new tools for the treatment and detection of cancer by expanding research in experimental therapeutics.
- Strengthening cutting-edge research in tumor immunology, which harnesses the power of the immune system to fight cancer.
- Building a program in cancer prevention and control to identify lifestyle, environmental, and genetic factors that influence cancer susceptibility and progression.
- Introducing promising drugs, vaccines, and diagnostic procedures directly to patients through clinical trials.
Achieving excellence in cancer drug development and patient outcomes
Across the United States, earlier detection and improvements in treatment have increased the five-year survival rate for cancer patients to 68 percent, from just 50 percent 30 years ago. Although cancer deaths are on the decline, Kentucky still has the highest cancer death rate in the nation. Furthermore, the state’s rate of new cancer cases — an estimated 25,000 in 2014 — is the highest in the country.
Because Kentuckians bear a disproportionate burden of cancer, the JGBCC focuses on research with the potential to rapidly translate laboratory findings into medical practice, where patients can benefit from effective new therapies. The emphasis on translational research has created one of the most robust pipelines of anti-cancer drugs of any American cancer center. JGBCC basic and clinical researchers have participated in more than 500 clinical trials, and more than 30 novel therapies are currently in preclinical development in JGBCC laboratories.
Translational scientists at the JGBCC have made a remarkable number of important first-of-their-kind discoveries that have propelled the Cancer Center onto the international stage
- First development of a cancer vaccine produced in tobacco plants (for cervical cancer)
- First description of VSELs (very small embryonic-like stem cells), which hold great potential to revolutionize applications of cell-based therapies against cancer
- First discovery that G-rich oligonucleotides inhibit cancer cell growth, and first development of an anti-cancer drug (AS1411) derived from these proteins
- First use of nuclear magnetic resonance (NMR) imaging to follow individual glucose atoms in patients with lung cancer, revealing unexpected metabolic differences between normal and malignant lung tissue
- First use of beta-glucan, an orally available dietary stimulant, to stimulate the immune system against tumor cells
- First use of colored berries (blueberries) to prevent cancer in high-risk people
- First phase I clinical trial of an inhibitor of cancer metabolism, PFK-158
- First phase II clinical trial to test the concept that depletion of regulatory T cells can stimulate immunity in advanced cancer patients
- First phase II clinical trial to test vesicles derived from grapes as anti-inflammatory agents and drug delivery vehicles in cancer patients
Excellence extends into the clinic, where the JGBCC is surpassing some of the nation’s top cancer centers in patient survival
For patients with advanced pancreatic cancer (stage II and III), the average survival rate in the U.S. within five years of diagnosis is 5.3 percent. But at the JGBCC, five-year survival rates for patients with advanced pancreatic cancer are 10.8 percent — more than twice the national average. Similarly, for JGBCC patients with advanced rectal cancer (stage II and III), the five-year survival rate is 68.9, nearly 18 percent higher than the national average of 58.5. Survival rates at the JGBCC are also higher for patients with curable breast cancer (87.3 compared to 85.0 nationally) and brain tumors (two-year survival rate of 33.7 compared to 31.6 nationally).
The JGBCC’s renowned successes in research and patient care have allowed us to raise $195 million in philanthropic support since 2000, including more than $50 million from the James Graham Brown Foundation and $12.5 million from Kosair Charities. With its national reputation for innovative research, the JGBCC has also secured support from organizations outside of the Louisville region. For example, the Helmsley Charitable Trust has donated more than $9 million to support research on plant-based cancer treatments and vaccines. And in the past year, the JGBCC also netted three prestigious multimillion-dollar grants from the National Institutes of Health. This unprecedented level of support has transformed the JGBCC from a small patient care facility to an academic cancer center with a national reputation for innovative research.
Blazing new trails in the war on cancer
For decades, academic researchers and their counterparts in the pharmaceutical industry have focused much of their efforts on developing anti-cancer drugs that target the downstream effects of cancer-causing genetic mutations. Unfortunately, almost none of the drugs developed within this framework lead to a lifelong cure. Most cancer cells are inherently genetically unstable and eventually develop additional genetic mutations that subvert a drug’s activity.
Under the direction of the Deputy Director, Dr. Jason Chesney, JGBCC scientists pursue a very different strategy. Instead of targeting the genetic mishaps that induce cancer, researchers at the JGBCC investigate chemical reactions shared by cancer cells that differentiate them from normal, healthy cells. For example, cellular metabolism — the process that creates energy and building blocks by which cells grow and proliferate — requires the breakdown of glucose. To induce the rapid cellular growth that characterizes cancer, tumor cells turn up the levels of the proteins that move glucose molecules into cells and convert them into building blocks to produce energy that accelerates cell growth.
The JGBCC is at the forefront of an effort to develop new classes of anti-cancer drugs that inhibit glucose metabolism. This novel strategy recently led to a phase I clinical trial of a drug that targets glucose metabolism — the first of its kind anywhere in the world. Called PFK-158, the drug works by inhibiting a protein called PFKFB3 that stimulates glucose metabolism in cancer cells and promotes tumor growth. JGBCC researchers led by Drs. Jason Chesney and John Trent demonstrated in mice that PFK-158 blocks glucose uptake by inhibiting PFKFB3’s normal activity, limiting cancer cell growth. Because it inhibits a metabolic process common to most cancer cells, PFK-158 is likely to be effective against a broad spectrum of human cancers. A Louisville-based biotechnology company, Advanced Cancer Therapeutics, licensed and developed PFK-158 which is now being evaluated for activity in patients with skin, lung, colon, breast, and pancreatic cancers at the University of Louisville, Georgetown University and MD Anderson Cancer Center.
Although we have multiple specific scientific programs, our clinical and translational researchers are clustered into four areas of cancer research: Experimental Therapeutics and Diagnostics, Tumor Immunology, Cancer Prevention and Control, and Clinical Trials.
Researchers in this program identify molecular targets and pathways that may be used to develop the next generation of cancer therapeutics and diagnostics. They use a unique structure-based strategy developed by Dr. John Trent that can greatly accelerate the clinical testing of promising drug candidates. Traditional drug design often means random testing of hundreds — if not hundreds of thousands — of compounds. But by knowing a drug candidate’s precise structure (its shape and chemical properties), JGBCC scientists use a rational approach that quickly discards candidate molecules that have the wrong shape or properties.
This approach has contributed significantly to the JGBCC’s emergence as a leader in experimental therapeutics research. Important advances to date include:
- Two novel drugs that have successfully “graduated” from preclinical tests in animal models to clinical trials in humans (AS1411 and PFK-158)
- Two novel drugs that are now licensed by the pharmaceutical industry and undergoing pre-clinical FDA evaluation for phase I trials (CKa15 and PU27)
- The first demonstration that advanced-stage cervical cancer, melanoma, lung cancer, head and neck cancer, breast cancer, and colon cancer can be detected with a single drop of blood in an assay called a plasma thermogram
- Exciting evidence that the presence of specific compounds called carbonyls in exhaled breath can be used to diagnose early-stage lung cancers
Researchers focused on Experimental Therapeutics and Diagnostics include: Drs. Donald M. Miller, Jason A. Chesney, John O. Trent, John W. Eaton, J. Brad Chaires, Levi Beverly, Al Cunningham, Nichola Garbett, Sucheta Telang, Brian F. Clem, Leah J. Siskind, Hong Ye, Wolfgang Zacharias, Lacey McNally, Christopher States, Paula Bates, Geoff Clark, Howard Donninger, Brian Ceresa, Chi Li, Tariq Malik, Robert A. Mitchell, Binks Wattenberg, Farrukh Aqil, Sam Zhou, Doug Dean, Qiutang Li and Qingxian Lu.
Decades of research suggest that a person’s own immune system can be activated to attack cancer cells. Paradoxically, inflammation mediated by the immune system can create a micro-environment that promotes cancer development. Tumor immunology research seeks to understand and manipulate this complex interplay to create new cancer prevention and treatment approaches. The research goals of this program are thus two-fold: (1) to activate host immunity against cancer cells, and (2) to suppress inflammation that can lead to cancer.
Ongoing tumor immunology projects include:
- The first demonstration that depletion of immune cells called T-regulatory cells causes tumor regression in cancer patients (currently in a multi-center phase II clinical trial resulting from research and a phase I/II trial conducted at the JGBCC)
- Discovery that interactions between the immune system and gut microorganisms can contribute to colon cancer progression
- Using molecules called beta-glucans in combination with cancer-specific antibodies to boost the anti-cancer efficacy of either agent alone
- First use of edible, plant-derived microparticles called exosomes to modulate inflammation in cancer patients
- Testing of an oral vaccine against colon cancer
- Testing of an embryonic stem cell vaccine to universally prevent human cancers
Researchers focused on Tumor Immunology include: Drs. Hari Bodduluri, Jun Yan, Nejat Egilmez, Ben Jenson, Shin Je Ghim, Jason Chesney, Chuanlin Ding, Venkatakrishna Rao Jala, Huang-Ge Zhang, Krystal Teasley Hamorsky, Nobuyuki Matoba, Kavitha Yaddanapudi, Magdalena Kucia, Mariusz Ratajczak, Janina Ratajczak and Zhong-bin Deng.
Cancer Prevention and Control
The goals of this program are to use a combination of epidemiological and outreach approaches to reduce cancer risk, find cancers earlier, and increase the number of people who survive cancer. Although some factors that contribute to cancer risk are well known — obesity, smoking, and human papillomavirus infection, for example — physicians need new tools to identify patients who are at high risk of cancer to allow them to intervene as early as possible. At the same time, physicians also need a profile of factors that protect a patient from cancer progression or predict successful recovery after chemotherapy.
Cancer prevention and control research often uses large data sets from population-based studies to determine the genetic factors, environmental effects, lifestyle choices, and biomarkers that contribute to cancer or protect against disease. Identifying the risk factors that predict a patient’s likelihood of developing cancer can help physicians tailor the most effective regimen to prevent or treat disease — the right therapy for the right person at the right time.
The program is closely integrated with the Kentucky Cancer Program, which is based at the James Graham Brown Cancer Center and is a national leader in cancer control and education. Through a network of 13 regional offices, the Kentucky Cancer Program promotes cancer prevention measures and serves as a bridge between scientists and the public, bringing the latest discoveries to the community through clinical outreach sites.
Researchers focused on Cancer Prevention and Control include: Drs. Shesh Rai, Brad Rodu, Chendil Damodaran, David Hein, LaCreis Kidd, Ramesh Gupta, Radha Munagala, Nichola Garbett, Manicka Vadhanam, and Kathy Baumgartner.
After rigorous testing in animal models, new diagnostics and therapeutics discovered by JGBCC researchers enter into early-phase clinical trials (phases I, II, and III), which screen for safety and efficacy in humans. A strong clinical trials program at the JGBCC ensures that Kentuckians have access to cutting-edge anti-cancer agents without having to leave the state.
Our clinical trials program for cancer patients has achieved national recognition as a major trial site for large pharmaceutical companies including Genentech, Amgen, Bristol Myers Squibb and Merck as well as the National Cancer Institute (NCI). On average, we have over 100 open clinical trials and 750 cancer patients actively participating in clinical research. Our Cancer Center along with Moffitt Cancer Center were the top two accruing sites for the largest ever NCI-sponsored trial for head & neck patients, RTOG0522 which tested the efficacy of an anti-EGFR cetuximab, and, in 2014, Dr. Chesney's clinical research group and a group from Memorial Sloan Kettering Cancer Center were the top two accruing sites for a combination trial of two immunotherapies that demonstrated the greatest clinical efficacy ever observed for an immunotherapy regimen. Importantly, our clinical trialists are helping our scientists to translate basic discoveries into clinical benefits for our patients and are also making astute clinical observations that are leading to new ideas to test in our laboratories.
Clinical researchers include: Drs. Michael Bousamra, Neal Dunlap, Goetz Kloecker, Cesar Perez, Jorge Rios, Tanya Wiese, Victor Ban Berkel, Jason Chesney, Donald Miller, Kelly McMasters, Craig Silverman, Beth Riley, Dharamvir Jain, Nicholas Ajkay, Anthony Dragun, Sarah Mizuguchi, Lane Roland, Stacey Crawford, Mary Ann Sanders, Carrie Lenneman, Megan Nelson, Jarrod Little, Bradon Wilhelmi, Terry McCurry, Mary Huber, Robert Martin, Rebecca Redman, Charles Scoggins, Vivek Sharma, Douglas Coldwell, Stephen Pirrone, Kelli Dunn, Adam Rojan, Missy Potts, Maria Gurka, Prejesh Philips, Jeffrey Bumpous, Kevin Potts, Neal Dunlap, Liz Cash, Paul Tennant, William Tse, Ju-Hsien Chao, Maxwell Krem, Cesar Rodriguez, Padmini Moffett, Jamie Messer, Moataz El-Ghamry, Warren Boling, Maxwell Boakye, Thomas Altstadt, Eric Burton, Shiao Woo, Harig Nauta, Sharmila Makhija, Dan Metzinger and Lynn Parker.
Owensboro Cancer Research Program
The Owensboro Cancer Research Program (OCRP) is a partnership between the Brown Cancer Center and the Owensboro Mercy Healthcare System. This program has laboratories in the Owensboro Hospital, providing the home for two BCC faculty, Dr. Ken Palmer and Dr. Nobuyuki Matoba. The goal of this unusual program is to develop novel therapeutics using the unique facilities in Owensboro for plant-made pharmaceutical development and production. This program has already produced a tobacco-based HPV vaccine, which promises to be much less expensive than the one currently available. Taking advantage of natural synergies between the BCC Molecular Targets and Structural Biology Programs, the OCRP will be able to move quickly into PMP-based drug development.
Molecular Targets Center of Biomedical Research Excellence (MT-COBRE)
The Molecular Targets Center of Biomedical Research Excellence (MT-COBRE) is an NIH/NIGMS grant at the James Graham Brown Cancer Center, University of Louisville, that successfully supported the early career of fourteen junior faculty members during its Phase I (2003-2008) and Phase II (2008-2013) funding periods. The current grant (2013-2018), a Phase III P30, reflects the maturation of the Molecular Targets Program and its faculty. The overall goal of this Phase III grant is to ensure that the novel targets and compounds that have been and continue to be identified by MT-COBRE faculty are translated to pivotal human clinical trials.
Several strengths have enhanced the success of this program including: 1) Stability of program leadership; 2) Successful retention of all fourteen faculty members; 3) Institutional support for the program totaling over $30 M; and 4) Creation of a University of Louisville-owned company dedicated to translating important discoveries of MT-COBRE investigators.
The ability of MT-COBRE faculty to test their novel compounds in humans distinguishes this program from similar programs at other institutions. To this end, the MT-COBRE has supported the development of a unique translational research infrastructure, which has enabled the characterization of more than 30 novel targets. The Phase III grant supports four closely integrated core facilities which, in turn, support this goal: 1) Microarray/Genomics Core; 2) NMR Core; 3) Molecular Modeling Core; and 4) Animal Model Core. Additionally, the James Graham Brown Cancer Center has created complementary research cores that are available to MT-Program members including the Biostatistics Core, Clinical Trials Office, Biophysical Cancer Core, and the Cell Sorting and Flow Cytometry Core.
The MT-COBRE administration continues to provide intensive support for development of the fourteen faculty members (13 in the JGBCC; 1 in the Department of Chemistry), many of whom have assumed leadership roles within the Cancer Center and University, and the four core facilities mentioned above. The robust translational research infrastructure at the James Graham Brown Cancer Center and University of Louisville ensure the success and sustainability of this unique program.
Phase I (2003-2008)
Donald M. Miller, M.D., Ph.D. and John W. Eaton, Ph.D., co-PIs
- This project also supported Sucheta Telang, M.B.B.S.
Phase II (2008-2013)
Donald M. Miller, M.D., Ph.D. and John W. Eaton, Ph.D., co-PIs
See above: Chi Li, Ph.D., Geoffrey J. Clark, Ph.D., Qiutang Li, Ph.D., Albert R. Cunningham, Ph.D. and Magdalena J. Kucia, Ph.D.
Phase III (2013-2018)
Donald M. Miller, M.D., Ph.D., PI