A Comprehensive Cancer Center Designated by the National Cancer Institute

Pathways to Discovery: Fall 2010

Feature Articles
Volume 5 | Number 3

  1. Killer tRNAs Offer Unique Approach for Cancer Therapy
  2. Researcher Discovers New Method to Kill Cancer Cells
  3. Three Important Protein Modifications Identified
  4. Cancer Researchers Share Lab with High School Students
  5. Team of Experts Treats Patient’s Multiple Cancers

Killer tRNAs Offer Unique Approach for Cancer Therapy

The cell can’t handle the stress, so it will commit suicide.
–Marsha Rosner, PhD

Cancer cells can adapt over time and become resistant to drug therapy. This is the main challenge for treating patients with cancer. Breast cancer, in particular, can reoccur in patients 10 to 15 years after receiving successful treatment. Marsha Rosner, PhD, Charles B. Huggins Professor and director of the Ben May Department for Cancer Research, and professor of neurobiology, pharmacology, and physiology, has formed a unique collaboration with Tao Pan, PhD, professor of biochemistry and molecular biology, to develop a new class of therapeutic molecules, called killer-transfer RNAs (tRNAs), to overcome this problem.

 “tRNA is a housekeeping molecule. Everyone thinks that it is boring, but it is not,” said Dr. Rosner, who is also a co-deputy director of the UCCCC. When DNA is translated into protein, tRNA functions as the molecule that transfers amino acids, the building blocks of proteins, to proteins as they are being formed. “Imagine you are constructing a brick building. The final building is equivalent to a protein. The blueprint for the building is your DNA. Determining which brick gets put in a specific place is the job of tRNA,” explained to Dr. Rosner.

Dr. Pan’s laboratory has engineered killer-tRNAs, which incorporate certain wrong amino acids into proteins. “If you do this enough times, the protein just can’t function. The cell can’t handle the stress, so it will commit suicide,” explained Dr. Rosner. “This is a new concept for cancer therapy. Instead of using a drug to attack cancer cells, we are using something that is so vital to the cell that it has no mechanism to get rid of it or become resistant to it.”

Drs. Rosner and Pan are working together to test killer-tRNAs in breast cancer cells and develop methods for effective delivery to breast tumors. Their goal is to deliver killer-tRNAs to breast tumor cells while leaving healthy cells intact. Renaud Geslain, a postdoctoral researcher who helped develop the concept in Dr. Pan’s laboratory, has tested a range of killer-tRNAs. “The efficacy of killer-tRNAs is influenced by which amino acid it inserts into the protein. We are examining what will be most selective for tumor cells,” explained Dr. Pan. 

This research is an example of a cross-disciplinary study, where an approach or technology from one field is applied to the problems of another. Dr. Rosner brings her expertise in cancer biology and cell signaling pathways to the project, while Dr. Pan brings expertise in tRNA biology and technologies. They are merging two different fields of study to develop innovative therapies for breast cancer. Their work is being supported by the Congressionally Directed Medical Research Program, funded by the Department of Defense.

Researcher Discovers New Method to Kill Cancer Cells

This study is unique because we are targeting the loss of tumor suppressor function in cancer cells.
–Wei Du, PhD

Targeted cancer therapies are designed to attack the features of tumor cells that are distinct from features found in normal cells. These therapies generally target signaling pathways that are deregulated and cause uncontrolled cell growth. Wei Du, PhD, associate professor in the Ben May Department for Cancer Research, is an expert in mechanisms that control cell proliferation. “Single-target drugs are often not successful in treating cancers because cancer cells can adapt over time and become resistant to therapy,” explained Dr. Du. “We need to develop more effective therapies by targeting multiple properties that are unique to cancer cells.”

In addition to deregulated signaling pathways, cancer cells often acquire inactivation of tumor suppressors, such as the retinoblastoma protein (Rb). Investigators, however, have had little success in developing cancer therapies that target cells with inactivated tumor suppressors. “Researchers have not found an approach to restore the function of tumor suppressors in cancer cells,” according to Dr. Du. “We also don’t know how to kill just tumors with loss of tumor suppressor function because we don’t know what to target.”

To tackle this problem, Dr. Du conducted a genetic screen in fruit flies to search for genes that can be used to target cancers showing loss of Rb function. The Rb pathway is highly conserved between the fruit fly and mammalian systems. He searched for mutations that caused death in cells with loss of Rb function but not normal cells. His screen led to TSC2, a gene that regulates cell growth. “This study is unique because we are targeting the loss of tumor suppressor function in cancer cells,” said Dr. Du. “Our study suggests that TSC2, which can be used to specifically kill cancers with inactive Rb, is potentially a new therapeutic target.” These research findings were published in the May 18, 2010, issue of Cancer Cell.

Dr. Du is now conducting studies to understand how TSC2 inactivation leads to cell death. One of his main goals is to develop inhibitors that disrupt TSC2 function. “These inhibitors can potentially be complemented with inhibitors that target deregulated signaling pathways. By combining these two types of inhibitors, we are more likely to prevent drug resistance in cancer cells,” explained Dr. Du. “This research will open new avenues for finding therapeutic targets for the treatment of cancer.”

Three Important Protein Modifications Identified

If we want to understand disease, then it is important for us to have a complete understanding of a cell’s regulatory mechanisms.
–Yingming Zhao, PhD

As researchers worked to complete the Human Genome Project, it was widely thought that having a map of the human genome sequence would dramatically accelerate the process of identifying drug targets and developing diagnostic tools. That hasn’t  happened—largely because of the fact that even though a person’s genes are almost identical throughout their body, the genes that code protein sequences are interpreted differently in different parts of the body and under diverse physiological conditions.

One newer area of research is proteomics or the study of the proteins—particularly protein structures and functions—in an organism, tissue, or cell. Yingming Zhao, PhD, an associate professor in the Ben May Department for Cancer Research, and his team focus their work on the chemical modifications of proteins, known as post-translation modifications (PTMs), which are associated with a majority of diseases and almost all cellular pathways.

Dr. Zhao said that about 300 types of PTMs are known to exist opening the possibility for more than a million protein structures—all with potentially different functions. The PTM profiles can be dynamically changed in response to environmental, genetic, and psychological factors. “To date, a huge knowledge gap still exists about the role of PTMs in cellular pathways, and how they regulate physiological conditions and diseases, including cancer. And this is part of a major knowledge gap in biomedicine,” he explained. Some extensively studied PTMs, such as protein phosphorylation and lysine acetylation, are dysregulated in diseases and are popular targets for drug design. For example, Janet Rowley, MD, pioneered studies in the 1970s that led to the foundation for Gleevec®, a blockbuster leukemia drug that targets a protein kinase modulating a protein phosphorylation pathway.

Dr. Zhao and his team have recently discovered three novel PTMs—lysine propionylation, lysine butyrylation, and lysine succinylation. Details about the first two PTMs have already been published, while information about lysine succinylation will soon be published.

The significance of these discoveries is that the enzymes that regulate PTMs can become targets of new drug therapies, and proteins bearing these PTMs could be biomarkers. “If we want to understand disease, then it is important for us to have a complete understanding of a cell’s regulatory mechanisms,” said Dr. Zhao. “These new cellular pathways will provide an additional level of understanding about a cell’s regulatory network.”

Although it may take years to have a good understanding of these PTM pathways and their roles in diseases, Dr. Zhao said he believes his discoveries are an important first step. “The history of biomedicine shows basic research is intimately connected to translational research—it is the foundation for the cures we have today, as demonstrated in the case of the drugs Avastin® and Herceptin®,” he said. “Many diseases are caused by dysregulation of PTM pathways. That’s why it is essential to characterize the changes associated with pathogenic processes for disease.”

Dr. Zhao and colleagues in the Laboratory of Proteomics and Protein Modifications are also applying new bioinformatics tools that they have developed to gain a better understanding of PTMs and how they work alone, as well as in combination with other PTMs. One such tool is called PTMap, a sequence alignment software enabling identification of all the known PTMs and novel PTMs, a research area that has been largely overlooked.

 

Cancer Researchers Share Lab with High School Students

We are forced to take a ‘birds eye’ view of our work reminds us of the importance of our research.
–M. Eileen Dolan, PhD

Four Chicago high school students learned what it is like to perform medical research during an 8-week program at UChicago this summer. Sponsored by the Illinois Division of the American Cancer Society (ACS), the program’s goal is to introduce high school juniors to scientific research—specifically cancer research—to promote career opportunities in the fields related to cancer.

“This program is important because it allows high school-level students to gain experience in a ‘real life’ cancer laboratory setting,” said Professor of Medicine M. Eileen Dolan, PhD, who has been instrumental in helping ACS develop the program since its inception in 2003. “Students are exposed to faculty who have dedicated their careers to cancer research making them excellent role models.”

The Projects
The students worked on activities involving breast cancer, lung cancer, acute myeloid
leukemia (AML), and optimal X-ray imaging.

Alexandra Rojek of Northside College Prep was paired with Patrick La Riviere, PhD, assistant professor of radiology, on a project involving imaging zebrafish, a simple vertebrate that serves as a model research organism.

“Using synchrotron-based microCT, which is similar to a CT scan for humans but at a microscopic level, we apply heavy metal-based stains to the zebrafish that bring out contrast you wouldn’t normally see in X-rays,” Dr. La Riviere explained. “We end up with a 3D X-ray image that allows us to see individual cells across an entire organism.”

Rojek’s role in the project was to optimize some of the imaging parameters—in particular, she needed to determine which X-ray energy would provide the highest-contrast images for different metal stains and different sized zebrafish.

“This was a completely different experience from what I’ve been exposed to in high school,” said Rojek. “It was overwhelming at first, but it was very exciting to gain a good grasp of all of these concepts and work with real data.”

Classmate Mary Mussman of Northside College Prep worked with Maryellen Giger, PhD, professor and vice chair of research in the Department of Radiology. Her project involved image-based biomarkers for the assessment of breast cancer risk. “Mary analyzed the parenchymal pattern on digital mammograms and breast MR images and extracted features related to the texture and dynamic characteristics of the parenchymal pattern,” said Dr. Giger. “Mary is continuing to evaluate these image-based risk signatures in terms of distinguishing between women at high risk for breast cancer and those at low risk.”

Noelle Bradley of St. Ignatius College Prep was paired with Rifat Hasina, DDS, PhD, assistant professor of medicine. “We worked on a project involving a focal adhesion protein called paxillin, which is very important in signal transduction pathways and has been found to be aberrant in lung cancer,” noted Dr. Hasina. “Noelle’s assignment was to work on a genetically altered version of paxillin and systemically define how a mutated gene affects the progression of cancer.”

Brittany Hughes of Lane Tech College Prep worked with Kenan Onel, MD, PhD, assistant professor of pediatrics. “Brittany’s primary project was to help us understand how AML cells respond to chemotherapy in order to design efficient screens for new drugs to treat patients with AML,” Dr. Onel said.

The Results
The learning experience that comes with this program tends to go both ways. “Articulating what we are working on at a high school level helps us think about our research in very broad terms,” said Dr. Dolan. “We are forced to take a ‘birds eye’ view of our work, which reminds us of the importance of our research.”

Prior to participating in the program Rojek planned on majoring in biology and chemistry in college. She is now rethinking her decision. “After getting over the frustration of getting things wrong, it’s been very exciting to learn new concepts and be exposed to a new field of science,” she said. “With my zebrafish project, it turned out that different fluctuations in density or length indicated an optimal energy that was nowhere near what I had expected.”

In fact, Dr. La Riviere was surprised by some things too. “This wasn’t a canned project. Alexandra has very strong math skills and she was able to understand the mathematical derivations I made and implement them on the computer,” he said. “I expected a certain set of results—some of my expectations were accurate, but some results were surprising. We are considering writing a paper because I don’t think our findings are well known in the field.”

 

Team of Experts Treats Patient’s Multiple Cancers

This experience confirms my belief that no other staff is more committed and dedicated than ours is.
—Edwin Posadas, MD

The story of attorney Gilbert Blackmun’s, fight against multiple cancers is chronicled in a thick, blue binder that his wife Gail carries around in a colorful, large tote bag. She has packed the binder with pages dense with neat, handwritten notes, phone numbers, and internet URLs related to Gib’s battles against prostate, skin, and colon cancers. Gib calls Gail his most relentless advocate.

Two of Gib’s cancers—his skin and colon cancers—are now in remission. Doctors are trying a novel therapy to get his prostate cancer under control. The Blackmuns said they are hopeful. Gail pointed to Gib’s continued work in his law practice. “It is hard to keep him away from the office,” she said. Since his colleagues are retiring, Gib is dissolving his current practice, and he is busy setting up a new firm.

Gib said he is thankful for the care he receives at UChicago. “I am so lucky to be here,” said Gib. “The doctors and nurses take a personal interest in me, and I know they’re willing to do everything they can to make me well. I can’t say enough about Dr. Posadas and his colleagues.”

As Gib’s primary oncologist, Edwin Posadas, MD, assistant professor of
medicine, is pursuing an integrated treatment plan that takes advantage of the investigational therapies available through UChicago’s extensive clinical trials program.

“We are doing all we can. Gib is a wonderful person with a powerful will. He’s a fighter,” Dr. Posadas said. “And so is Gail. She is completely engaged in staying on top of the latest developments and is constantly gathering information. I think of them as part of the treatment team.”

Gib was diagnosed with prostate cancer in 2006 and was treated at a local facility near
their home in Schererville, Indiana. They came to UChicago because the complexity of his disease required more sophisticated care.

In fall 2009, Dr. Posadas enrolled Gib in a phase III clinical trial investigating the effectiveness of a combination of two drugs: dasatinib (Sprycel®) and docetaxel (Taxotere®). “The trial was effective in treating Gib’s prostate cancer, and we maintained therapy with docetaxel after he left the investigation,” said Dr. Posadas. “But we put a temporary halt to the treatment to deal with a flare-up of Gib’s skin cancer.”

Bernhard Ortel, MD, associate professor of medicine, and a world-class authority on medical and surgical dermatology, became part of the team.

“We were concerned that the growing number and severity of the skin cancers might be therapy related, and I aggressively treated the multiple malignancies with topical agents and additional therapeutic procedures,” said Dr. Ortel. “This was a difficult case, but it was rewarding to help Gib battle his cancers.”

Dr. Ortel brought the skin cancer under control, but Dr. Posadas could not return Gib to his docetaxel treatment as planned because the treatment team discovered he had colon cancer. “It was frustrating to have things go smoothly only to face yet another cancer,” said Gib.

Consequently, the team added another specialist—Alessandro Fichera, MD, a renowned surgeon who specializes in surgery for colorectal cancer, inflammatory bowel disease, and other colon and rectal problems. “Ed contacted me and we immediately began planning the best way to approach this new cancer,” said Dr. Fichera, associate professor of surgery. “I welcome and admire Ed’s persistent advocacy of his patient’s needs. We performed surgery and successfully removed the tumor using minimally invasive surgery.”

Dr. Posadas put Gib back on docetaxel, but the drug was no longer able to control the prostate cancer, and he searched for another option. He found one in cabazitaxel (Jevtana®). The Food and Drug Administration approved second-line use of cabazitaxel for prostate cancer following treatment with docetaxel last June. Gib is the first UChicago patient to receive it.

All three physicians continue to communicate about Gib’s progress. “Drs. Ortel and Fichera contact me on regular basis to check on Gib’s condition. This experience confirms my belief that no other staff is more committed and dedicated than ours is,” Dr. Posadas said. “Only a major teaching hospital like UChicago would have been able to create a treatment team with the knowledge and expertise to successfully handle a case like Gib’s.”

 

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