CENTER NEWS: SPRING 2009

BYERS NAMED UCCC INTERIM DIRECTOR

Tim Byers, MD, MPH, was named interim director of the University of Colorado Cancer Center on Jan. 1, 2009, when Paul A. Bunn, Jr., MD, stepped down after more than 20 years at the helm. Byers has been UCCC’s deputy director for the past four years. He is a national leader in cancer prevention and control, and sits on the board of directors of the American Cancer Society. He has been a member of UCCC for 14 years, first as a program leader, then as an associate director and deputy director. Byers is a professor, associate dean for Public Health Practice and director of the Center for Public Health Practice in the new Colorado School of Public Health. A national search for a permanent director is underway. Read an interview with Byers in CONVERSATION, and the Director's Message.

JONES BECOMES PI FOR LIVESTRONG™ SURVIVORSHIP CENTER OF EXCELLENCE

Alison Jones, ND, RN, has become the principal investigator for UCCC’s Lance Armstrong Foundation LIVESTRONG™ Survivorship Center of Excellence grant. Jones most recently has managed UCCC’s clinical psychosocial programs, including the Monfort Family Cancer Resource Center. Jones’s clinical nursing expertise and experience with cancer survivor issues will help UCCC develop robust programs and clinics for cancer survivors throughout the region.

SURVIVORSHIP CLINIC DEBUTS IN JANUARY

UCCC consortium member University of Colorado Hospital, has launched the region’s first clinic for adult cancer survivors. The THRIVE clinic will first be piloted with breast cancer patients with co-morbidities such as high blood pressure or diabetes, with the goal of helping them understand late effects of treatment and put them in touch with relevant specialists who have expertise in cancer survivorship. Alison Jones, ND, RN, and Linda Overholser, MD, an internist, are collaborating on the  project.

This is the second survivorship clinic at UCH. The TACTIC clinic, which began in July 2008, targets adult survivors of pediatric cancers. In both clinics, patients see an oncologist, an internist, a clinical psychologist and a nurse educator, and they leave with a “passport” to help educate health care providers about their cancer treatment.

UCCC ONCOLOGISTS OPEN PRACTICE IN SAN LUIS VALLEY

In November, residents of the San Luis Valley in south central Colorado gained access to world-class cancer care from UCCC medical oncologists in their own backyards. San Luis Valley Regional Medical Center (SLVRMC) in Alamosa and UCCC formed a new partnership to bring cancer specialists to SLVRMC at least twice a month. SLVMC does not currently have medical oncology or hematology specialists on staff, but it does have an infusion center for cancer chemotherapy  treatments. The UCCC physicians will collaborate with local physicians to help ensure patients receive comprehensive cancer care from top cancer experts.

J. Fred Kolhouse, MD, a hematologist specializing in blood cancers, and Madeleine Kane, MD, PhD, a medical oncologist, will visit SLVRMC and open clinical trials there. UCCC cancer specialists also travel to hospitals in Montrose, Glenwood Springs and Vail each month, bringing clinical care and cancer clinical trials to nearly 200 patients.

NICKOLOFF JOINS CSU AND UCCC

Jac Nickoloff, PhD, has joined Colorado  State University as professor and head of the Department of Environmental and Radiological Health Sciences in the College of Veterinary Medicine and Biomedical Sciences. He was previously with the University of New Mexico, where he was co-director of the Cancer Biology and Biotechnology program in the UNM Cancer Center and professor of molecular genetics and microbiology.

“(CSU’s being part of UCCC) was huge in my decision to take this position,” he says. “It’s such an honor to be part of a group like the University of Colorado Cancer Center. Collaboration is in my blood, and I know quite a few people in Denver who I’m excited to work with.”

Dr. Nickoloff is a basic scientist who studies DNA repair, specifically determining the molecular mechanisms that maintain eukaryotic genome stability. He works in both yeast and mammalian cell systems.

“There is strong evidence linking genetic recombination and other DNA repair processes to cancer initiation and progression,” he says. “DNA damage stimulated recombination is potentially mutagenic or carcinogenic. We’re trying to understand the genetic consequences of DNA double-strand breaks and other DNA lesions, such as those caused by UV light and chemical agents, as well as the mechanism and genetic consequences of delayed genomic instability induced by low doses of ionizing and non-ionizing radiation.”

Dr. Nickoloff is also working with a newly discovered human integrase called Metnase, which he says promotes random DNA integration and nonhomologous end-joining, as well as chromosome decatenation through interactions with Topoisomerase IIa. Some chemotherapy drugs work by hindering topoisomerase activity in cancer cells, and his group has found that Metnase promotes topoisomerase activity in the presence of topoisomerase inhibitors.

“Metnase may be a good marker for treatment,” he says. “If a patient has high levels of Metnase, the tumor may be resistant to these drugs. My colleague Dr. Robert Hromas at New Mexico and I have new R01s to investigate this idea further. We are focused on this protein, and ultimately want to come up with a small molecule inhibitor to use in combination therapy with tumors that are resistant to these drugs. We don’t have a crystal structure or functional in vitro assays yet, and we’re just starting to think about drug screens.”

Dr. Nickoloff says he will be hiring several new faculty over the next year or two with interests in radiation biology, cancer biology, DNA repair/replication, cell cycle/checkpoint control and genome instability.

“Our department houses an outstanding set of radiation sources that allow high and low dose rate exposures of cells and mice,” he says. “The department also has programs in health and medical physics, and veterinary radiology and radiation oncology on the Radiological Health Sciences side, and industrial hygiene, epidemiology and toxicology on the Environmental Health Sciences side. You can say I wear a few different hats here.”

Dr. Nickoloff just returned from a trip to Japan with Colorado Gov. Bill Ritter and a group of others from CSU to learn about opportunities to share faculty and ideas between CSU’s radiological sciences group and those at the Japan National Institute of Radiological Sciences.

“They’re doing some amazing imaging work over there,” he says. “We want to connect our veterinary radiologists with the Japanese, and maybe bring some of their faculty over here. We’re looking at student cross training programs, post-doc exchange programs and possibly even tenure-track faculty lines. They have several CSU graduates in their program, so we have a great connection with an impressive facility.”

Dr. Nickoloff received his PhD in biochemistry from the University  of Colorado at Boulder. He did his postdoctoral work at the Scripps Clinic and Research Foundation in La Jolla, Calif., and the Los Alamos National Laboratory. He held a faculty positions at the Harvard School of Public Health, Department of Cancer Biology before moving to the University of New Mexico. While there, he was chair of the Department of Molecular Genetics and Microbiology for eight years.

UCCC RADIATION ONCOLOGY GAINS PHYSICS EXPERT MIFTEN

The UC Denver Radiation Oncology Department has a new chief physicist. Moyed Miften, PhD, joined the faculty as professor on Oct. 15. He was previously chief of medical physics at Allegheny General Hospital Department of Radiation Oncology and West Penn Allegheny Health System Radiation Oncology Network and as associate professor of Radiation Oncology at Drexel University College of Medicine.

"It's exciting to be part of us a great group of cancer specialists," he says."The radiation oncology community is a close family. It's really easy to recognize excellence. Dr. Gaspar and the other faculty here have outstanding reputations, and are considered to be among the best in their field."

Dr. Miften's wide view of radiation oncology within the university setting, tertiary care and community hospital settings, and industry is particularly valuable for optimizing programmatic clinical capabilities in an era of rapidly accelerating technical advancements. He is board certified in Therapeutic Radiologic Physics, American Board of Radiology. He has expertise in advanced radiation oncology practice based on advanced mathematical and computational skills: IMRT‑IGRT; mathematical modeling of dose‑volume radiation data and clinical outcomes; functional imaging; complex radiation computerized dose calculation algorithms.

He will be leading UCCC's radiation oncology physics R&D efforts and implementing a physicist residency program. He is also supervising 10 members of the physics group, says he is planning to add two post-docs to the research staff. His research focuses on improved targeting and treatment planning in radiation therapy by integrating novel imaging and biological methods.

"I've been working on multiple individual projects that integrate and mutually reinforce to address the most critical current themes in radiation therapy," he says. "We're looking at using online imaging modalities to achieve a quantum leap in the accuracy of radiation targeting, and the second is incorporating the power of new biological models, biological imaging data and biological imaging agents to create more effective biologically drive treatment plans and radiation targeting."

Specifically, he has been working on online compensation of patient setup variations and real-time treatment plan adaptation. The technology of on-board imaging technologies such as online fluoroscopy, radiography, 3D cone-beam CT (CBCT) imaging and 4D-CBCT have widespread application in the clinical, he says, and contain the potential to radically impact clinical practice.

"Although the crucial influence of tissue biology on treatment complications and outcome have long been known, it is only recently that sophisticated hybrid imaging machines such as PET-CT, SPECT-CT and functional MRI, biological imaging agents for tumors and organs at risk, and biological and mathmatical models have been developed that are enabling practical applications in treatment planning," he says. "All of this is applicable across tumor sites. Our ultimate goal is to maximize patient care outcomes, to destroy all tumor cells and minimize normal tissue damage."

RICHER: DOD BREAST CANCER RESEARCH IDEA AWARD TO STUDY MICRORNA-200C

Congratulations to Jennifer Richer, PhD, associate professor of Pathology at UC Denver and member of the Hormone Related Malignancies Program, on her new Department of Defense Breast Cancer Research Idea Award for her project, “MicroRNA-200c: A Novel Way to Attack Breast Cancer Metastases by Restoring the Epithelial Phenotype.”  Dr. Richer will receive $572,130 over three years.

Her group has previously found that in carcinomas, epithelial cells that start losing their normal, row-like characteristics have lost miRNA-200c. They learned that the molecule E-cadherin is the "glue" that keeps the cells sticking together, and miRNA-200c makes the epithelial cells retain E-cadherin. When E-cadherin is lost, the epithelial cells are able to express genes normally only made in a different type of cells, those of mesenchymal origin, allowing them to become aggressive invaders.

Dr. Richer's group was able to put miRNA -c back into breast carcinoma cells in vitro, and when they did, they found that the cells looked more normal and lost their ability to invade other tissues by about 80 percent. The DOD grant will allow them to see if they can do the same thing in vivo.

"Adding miRNA-200c back makes the E-cadherin come back on by supressing Zeb1, a protein that's found in aggressive tumor cells but not in normal epithelial cells," she says. "The main function of Zeb1 is to repress E-cadherin. I anticipate that Zeb and miRNA 200c are also in play in a lot of carcinomas."

In vitro, they also looked to see if miRNA-200c loss plays a part in chemotherapy resistance.

"A lot of aggressive tumor cells are resistant to chemotherapy," Dr. Richer says. "One of the classes of drugs--including palitaxel--attacks microtubuals that are important in cell division. We found that when we put miRNA-200c back into breast tumor cells where it had been lost, those cells became up to 85 percent more sensitive to this particular class of chemotherapy drug. This therapy is used in almost all solid tumors."

She said her group will work with Leila Varella-Garcia, PhD, in the Cancer Center Cytogenetics Core to see how miRNA-200c is lost by chromosomal deletion or by some other mechanism.

A few other Cancer Center members also received DOD awards during this funding cycle. I'll write about them in the next week or so.

FORD AND ZHAO: DOD BREAST CANCER SYNERGISTIC AWARD TO STUDY SIX1 STRUCTURE AND FUNCTION

Congratulations to Heide Ford, PhD, and Rui Zhao, PhD, on their Department of Defense Breast Cancer Synergistic Idea Award for their project, “Structural and Functional Analysis of the Six1 Transcriptional Complex for Anti-Breast Cancer Drug Design.” Ford, who is associate professor of obstetrics and gynecology at UC Denver and member of the Cancer Center Hormone Related Malignancies Program, and Zhao, who is assistant professor of biochemistry and molecular genetics at UC Denver and member of the Molecular Oncology Program, will share $770,000 over two years.

The Synergistic Awards are given to projects that have two PIs from disparate fields. Zhao is a structural biologist/biochemist and Ford is a cancer cell biologist. They’ve collaborated before, but this is the first big award they’ve received together.

The project continues their work on Six, a transcription factor that binds to DNA and controls the activity of other genes. Ford and her collaborators have found that in 50 percent of primary breast cancers and 90 percent of metastatic disease, Six is overexpressed. They also know that knocking out the gene inhibits cancer cell proliferation and metastasis in cell culture and animal models.

Ford and Zhao believe that Six needs Eya2, a co-activator, to initiate tumorigenesis and metastasis. Since Eya2 is a phosphatase—it might be easier to target with small molecules. The first part of the project involves proving that Eya2 is required to mediate breast cancer tumorigenesis and metastasis to determine whether they can target the Six1/Eya interaction. Then, Dr. Ford’s lab will replace Eya2 with phosphatase dead and wild type Eya2 and see what happens.

“If the phosphatase dead-type doesn’t allow tumorigenesis but the wild type does, then we know that the Eya phosphatase activity is essential to the process,” she says. “Then we can target it. We don’t think this tumorigenesis and metastatic mechanism is limited to breast cancer, because our own group as well as other groups have shown that Six is overexpressed in many other tumors. And when it is expressed, it often indicates poor prognosis.”

Zhao’s part of the project involves coming up with inhibitors using structure-based drug design and high throughput screening. She already has a preliminary crystal and is in the process of determining the structure. The structure can be used to screen virtual libraries of small molecule inhibitors. Her lab is also designing the high throughput screening assays to screen a pilot library of 1990 small molecule compounds against the Six1/DNA and Six1/Eya2 interactions. They are planning to eventually screen the 300,000 small molecule compounds through the NIH Molecular Library’s Probe Production Network.

Dr. Ford and Dr. Zhao also obtained a State Proof of Concept grant ($185,000 for a year) that supports their efforts in identifying inhibitors of the Eya phosphatase. Together with the DOD award, they are targeting the Six1 transcriptional complex from all possible angles.

“This project has huge potential,” Zhao says. “Six 1 is a very interesting target, and no one has targeted it yet. If we’re lucky, we’ll get a good hit via our small molecule screening. Then Heide will take the drug into cell lines and animal models.”

SCHIEMANN: DOD BREAST CANCER RESEARCH AWARD TO STUDY FIBULIN 5 AND TGF-BETA

William Schiemann, PhD, associate professor of Pharmacology at the University of Colorado Denver and member of the University of Colorado Cancer Center Hormone Related Malignancies Program, has won a Department of Defense Breast Cancer Research Award for his project, “Chemotherapeutic targeting of Fibulin 5 to suppress breast cancer invasion and metastasis stimulated by TGF-b.” The award, which starts in February, is for $569,699 over three years.

Transforming growth factor beta, or TGF-b, is a protein with a dual personality. It is active in normal epithelial cells, functioning as a cell-growth braking system to suppress cancer. However, TGF-bis also active in carcinomas, behaving as an aggressive stimulus for cell growth. No one understands for sure what happens in the gray area where the protein switches from being protective to being tumorigenic, but Schiemann and his research team have some ideas. He recently identified a protein called fibulin-5, which is expressed more abundantly in human breast cancers as compared to normal breast tissue. He thinks this protein plays a pivotal role in that gray area.

“We think that TGF-b gets drowned out by all these other signals, like if you walk into a noisy classroom and can’t hear the teacher talking,” Schiemann says. “We think that if we can turn down the volume that the cells will hear TGF-b again and it will again work as a braking system instead of an accelerant. One way we think we can do this is by adding fibulin-5 back in to regulate the signaling noise.”

The grant will allow him to attempt to confirm his theory that epithelial cells without correct levels of fibulin-5 causes them to become cancerous. The information is important, Schiemann says, for two reasons.

“We have found that once cells sense TGF-beta as an accelerant, those cells become resistant to common chemotherapy drugs,” Schiemann says. “We’ve also found that, in cell lines and in breast tumors produced in mice, too much fibulin-5 enhances the accelerant activity of  TGF-beta in normal and malignant mammary epithelial cells. When that happens, the cells become less sensitive to chemotherapy. We think it’s possible that fibulin-5 antagonists could be a new therapy for breast cancer and other carcinomas by sensitizing these cells to chemotherapeutics and by reestablishing tumor suppression to TGF-b. ”

The findings that led to the grant were published online in advance of print publication in the August issue of Carcinogenesis: Fibulin-5 Initiates Epithelial-Mesenchymal Transition (EMT) and Enhances EMT Induced by TGF-{beta} in Mammary Epithelial Cells Via a MMP-Dependent Mechanism. 

BORGES: AACR/BREAST CANCER RESEARCH AWARD FOR PREGNANCY ASSOCIATED BREAST CANCER

Virginia Borges, MD, MMSc, is the recipient of  a new grant from the AACR/Breast Cancer Research Fund for her project, “Targeting the Inflammatory Milieu of Pregnancy Associated Breast Cancer.” Dr. Borges, who is an assistant professor of medical oncology at UC Denver and member of the Immunology Program, will receive $246,667 over two years starting in January.

Dr. Borges and Pepper Schedin, PhD, associate professor of medical oncology at UC Denver and member of the Cancer Cell Biology Program, are some of the nation’s foremost experts on young women’s breast cancer and its subset of pregnancy-associated breast cancer. They have found that women under age 45 who are diagnosed with breast cancer within five years of giving birth tend to have higher rates of metastases and poorer outcomes. About 11,000 women under the age of 40 are diagnosed with breast cancer in the United States each year. Of that number, about 50 percent had a baby in the six years prior to diagnosis. Those who are diagnosed within two years of giving birth have a 40 percent five-year survival rate, compared to an 70 percent five-year survival rate for women who are 15 years post-delivery at diagnosis.

“This is a large number of our young women, who are a vital part of our society,” says Dr. Borges, who is also a breast cancer clinician. “We’re talking about 30- and 40-something year old women with young children who are entering the vital part of their lives, and we’re losing them to breast cancer for reasons we do not currently understand.”

Borges and Schedin want to know why breast cancer that arises after a completed pregnancy has a greater ability to metastasize. After several years of looking at inflammation related to weaning as the cause of poorer prognosis, they now think the condition may also be related to the normal pregnancy immune response that keeps a woman’s body from rejecting the developing fetus. They will be testing this hypothesis in the first part of the project by comparing inflammation and immune response markers in women under age 50 who have and have not been diagnosed with breast cancer within six years of giving birth.

“We’re beginning to realize that some of same immune mechanisms that are suppressed during pregnancy are the same mechanisms that cancer cells use to escape the immune system,” she says.

The second part of the project is what Borges calls “a window of opportunity” study. All women have a normal two- to three-week window between being diagnosed with breast cancer and undergoing their surgery. She is going to take advantage of that time to see if they can measurably change the inflammatory and immune system markers by asking women to take a two-week course or placebo or fish oil or the NSAID celecoxib (brand name Celebrex) and comparing results from the biopsy material and diagnostic blood samples to the tissue and blood retrieved during surgery.

“We know how celecoxib works,” she says. “We’re not so clear about fish oil, but we anticipate that it is safe for future study in nursing women because it the same components that are routinely added to baby formula for healthy brain development. Fish oil is also reported to have anti-cancer and anti-inflammatory properties. If we can blockade this increased risk of metastases by having women take fish oil, how beautiful is that?”

UCCC AWARDS $495,000 IN SEED GRANTS

We are pleased to announce the first round of awards for 2009 UCCC Seed Grants. These pilot projects are funded by the Cancer Center support grant, by an institutional grant from the American Cancer Society, and by an NCI  P20 grant on Cancer & Aging. Congratulations to all of the grantees.

2009 Cancer & Aging Grants: $255,000

Dr. Anna Barón (Developmental Therapeutics) and Patricia Valverde
University of Colorado Denver
$30,000
Examining the Impact of Socioeconomic Status and Patient Characteristics on 5-Year Cancer Survival among Colorectal, Lung, Breast and Prostate Cancer Cases of All Ages

Dr. Mehdi Fini (Developmental Therapeutics)
University of Colorado Denver
$20,000
Chemotherapy-induced Cardiotoxicity in Geriatric Oncology; Implications for Novel Combinatorial Treatment

Dr. James DeGregori (Cancer Cell Biology)
University of Colorado Denver
$30,000
Exploring Why Aged Lymphopoiesis Selects for Bcr-Abl and Promotes Leukemogenesis

Dr. John Cambier (Immunology & Immunotherapy)
National Jewish Health
$30,000
B Cell Development in Aging

Dr. Tom Denberg (AMC Cancer Prevention & Control)
University of Colorado Denver
$25,000
Elderly Women and Female Endoscopist Screening Colonoscopy Study

Drs. Catherine Jankowski and Betsy Risendal
Colorado School of Public Health/UC Denver
$35,000
Long-term Effects of Breast Cancer on Physical Function

Dr. Kristin Kilbourn
University of Colorado Denver
$10,000
Support by Telephone for Caregivers in Hospice (Support TECH)

Dr. Al Marcus (Program Leader, AMC Cancer Prevention & Control)
University of Colorado Denver
$20,000
Implementation and Feasibility Evaluation of the Cancer Survivor Telephone Education and Personal Support Program (C-STEPS)

Dr. Robert Sclafani (Program Leader, Cancer Cell Biology)
University of Colorado Denver
$20,000
Natural Plant Polyphenols as Potentiators of Radiation Therapy in Head and Neck Cancer

Dr. Dylan Taatjes (Molecular Oncology)
University of Colorado at Boulder
$15,000
Support for RT-QPCR Experiments at Aging-related p53 Target Genes in HCT116 Cells

Dr. Deborah Wuttke (Molecular Oncology)
University of Colorado at Boulder
$20,000
Identification and Validation of Small Molecules that Disrupt Telomere Capping

CCSG Seed Grants: $60,000

Dr. Natalie Ahn (Molecular Oncology)
University of Colorado at Boulder
$20,000
Cell and Animal Models for Drug Resistance in Melanoma

Drs. Antonio Jimeno (Developmental Therapeutics) and Woujhang Park (Lung/Head & Neck Cancers)
$20,000
University of Colorado Denver / University of Colorado at Boulder
Gold Nanoparticle-based Delivery of siRNA against Metabolic Genes in Head and Neck Cancer

Dr. Monica Ransom (Fellow, Dr. Jessica Tyler Sponsor)
University of Colorado Denver
$10,000
Histone Modifications as Novel Epigenetic Markers of Cancer

Dr. Jeffrey Knipstein (Fellow, Dr. Jeannette Davies Sponsor)
University of Colorado Denver
$10,000
Decorin as a Potential Modulator of T-cell Function in the Setting of Glioblastoma Multiforme

ACS IRG Seed Grants: $180,000

Dr. Jena French
University of Colorado Denver
$20,000
Regulatory T Lymphocytes and Papillary Thyroid Cancer

Dr. Michael Weyant (Lung/Head & Neck Cancers)
University of Colorado Denver
$20,000
Inhibition of Group IIa Secretory Phospholipase A2 Reduces Growth and Attenuates Expression of ICAM-1 in Human Esophageal Cancer Cells

Dr. Bolin Liu (Cancer Cell Biology)
University of Colorado Denver
$30,000
ErbB3/ErbB2/IGF-1R Heterotrimer-induced Trastuzumab Resistance in Breast Cancer Cells

Dr. Stephen Malkoski (Lung/Head & Neck Cancers)
University of Colorado Denver
$20,000
PTEN and TGFbeta Cooperation in Lung Squamous Cell Carcinoma

Dr. Shi-Long Lu
University of Colorado Denver
$30,000
Experimental Therapy of Head and Neck Squamous Cell Carcinoma in a PTEN Genetically Engineered Mouse Model

Dr. Allen Waziri (Immunology & Immunotherapy)
University of Colorado Denver
$30,000
Exploration of the Natural Killer T Cell - Myeloid Suppressor Cell Immunoregulatory Circuit in Patients with Glioblastoma Multiforme

Dr. Scott Oliver (Developmental Therapeutics)
University of Colorado Denver
$30,000
Attenuation of Iodine-125 Radiation with Vitreous Substitutes in and Animal Model for the Treatment of Ocular Melanoma