Center News: Summer 2009

• Dinarello shares Royal Swedish Academy of Sciences Prize
• Leong, Macy are new Calabresi Scholars
• Kieft, Espinosa named HHMI Early Cancer Scientists
• Spillman receives award for ovarian cancer research
• Ahn shares $1.2 M collaborative grant
• Lung cancer program grew by 45% in 2008
• UCCC opens Colorado Molecular Correlates Lab
• White kids face higher risk of moles, skin cancer
• Natural substance may shrink prostate tumors
• UCCC scientists find new epigenetic mark that is more abundant as tumor grade increases
• Cancer Center Members net 7 of 39 CCTSI Pilot Awards
• Yin wins Elion Award
• Adjuvant Gleevec therapy improves recurrence rate in GIST
• 12 new members join UCCC

Dinarello shares Royal Swedish Academy of Sciences Prize

Dr. Charles Dinarello, professor of infectious diseases at the University of Colorado Denver, shared the Royal Swedish Academy of Sciences’ $500,000 Crafoord Prize with a pair of Japanese researchers. The  three were honored for their examination of polyarthritis and other autoimmune diseases, leading to the development of drugs to treat these conditions. He has received several international awards for his work with cytokines, which are increasingly of interest as agents driving increased risk and/or promotion of cancer.

Leong, Macy are new Calabresi Scholars

Dr. Stephen Leong and Dr. Meg Macy are the newest Paul Calabresi Clinical Oncology Research Scholars. Calabresi Scholars are recipients of a K12 award that  provides five years of mentored support leading to becoming translational researchers.

Leong is assistant professor of Medical Oncology at UC Denver. He did his fellowship under Dr. Gail Eckhardt, who continues as his K12 mentor along with Dr. Wells Messersmith.  Leong specializes in GI cancer with an emphasis on Phase I trials. He works with IGF1-R inhibitors combined with chemotherapy.

“When I started working in GI oncology during my residency in Ireland , we had only one drug for treating colon cancer,” he said. “I have seen the introduction of a number of chemotherapy agents, which makes this field really interesting. I wanted to have more of an active role in actually developing and testing these agents.”

Macy is instructor of Pediatric Hematology/Oncology/Bone Marrow Transplantation at UC Denver and The Children’s Hospital. She did her fellowship here under the mentorship of Dr. Lia Gore, who is head of Experimental Therapeutics at Children’s (Lia was previously also a recipient of this K12 award). During her fellowship, Macy split her time between working with pediatric brain tumors with Dr. Nicholas Foreman, on early phase clinical trials withGore and working on VEGF receptor inhibitors in acute lymphoblastic leukemia in the lab.

“I want to work on developing new clinical trials for relapse-refractory tumors for the mere fact that we don’t have a lot of options for treatment,” she said. “There are so many new drugs in development. In order to understand how to rationally target therapies, you really have to understand the basic science. This grant will provide me with additional training that you just can’t get in three years of fellowship.”

Kieft, Espinosa named HHMI Early Cancer Scientists

Two UCCC members have been selected as Howard Hughes Medical Institute Early Cancer Scientists. This honor brings with it a six-year appointment to the Institute, full salary support, and $1.5 million in research support awarded over the six years.

Dr. Jeff Kieft, associate professor of biochemistry and molecular genetics at UC Denver, is a structural biologist who is interested in RNAs from the hepatitis C virus, which causes 100,000 cases of hepatocellular carcinoma each year. He aims to identify targets that might be used to develop new therapies against hepatitis C and other viruses.

“This award will give me a tremendous amount of freedom to pursue important questions without having to worry about writing a grant for everything I want to try,” he said. “It presents a big challenge – to live up to the opportunity I have been given. I feel strongly that this is an award that is not just mine. It also belongs to the people in my lab, past and present, and to my colleagues. Their hard work and support has been and will be critical.”

Dr. Joaquin Espinosa, associate professor of molecular, cellular and developmental biology at the University of Colorado at Boulder, aims to be the first scientist to map all the effects of the tumor suppressor protein p53. He said his goal is to redraw the p53 gene network from scratch by employing new genomics and proteomics technology that will enable a fresh, unbiased look at this important tumor suppressor gene.

“This award is very encouraging, but it also creates a deep sense of responsibility,” he said. “We are glad to be given an opportunity to go bigger and riskier in our science, but we are also aware of the challenge.”

Spillman receives award for ovarian cancer research

Dr. Monique Spillman has received the Liz Tilberis Scholars award from the Ovarian Cancer Research Foundation.

This highly competitive award, given to early-career researchers who are developing techniques for early diagnosis and improved care for women with ovarian cancer, comes with a $450,000, three-year grant.

Her project builds on her recent success showing that ovarian cancer cells with estrogen receptors grow faster than estrogen-negative cells when estrogen is present. Spillman is assistant professor of obstetrics and gynecology at UC Denver.

“We know that about two-thirds of ovarian cancer cells have steroid hormone receptors, but estrogen appears to act differently in ovarian cancers than in breast cancers,” she said. “Breast cancer is currently treated with anti-estrogen drugs and aromatase inhibitors, but ovarian cancer is not. In the early 1980s, women with end-stage ovarian cancer were treated with Tamoxifen, but it didn’t work, so it got dropped. At that time, they didn’t really understand how the drug worked and how cancer changes with chemotherapy. The problem with the early data may have been with the drug, not with the cancer.”

No one has ever done any studies in which the primary tumor is treated, then the patient is put on anti-estrogen or aromatase inhibitors to see if you can prevent recurrence or the formation of new tumors, Spillman said. In this new study, she will investigate the hypothesis that using anti-estrogen drugs or aromatase inhibitors will have a direct anti-tumor effect on estrogen-positive ovarian cancer tumors.

“If we’re able to prove this hypothesis, it can mean a new way to treat obese women who have had ovarian cancer,” she said. “Even without their ovaries, and even if they are not taking HRT, these patients’ excess body fat causes them to produce a lot of estrogen, which may increase the risk of recurrence. We hope that we can reduce that risk for these patients.”

Ahn shares $1.2 M collaborative grant

UCCC member Dr. Natalie Ahn, professor of chemistry and biochemistry at CU-Boulder, is one of eight project collaborators sharing a $1.2 million grant from the W.M. Keck Foundation for work that may identify all proteins present in a single cell type.

This knowledge could better enable us to understand the complex changes within a cell that are triggered by disease, food or other means, and could accelerate development of targeted therapies for cancer, heart disease and other diseases.

"We want to learn what causes changes in cells: for example, how a cancer cell alters cellular proteins, making them different from proteins in a normal cell," Ahn said. "Our goal is to analyze proteins in cells and their chemical properties, and identify those that change in cancer."

Defining the complete composition of cells is a new scientific and medical frontier, and technologies to investigate this problem at a molecular level are evolving rapidly. Mass spectrometry has emerged as a powerful technology for monitoring proteins within complex samples, enabling the detection of changes in protein chemistries that cannot otherwise be observed. However, no study has achieved complete identification of proteins in any cell type, tissue or fluid.

"We need new strategies to completely define the molecules that underlie cell regulation, map proteins that can be used to detect diseases and determine how well patients respond to therapy," she said.

Lung cancer program grew by 45% in 2008

Dr. Ross Camidge, assistant professor of medical oncology at the University of Colorado Denver School of Medicine and co-director of the UCCC Lung Cancer Program reported a 45 percent growth in the program in 2008:

• 220 new patients were seen by the lung medical oncologists in 2008, up from an average 152 per year in the preceding 3 years
• Non-small cell lung cancer patients led this increase, with 106 NSCLC patients in 2008 compared to an average of 56 per year in the preceding three years
• 47 percent of these patients came to UCH for their first course of treatment
• 35 percent of these patients were put on a clinical trials

In 2008 the service began offering clinic coverage by attending physicians and its nurse practitioner five days a week; improvements in clinical scheduling have been made; and the new University of Colorado Denver lung cancer website provides clear contact details and up-to-date information. Plans for the future include advertising to local pulmonologists, including telemedicine affiliate sites at the weekly tumor board meeting, and a new National Jewish Health/UCCC collaboration.

Dr. Camidge also reported that the Clinical Investigations Core is more efficient at opening lung cancer trials because there is now a single regulatory affairs coordinator for all lung trials, and Denver Health patients are being enrolled on lung cancer clinical trials, thanks to the hard work of Dr. Ana Oton, a UCCC oncologist working principally at DH.

UCCC opens Colorado Molecular Correlates Lab

Another new development in 2008 was the opening of the Colorado Molecular Correlates lab by Dr. Wilbur Franklin, professor of pathology at UC Denver SOM. CoMoCo tests clinical samples from patients enrolled in UCCC lung cancer trials. In 2008, more than 50 patients were screened using UCCC's pioneering EGFR tests for NSCLC--EGFR FISH, immunohistochemistry and mutations. The lab also tests tumors for KRAS mutations and P53 mutations. Together, these tests help determine those patients who are likely going to be responders (or not) to EGFR inhibiting agents. Tailored clinical care is no longer a dream at the University of Colorado , but it is now a new standard of care.

White kids face higher risk of moles, skin cancer

Dr. Lori Crane, chair and professor of community & behavioral health at the Colorado School of Public Health, found that vacationing at the shore led to a 5 percent increase in nevi (more commonly called ‘moles’) among 7-year-old children. Number of nevi is the major risk factor for malignant melanoma, the most dangerous form of skin cancer. The study was conducted among children who lived in Colorado, but Crane said the findings are universally applicable.

Natural substance may shrink prostate tumors

Drs. Raj Agarwal, Chapla Agarwal, Bob Sclafani and members of Raj Agarwal’s lab have a new publication in the February 2009 issue of Cancer Research that explains the mechanism of the chemopreventive substance, Inositol Hexaphosphate (IP6), in prostate cancer.

IP6 is a substance naturally found in whole grains and high fiber foods such as beans and brown rice. It is nontoxic. Studies have correlated lower incidences of breast, colon and prostate cancer with eating lots of foods that contain IP-6. But until now, no one understood how the mechanism worked.

Previously, Agarwal’s lab showed that IP6 induces cell growth inhibition and apoptosis in advanced prostate cancer cells both in vitro and in vivo during G1 of the cell cycle. In the experiments behind this paper, they worked to figure out how IP6 works as a chemopreventive agent. They showed that IP6 targets the p21 and p27 proteins, which are known to be inhibitors of cell division. They also showed that when p21 and p27 are both knocked out, cancer cells become resistant to IP6.

“IP6 has to be working through that mechanism,” Sclafani said. “The bottom line is IP6 is effecting the normal cell regulatory system.”

The next step for the group is designing a clinical trial using IP6 for treatment of prostate cancer. Sclafani said they hope to show that the substance can be used to shrink prostate tumors

UCCC scientists find new epigenetic mark that is more abundant as tumor grade increases

Drs. Jessica Tyler, Chandrima Das, Scott Lucia and Kirk Hansen have a paper in Nature that was published online on March 8. This paper describes a new histone modification, or epigenetic mark, that they have discovered in humans and have found is abundant in human cancer. The mark appears to become more abundant as tumor grade increases.

The group discovered which enzymes are laying down and taking off the epigenetic mark, which loosens chromosome structure and alters gene expression. Previous work in the yeast model system from Tyler ’s lab had also shown that this mark is implicated in DNA repair and turning off cell cycle checkpoints that signal when repair is finished. Curiously, the enzyme that removes the mark is activated by resveratrol, an anti-cancer substance found in red wine.

“What it definitely tells us is that the activity of the genome is very different in cancer cells compared to normal cells,” Tyler said. “Exactly how it is different, we don’t know. We are now following that thread to find out why this epigenetic mark is so abundant in human cancer and what that means for cancer cell biology.”

Tyler surmises this epigenetic mark could be a biomarker for completion of DNA repair, and it could be used as a measure of DNA repair capacity of cancer cells that could help determine a therapeutic route. Tyler is leader of the UCCC Molecular Oncology Program. Hansen is manager of the UCCC Proteomics Core. Dr. Lucia is co-director of the UCCC Pathology Core and co-leader of the UCCC Hormone Related Malignancies Program. Das is a postdoc in Tyler ’s lab.

Cancer Center Members net 7 of 39 CCTSI Pilot Awards

UCCC members are receiving the first Colorado Clinical & Translational Sciences Institute Pilot Awards. In fact, UCCC members were awarded 7 of 39 awards given:

• Drs. Bob Sclafani, Raj Agarwal, David Raben and Barbara Frederick: Team Science Award for Oncology Combined Resveratrol and Radiation Therapy in Head and Neck Cancer.
• Dr. Hubert Yin: Junior Investigator award for Optimizing the Clinical Efficacy of Opioids by TLR4 Blockade.
• Dr. Jena French: Junior Investigator award for Immune Suppression and Papillary Thyroid Cancer.
• Dr. Neil Box: Child and Maternal Health award for Gene and Environmental Influences on Melanoma Risk Phenotypes in Colorado Children.
• Drs. Ellyn Matthews, Madalynn Neu, Tim Garrington, Paul Cook and Nancy King: Child and Maternal Health award for Caregiver-Child Sleep Patterns and Distress During Maintenance Therapy for Acute Lymphocytic Leukemia.
• Dr. Arnold Levinson: Community Engagement pilot grant for Community-Embedded Navigators and Health Promoters for Disease Prevention and Control.
• Dr. Jean Kutner: Community Engagement pilot grant for Hospice-Academic Partnership to Improve Care for Vulnerable Populations at the End of Life.

Yin wins Elion Award

Dr. Hubert Yin, assistant professor of chemistry and biochemistry at the University of Colorado at Boulder, received the 2009 Gertrude B. Elion Award from the American Association of Cancer Research. Yin received a one-year, $50,000 grant as part of the award. The award is named after the Nobel Laureate whose research revolutionized cancer therapeutics. Dr. Yin said the award will allow his lab to move forward its work on novel computer-guided screening techniques that can identify agents that target protein transmembrane domains, a major focus of his work.

Adjuvant Gleevec therapy improves recurrence rate in GIST

Patients with gastrointestinal stromal tumors who are treated adjuvantly with the oral medication imatinib mesylate (Gleevec) have a greater chance of recurrence-free survival than those who receive standard of care--observation, according to a new paper in the March 28, 2009 issue of The Lancet.

Surgical oncologist Dr. Martin McCarter, associate professor of Surgery at UC Denver, was the local PI for the phase III study, which enrolled 18 patients here in Denver and 713 overall.

Dr. McCarter said that traditional cancer therapies have minimal effect on GIST, a rare tumor that affects between 2,500 and 5,000 people in the United States each year. By chance, researchers discovered that imatinib mesylate, which has been lifesaving for people with chronic myelogenous leukemia, inhibits the KIT and PDGFRa proto-oncogenes which are often mutated in GIST.

The trial showed that the one-year recurrence-free survival rate for patients taking imatinib mesylate was 98 percent, compared to 83 percent of patients receiving placebo. The FDA approved the drug for adjuvant use in December 2008, and it is now covered by insurance companies.

"This study represents a large leap forward for the treatment of these patients," he said. "And our high participation level also puts UCCC on the radar for additional clinical trails we might not have before because we were deemed too small to contribute meaningfully."

Dr. McCarter is in the process of opening a phase II trial for GIST patients.

12 new members join UCCC

• Dr. Carlton Barnett, associate professor of surgery, University of Colorado Denver. Full member, Cancer Cell Biology Program. Director of surgical oncology, Denver Health, specializing in GI malignancies. Translational researcher with interests in pancreatic cancer.
• Dr. Barbara Biller, assistant professor of oncology, Colorado  State University . Full member, Immunology & Immunotherapy Program. Research interests: effects of chemotherapy on antitumor immunity and developing novel immunotherapeutics for cancer.
• Dr. Michael Graner, associate professor of neurosurgery, UC Denver. Full member, Immunology & Immunotherapy Program. Translational researcher with interests in adult and pediatric brain tumors, hematologic malignancies and CNS tumors arising from metastases from other organ sites.
• Dr. Jena French, instructor of endocrinology/metabolism/diabetes, UC Denver. Associate member, Immunology & Immunotherapy Program. Research focus: Role of the immune system in papillary thyroid cancer, particularly the role of lymphocytes in primary thyroid cancer.
• Dr. Eva Grayck,  associate professor of pediatrics, UC Denver. Associate member, Cancer Cell Biology Program. Director of the UC Denver/The Children’s Hospital Pediatric Critical Care Fellowship Program and faculty in the UC Denver Cell Biology, Stem Cell and Development Graduate School. Research goal: understand the role of reactive oxygen species and extracellular superoxide dismutase in pulmonary vascular remodeling in the developing lung.
• Dr. Maranke Koster, assistant professor of dermatology, UC Denver. Director, Morphology and Phenotyping Core, Regenerative Medicine and Stem Cell Biology Program, UC Denver. Full member, Cancer Cell Biology Program. Research Focus: developing mouse models for inherited and acquired skin diseases, including squamous cell carcinomas.
• Dr. Paul Jedlicka, assistant professor of pathology, UC Denver. Full member, Molecular Oncology Program. Research interests: Function of Ets factors in colon cancer initiation/progression in mouse and tissue culture models. miRNA regulation by the oncogenic EWS/Fli1 fusion in Ewing Sarcoma.
• Dr. Erica Pierce, research instructor of radiology and anesthesiology, UC Denver. Associate member, Developmental Therapeutics Program. Research interests: Pharmacokinetic (PK) and pharmacodynamic (PD) strategies in translationsal cancer therapeutics, including investigation of in vivo pharmacology of anti-cancer agents.
• Dr. Elizabeth Ryan, assistant professor of clinical sciences, Colorado State University Animal Cancer Center . Associate member, AMC Cancer Prevention & Control Program. Research interests: Evaluating bioactive, plant-derived food components for cancer control and prevention using comparative oncology models that have high translational potential for further investigation in humans.
• Dr. Jesus Rivera-Nieves, associate Professor of gastroenterology, UC Denver. Associate member, Immunology & Immunotherapy Program. Research Focus: Role of chronic inflammation/inflammatory bowel disease and dysregulated T cell responses as a cancer risk factor.
• Dr. Aik Choon Tan, assistant professor of bioinformatics, joint appointment in the Division of Medical Oncology, UC Denver, and Department of Biostatistics, Colorado School of Public Health. Full member, Developmental Therapeutics Program. Research interest: Develop and apply bioinformatics and systems biology tools and models for translational cancer research. Research focus: multi-level cancer genome characterization, and translating findings into clinical settings for personalized treatment.
• Dr. Deanna Worley, assistant professor of surgical oncology, Animal Cancer Center , Colorado State University. Associate member, Developmental Therapeutics Program. Research Focus: Adjuvant treatment for breast cancer in women. Sentinel lymph node mapping and surgical detection and resection of metastatic spread of neoplasia.