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University of Colorado Cancer Center
Project 1
The Role of Chromosome 3 in Lung Tumorigenesis
Principal Investigator:
Co-Investigators: Harry Drabkin, M.D., Robert Gemmill, Ph.D.
Cytogenetic and LOH studies have demonstrated that deletions of the chromosome 3 short arm (3p) occur at high frequency in all forms of lung cancer. Results from several labs, including ours, indicate that multiple deletion targets exist on 3p and that alterations affecting these loci are among the earliest observable genetic changes during lung cancer development. Project 1 has investigated 3p alterations by characterizing several critical targets regions, defining their minimal extent, and isolating candidate genes. Past results have included: 1) development of a YAC contig for the 3p12(13) target region; 2) DNA sequence analysis of the 3p14 fragile site, FRA3B, with identification of corresponding deletions and demonstrating that deletions were ongoing as a result of genomic instability in contrast to the selective loss of FHIT; 3) identification of a 3p21.3 homozygous deletion in the SCLC H1450 which overlapped deletions in SCLC GLC20 and H740. From the consistent lung cancer deletion region, two genes, SEMA3F and hDEF-3, were cloned and characterized. SEMA3F is a secreted member of the semaphorin family, originally identified as repulsive molecules for nerve growth cones. Furthermore, secreted Semaphorins bind high affinity Neuropilin (NP) receptors necessary for semaphorin actions. However, NPs are also co-receptors for selected forms of VEGF and semaphorin binding is competitive. We developed anti-SEMA3F Abs and demonstrated that SEMA3F and VEGF staining is inversely related in lung cancers and that these patterns are highly correlated with lung cancer stage in NSCLC. These interactions remain an area of active investigation. hDEF-3 occurs at the telomeric cluster of the 3p21.3 deletions and encodes a new family of RNA binding proteins. We found that hDEF-3 binds polyG RNA homopolymers though its RNA binding domains and that these domains were immunologically distinct from the closely related HU syndrome Ab targets identified in SCLC patients. Nevertheless, anti-hDEF-3(g16/NY-LU-12) antibodies are observed in ~10% of lung cancer patients. Our most recent studies involve alterations in HOX genes which are a complex set of master transcription factors influencing differentiation and growth which interact profoundly with WNT and FGF pathways during normal development. Using degenerate primers and RT-PCR, we identified a spectrum of expressed HOX genes in lung cancer cell lines and normal lung. Subsequent real-time quantitative PCR assays have allowed us to demonstrate that HOX expression patterns are altered in lung cancer and, moreover, that changes in WNT pathway components are highly correlated with HOX alterations. These results reinforce the notion that cancer is a developmental process gone awry and that these pathways provide a new, mechanism-based approach for the molecular analysis of lung cancer and targeted therapeutic interventions.
Project 2:
Analysis of Genetic Alterations at Multiple Loci in Lung
Tumorigenesis: Application to Early Detection of Lung Cancer
Principal Investigator: Marshall W. Anderson, Ph.D.
Co-Investigators: Jonathan Wiest, Ph.D., Wilbur Franklin, M.D.
Lung cancer is the leading cause of death in the United States and Western Europe. The goals of this project are to analyze the combination of genetic alterations and temporal sequence of events that occur in the development of human lung tumors. We have analyzed NSCLCs for allelic loss on chromosome 3 and 9. Approximately 80% exhibited allelic loss on both 3p and 9p. p16/CDKN2 is a well-established tumor suppressor gene which resides on 9p and is inactivated in approximately 50% of NSCLC. Immunohistochemical analysis showed that 60% of stage I adenocarcinomas stain positive for p16 with nuclear localization of the antigen. However, 80% of the tumors which stain positive for p16 exhibit allelic loss on 9p. Also, we have demonstrated homozygous deletion in a region on 9p which contain D9S126. This region is 2 to 3 cM proximal to p16. These data, together with numerous other reports in the peer-reviewed literature, suggest the existence of another TSG(s) on 9p. We believe that the region containing D9S126 is a candidate region for containing a TSG. We are presently examining this region for the presence of a TSG. In collaboration with Sanger Center, a PI/PAC/BAC contig has been developed covering ~ 500 Kb and ~ 400 Kb of sequence data has been generated. This sequence data will identify genes in the D9S126 region. Since allelic loss of 9p is observed in preneoplastic lesions, p16 and another TSG(s) on 9p may potentially be used as molecular markers in procedures to detect and subsequently localize lung cancer at earlier, more treatable stages.
The biological significance of LOH has also been a focus of efforts of Project II. Initially we found that LOH occurred in NSCLC at several loci on chromosome 3, despite an increased number of signals in the regions of allelic loss by 2 color FISH. We interpreted this to mean that LOH is usually a reflection of mitotic recombination rather than physical loss of chromosomal material. Subsequently we confirmed this hypothesis with a study of allelic loss at the p53 locus on chromosme 17p. In this study we also found that p53 mutation is associated with high variability of allelic copy number without specific loss of chromosomal material. This latter finding indicates that an initial p53 mutation may be followed by further LOH through mitotic recombination. These findings are of fundamental importance to the understanding of multistep lung carcinogenesis.
* This is a collaborative effort between the University of Colorado Cancer Center and the University of Cincinnati.
Project 3
The Role of TRAIL and TRAIL Receptors in Genotoxin Induced
Apoptosis of LUNG Cancer Cells
Principal Investigator: Gary Johnson, Ph.D.
Co-Investigator: Lynn Heasley, Ph.D.
We have used DNA array analysis to identify changes in gene profiles during the stress response of lung and breast cells to gentoxic agents. The expression of numerous anti- and pro-apoptotic genes is significantly altered in response to etoposide treatment of H157 squamous carcinoma cells. Etoposide and doxorubicin activate NFkB and many of the mRNA expression changes induced by etoposide treatment require NFkB activation. Inhibition of NFkB activation strongly suppresses etoposide-induced apoptosis of lung and breast carcinoma cells. Among the genes regulated in response to etoposide are the death receptors for TNF-Related Apoptosis Inducing Ligand (TRAIL) and TRAIL, itself. TRAIL is a cytokine that has been shown to induce apoptosis. Xenograft studies in nude mice have also demonstrated TRAIL in combination with chemotherapy or radiation can cause complete tumor regression. Gene expression profiling suggested the mechanism for the observed synergy between TRAIL and genotoxins resulted from the increased expression of DR4 and DR5 in response to the genotoxic agent, the functional death receptors for TRAIL. Etoposide and doxorubicin induced the upregulation of DR4 and DR5 as well as TRAIL mRNA as measured by RNase protection and surface protein as measured by flow cytometry in several carcinoma cell lines examined. The up-regulation of DR4, DR5 and TRAIL is dependent on the activation of the transcription factor NFkB. Two cell lines that expressed high basal levels of DR4 and DR5 which did not increase their death receptor expression upon etoposide or doxorubicin treatment were the most sensitive to chemotherapy induced apoptosis. Subsequent cloning of the cDNA for DcR1, a TRAIL binding receptor which inhibits TRAIL induced apoptosis, allowed the generation of several clones of a single cell line overexpressing DcR1. The overexpression of DcR1 inhibited both etoposide and doxorubicin induced apoptosis and caspase 8 cleavage. Furthermore, the surface expression level of DcR1 correlated to the calculated EC50 of etoposide. DcR1 overexpression did not inhibit taxol-induced apoptosis. Taken together, our findings indicate that genotoxic agents induce a paracrine secretion of TRAIL coupled to upregulation of DR4 and DR5 which bind the death ligand to cause apoptosis, and DcR1 overexpression can interfere with the autocrine action of local TRAIL. In summary, the TRAIL paracrine response is a major component of the genotoxin-induced apoptotic response.
Project 4
Inhibition of Peptide Signal Transduction for the Therapy and
Prevention of Human Lung Cancer
Principal Investigator: Paul A. Bunn, Jr., M.D.
Co-Investigators: Daniel C. Chan, Ph.D.; Gary Johnson, Ph.D.; Lynn Heasley, Ph.D., Karen Kelly, M.D.; John Stewart, Ph.D.
The objective of this project is to develop new agents to prevent and treat human lung cancer based on the inhibition of growth factor signaling pathways. Specifically, we conduct laboratory investigations evaluating signal pathways, design and develop novel agents, conduct pre-clinical testing and perform early phase I clinical trials of promising agents. We showed that peptide hormones (eg BK, GRP, AVP) stimulate two G protein coupled signal pathways in a coordinate manner to stimulate the growth of human small cell lung cancer (SCLC) cells. In one portion of this pathway, stimulation of Gaq proteins, leads to activation of PLCb, diacylglycerol, IP3 generation, increases in intracellular calcium levels, activation of PKC and calmodulin and proliferation. In the other portion, stimulation of Ga12,13 proteins leads to activation of JNK and MAP kinase pathways. We developed a novel bradykinin antagonist dimer, B201, which locked the stimulation of G2q and its downstream pathway but stimulated Ga 12,13 and downstream events. We termed B201 a "biased agonist" because it produced a discordant signal cascade. This discordant path led to activation of caspase 3 and an apoptotic response in addition to inhibition of proliferation. B201 inhibited the growth of human SCLC cell lines in vitro and in vivo in athymic mice with subcutaneous human tumor xenografts. It inhibited the growth of both drug sensitive and drug resistant cell lines and produced synergistic growth inhibition in combination with standard chemotherapy. B201 is more potent than substance P derivatives (SPD) which are also in development for SCLC therapy. Unlike SPD B 20 inhibits the growth of non-small cell (NSCLC) as well as SCLC lines. B 201 is being developed further in collaboration with the NCI through an NCI RAID grant.
B201 is a large peptide dimer which is expensive to produce and study. We have subsequently developed two peptidomimetic compounds termed B317 and B429 which are small, inexpensive, non peptide compounds which also inhibit the growth of SCLC and NSCLC cell lines in vitro, in atyhymic mice with subcutaneous xenografts and in athymic rats with orthotopic metastasizing xenografts. These compounds also induce apoptosis, inhibit the growth of drug resistant lines and synergize with cytotoxic chemotherapy.
We have studied a number of prostaglandin inhibitors because lung cancer cell lines have increased cPLA2. We showed that COX and LOX inhibitors are effective in inhibiting the growth of lung cancer cell lines in vitro and in vivo. Exisulind (sulindac sulfone, prevetac) is a sulindac metabolite which does not inhibit COX1 or COX2 but induces apoptosis through stimulation of cGMP and cGMP-dependent protein kinase G. Exisulind was shown to inhibit the growth of human lung cancer cells in vitro and in vivo in subcutaneous nude mouse xenografts and in orthotopic nude rat lung cancers. It also prevented lung cancer tumor formation in a carcinogen-induced mouse model. Exisulind synergized with chemotherapeutic agents including docetaxel in vitro and in the nude mouse and rat models. A phase I trial of exisulind alone was completed and a phase I trial exisulind plus docetaxel is in progress.
NSCLC's overexpress erbB-1 and erbB-2. We showed erbB-2 overexpression in 20% of NSCLC cell lines and tumors but 0% of SCLC cell lines and tumors. Overexpression was due to chromosome duplication and increased copy number, but rarely due to gene amplification. Trastuzumab inhibited the growth of Her-2/neu expressing NSCLC cell lines but not Her-2/neu non-expressing lines. Trastuzumab produced synergistic growth inhibition when combined with gemcitabine, paclitaxel, cisplatin and vinorelbine in Her-2/neu expressing lines. The combination index was the best in combination with gemcitabine which has led to a phase II clinical trial. ErbB-1 (EGFR) overexpression (2+ or greater) was present in 10/14 NSCLC cell lines but not in SCLC cell lines. Among 13 NSCLC cell lines tested for erbB-1 and erbB-2 overexpression, 3 expressed neither, 4 expressed both, 5 expressed erbB-1 only and 1 expressed erbB-2 only. Both the monoclonal antibody C225 and the receptor tyrosine kinase inhibitor ZD1839 inhibited the growth of erbB-1 positive cell lines and synergistic growth inhibition with radiation and chemotherapy was observed. Clinical trials were started on this basis.
Project 5
Neuropeptide Degradation and Pulmonary Carcinogenesis
Principal Investigator: York E. Miller, M.D.
Co-Investigators: Pamela Fain, Ph.D.; Andrea J. Cohen, M.D.; Tim Kennedy, M.D.
Neuropeptides, acting through seven membrane spanning segment receptors, are important growth factors, which modulate proliferation of pulmonary epithelial cells and epithelial-derived neoplasms. We have determined that clinically normal individuals reproducibly excrete widely varying amounts of the bombesin like peptide (BLP), gastrin releasing peptide (GRP). The best fit of the mixture of distributions for BLP excretion is a trimodal distribution, supporting determination of this trait by a small number of genes, possibly two alleles at one locus. Because long-term smokers without lung disease (either chronic obstructive pulmonary disease or lung cancer) have significantly lower BLP excretion than smokers with lung disease, high levels of BLP excretion may be a risk factor for smoking induced lung disease. We are carrying out both association studies of polymorphisms of candidate genes and collection of sib pairs and informative families to determine the genetic basis for variation in BLP excretion. Genes encoding peptidases, which degrade neuropeptides, are prime candidates for determining variation in BLP excretion. Furthermore, we have demonstrated that peptidase inactivation in lung cancer stimulates cellular proliferation. Thus, specific peptidases may be important regulators of tumor growth, analogous to tumor suppressor genes, in which germline inactivation is an important determinant of cancer susceptibility and somatic inactivation is a factor in tumor biology.
Project 6
Molecular Analysis of the Regulation Perturbation of Cell Cycle in
Lung Cancer with Potential Applications to Prognosis and Treatment
Principal Investigator: Robert A. Sclafani, Ph.D.
Co-Investigators: Thomas Langan, Ph.D.; Paul A. Bunn, M.D.; Karen Kelly, M.D.
This proposal is part of a joint effort (SPORE) to provide better methods of clinical diagnosis, prognosis and treatments for lung cancer patients by studying the molecular basis of the disease. This project interacts with many of the other projects of this SPORE by sharing results and similar technologies to produce a synergistic effort. The project utilizes the human tissue procurement, tissue bank and animal cores.
The focus of this project is on the role of cell cycle regulation in the etiology of lung cancer. The hypothesis is that precise, biochemical knowledge of the alterations of cell cycle regulatory molecules in cancer cells is essential for understanding the etiology of all cancers. This knowledge can then be exploited for solving the clinical problems of lung cancer patients, who have very little hope of treatment.
Molecular analysis focuses on the family of cyclin-dependent kinase (CDKs) and inhibitors (CDIs) and important CDK substrates such as the Rb (Retinoblastoma) tumor suppressor. A biochemical analysis of cyclin D1-CDK6 complexes and two CDIs, the MTS1 and MTS2 (multiple tumor suppressor) genes, is being performed in order to investigate the mechanism of perturbed cell cycle regulation in NSCLC cells. This molecular analysis can also reveal additional molecules altered in NSCLC and provide the basis for potential prognosis and therapy.
Potential gene therapies and a test of the hypothesis that overexpressed cyclin D1 and loss of MTS1-2 is important for aberrant proliferation in NSCLC is accomplished by the use of recombinant DNA technologies, which employ antisense cyclin D1 retroviruses, plasmids and synthetic oligodeoxynucleotides, as well as MTS1-2 expression plasmids. Liposome technologies are used to deliver the plasmids and synthetic oligodeoxynucleotides to NSCLC cells in vitro and in vivo. Nude rodents with xenografts of human tumor cells are used to test the efficacy of these genetic manipulations and therapies in vivo.
Molecular analysis of human tumors, dysplastic tissues and sputum samples are screened with a large panel of molecular markers, including but is not limited to, cyclin D1, CDKs, CDIs and Rb using PCR, PCR-SSCP, immunoblots and immunohistochemical analyses. In this manner, a systematic study of any genetic changes that occur during tumor progression is done. These genetic changes can then be correlated with pathological changes in the cells to produce a molecular model for tumor progression. Dysplastic human cells that have cell cycle alterations are transformed with a variety of oncogenes as an assay of their state of progression to provide direct experimental evidence for such a molecular model. This molecular model has the potential to be used as a monitor of tumor progression in patients by providing oncologists with both prognostic and diagnostic information.
Project 7
Role of Eicosanoids in Lung Cancer Growth
Principal Investigator: Raphael Nemenoff, Ph.D.
Co-Investigators: Lynn Heasley, Ph.D.; March Geraci, M.D.
The release of arachidonic acid from membrane phospholipids is mediated by phospholipase A2 (PLA2) and is the rate-limiting event in the subsequent biosynthesis of a host of bioactive and mitogenic eicosanoids. Emerging evidence indicates that eicosanoids are involved in the growth of both normal and transformed cells. Significantly, recent studies show that inhibition of eicosanoid production prevents and reverses polyp formation associated with early progression of colon cancer. Small cell lung carcinoma (SCLC) growth is driven by autocrine loops involving a host of secreted neuropeptides that initiate signalling extracellularly through specific G protein-coupled receptors expressed on the tumor cells. Our preliminary data indicate that neuropeptides stimulate arachidonic acid release in SCLC through the activation of PLA2. Furthermore, inhibitors of eicosanoid production inhibit the growth of these cells. Non-small cell lung cancer (NSCLC), in contrast to SCLC, is associated with overactivity of the EGF receptor tyrosine kinase and activating mutations in the ras protooncogenes. Activation of receptor tyrosine kinases stimulates arachidonic acid release in a variety of cell types and studies report elevated prostaglandin production in NSCLC. Thus, despite the widely diverging proximal receptor systems that signal growth of SCLC and NSCLC, PLA2 activation and arachidonic acid metabolism represents a potential convergence point in mitogenic signalling in lung cancer.
We hypothesize that production of specific eicosanoids contributes to lung cancer progression and transformed growth of both SCLC and NSCLC. Furthermore, we anticipate that distinct patterns of arachidonic acid metabolites will be characteristic of SCLC and NSCLC. To test this hypothesis, we will complete the following specific aims.
Identify specific arachidonic acid metabolites produced by SCLC and NSCLC cell lines. In addition, the expression of specific cyclooxygenase and lipoxygenase isoforms will be assessed using RT-PCR and immunoblotting strategies. The studies can be extended to examine eicosanoids and metabolizing enzymes in immortalized human lung dysplasias developed in the SPORE.
Define the mitogenic effects of arachidonic acid metabolites identified in Specific Aim 1 on lung cancer cells and examine their ability to regulate well-described mitogenic signalling pathways. PGE2 and PGF2a are known to be produced by NSCLC so that these eicosanoids can be immediately investigated.
Determine the influence of known inhibitors of PLA2 and arachidonic acid metabolizing enzymes on the in vitro and in vivo growth properties of SCLC and NSCLC. The effects of inhibitors will also be assessed on the immortalized dysplastic lung epithelia developed through the SPORE mechanism.
Our goal is to characterize the regulation of arachidonic acid metabolism in established SCLC and NSCLC cell lines and identify specific metabolites which may contribute to the growth of these tumor cells. This information will then allow us to screen available inhibitors of specific pathways for their ability to inhibit transformed growth in vitro and in vivo and thus, potentially serve as novel therapeutic agents relevant to treatment of lung cancer. Significantly, the pharmaceutical industry has developed a large panel of drugs that selectively inhibit the various pathways of arachidonic acid release and metabolism. We anticipate that these agents in conjunction with existing therapies will translate to more effective treatment of lung cancer. In addition to production by advanced lung carcinomas, eicosanoids may play significant roles in the progression of lung cancer similar to their emerging role in colon cancer progression. Thus, inhibitors of eicosanoid production may also have significant chemopreventative properties for the control of early lung dysplasias.
Project 8
Early Detection and Chemoprevention of Lung Cancer
Principal Investigator: Tim Kennedy, M.D.
Co-Investigators: Sheila Prindiville, M.D.; Karen Kelly, M.D.; York Miller, M.D.
The application of modern technologies to the biology of the normal, dysplastic, and malignant respiratory epithelium promises to allow better prediction of clinical behavior as well as to provide intermediate endpoint biomarkers for therapeutic trials. Major obstacles to the use of molecular genetics in the respiratory epithelium include the difficulty in identifying high-risk individuals for study and the inability to identify dysplastic epithelium for biopsy and the small amount of tissue available. As a result, virtually all studies of the biology of premalignant respiratory epithelium have either utilized screening methods, such as sputum cytology, or epithelial harvest of dysplastic areas in surgical resection specimens from individuals with lung cancer. The former has the disadvantage that limited analysis is possible and the latter approach likely biases analysis toward the examination of more advanced dysplasias which have already demonstrated the potential to progress to carcinoma. During the initial funding period of the University of Colorado SPORE in Lung Cancer, many of the difficulties involved in studying premalignant biology have been addressed through the validation of an appropriate high-risk population for initial screening, the use of fluorescence bronchoscopy for identification of dysplastic epithelium for biopsy, the development of methods for genetic analysis of respiratory epithelium, and the collaboration of several groups of basic scientists with interests in various aspects of the progression to lung cancer. The following hypotheses are being tested through their respective specific aims with the goal of developing improved methods of early detection and novel approaches to prevention.
Sputum cytological atypia is a risk factor for the development of lung cancer in a population with air flow obstruction and a significant smoking history.
Fluorescence bronchoscopy improves detection of premalignant dysplasias over white-light bronchoscopy.
Exposure to tobacco smoke and other carcinogens modifies the expression of molecular and phenotypic markers in airway epithelium, with more extensive alterations occurring in histologically advanced dysplasias.
Dysplastic airway epithelium reverts toward normal with therapeutic intervention, including smoking cessation, chemoprevention, and chemotherapy and/or radiotherapy.
Biomarkers identified in premalignant dysplasias and lung tumors have prognostic significance.
Each of these hypotheses will be tested through the development and implementation of clinical trial protocols. These studies will allow improvements in definition of high-risk individuals and populations, as well as provide intermediate endpoint biomarkers to accelerate the evaluation of therapeutic interventions.
Core 1
Clinical Investigation/Tissue Procurement Core
Principal Investigator: Wilbur A. Franklin, M.D.
The purpose of this core is to support translational research protocols designed to decrease the mortality rate from lung cancer. To accomplish this task the major responsibilities of the core are: a) to aid researchers in writing clinical trials, b) to ensure the trials meet all IRB and scientific approvals, c) to recruit patients to participate in SPORE-initiated trials, d) to collect data specimens, and e) to provide accessibility of data for analysis.
Core 2
Tissue Banks Core
Principal Investigator: Wilbur A. Franklin, M.D.
In order to evaluate the relevance of basic science discoveries to human lung cancer, it has been and will continue to be necessary to obtain and analyze human tissues. The purpose of this core is to provide to SPORE investigators a large number of well preserved and well-characterized tumors, dysplastic lesions, benign tissues, cell lines and cell and tissue fractions as well as relevant clinical information for laboratory study.
Core 3
Biostatistics Core
Principal Investigator: James Murphy, Ph.D.
Co-Investigator: Gary Zerbe, Ph.D
The Biostatistics Core provides statistical support for data collection and analysis. The members of the core assist in writing protocols, designing data collection and quality control strategies, collecting and storing data and analyzing the results of the designed experiments.
Core 4
Immunodeficient Rodent Laboratory Animal Core
Principal Investigator: James O. Stevens, DVM, Ph.D.
Co-Investigator: Ron Banks, D.V.M.
The overall objective of this core is to facilitate preclinical research in human lung cancer through use of animal models. This shared resource provides purchase, production breeding of and maintenance for, specific pathogen-free, barrier sustained, conventional, severe-combined-immunodeficient (SCID), athymic nude mice and rats and transgenic and gene null (knockout) mice for SPORE investigators.
Core 5
Administrative Core
Principal Investigator: Paul A. Bunn, Jr., M.D.
Co-Investigators: York Miller, M.D., Mary Jo Yantis, M.B.A.
The Administrative Core oversees all administrative and scientific activities of the SPORE program, reviews and regulates financial expenditures, and develops and prepares reports. This Core also develops and circulates research conference schedules, coordinates scientific review, schedules the monthly scientific meetings, and aids project investigators in the preparation and publication of manuscripts. It oversees the planning and scheduling of visits by external advisors, yearly internal retreats and NCI SPORE meetings; and meetings of the Executive, Developmental Research, and Career Development Committees.
List of Investigators
Marshall W. Anderson, Ph.D.
University of Cincinnati
206 Beecher Hall
Cincinnati, OH 45221
513-556-4816
513-556-4820 Fax
Ron Banks, DVM
University of Colorado Health Sciences Center
4200 East 9th Avenue
Denver, CO 80262
303-315-6237
303-315-3304 Fax
Ronald.Banks@UCHSC.edu
Bunn, Paul A., Jr., M.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-3007
303-315-3304 Fax
Paul.Bunn@UCHSC.edu
Daniel C. Chan, PhD
University of Colorado Health Sciences Center
4200 E 9th Avenue
Denver, CO 80262
303-315-5532
303-315-5275 Fax
Dan.Chan@UCHSC.edu
Andrea J. Cohen, MD
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-399-8020
303-315-3304 Fax
Andrea.Cohen@UCHSC.edu
Harry Drabkin, M.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, Co 80262
303-315-4759
303-315-8825 Fax
Harry.Drabkin@UCHSC.edu
Pamela Fain, PhD
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-8796
303-315-4124 Fax
Pam.Fain@UCHSC.edu
Wilbur A. Franklin, Ph.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-1807
303-315-3304 Fax
Wilbur.Franklin@UCHSC.edu
Robert Gemmill, Ph.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, Co 80262
303-315-3556
303-315-8825 Fax
Bob.Gemmill@UCHSC.edu
March Geraci, M.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-7507
303-315-3304 Fax
Mark.Geraci@UCHSC.edu
Lynn Heasley, Ph.D.
University of Colorado Cancer Center
4200 E. 9th Ave
Denver, CO 80262
303-315-6065
303-315-3304 Fax
Lynn.Heasley@UCHSC.edu
Gary Johnson, Ph.D.
University of Colorado Cancer Center
4200 E. 9th Ave
Denver, CO 80262
303-315-1009
303-315-3304 Fax
Gary.Johnson@UCHSC.edu
Kelly, Karen, M.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-3561
303-315-8825 Fax
Karen.Kelly@UCHSC.edu
Tim Kennedy, M.D
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-3007
303-315-3304 Fax
Tchesk@aol.com
Miller, York E., M.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-393-2869
303-315-3304 Fax
York.Miller@UCHSC.edu
James Murphy, Ph.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-5170
303-315-3304 Fax
James.Murphy@UCHSC.edu
Raphael Nemenoff, Ph.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-6733
303-315-3304 Fax
Raphael.Nemenoff@UCHSC.edu
Sheila Prindiville, M.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-3032
303-315-8825 Fax
Sheila.Prindiville@UCHSC.edu
James O. Stevens, DVM
Univ. of Colorado Hlth Sciences Center
4200 East 9th Avenue
Denver, CO 80262
303-315-4648
303-315-3304 Fax
Jim.Stevens@UCHSC.edu
John Stewart, PhD
University of Colorado Health Sciences Center
4200 E 9th Avenue
Denver, CO 80262
303-315-7534
303-315-3304 Fax
John.Stewart@UCHSC.edu
Jonathan Wiest, Ph.D.
University of Cincinnati
206 Beecher Hall
Cincinnati, OH 45221
513-556-4816
513-556-4820 Fax
Mary Jo Yantis, MBA
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-3001
303-315-3304 Fax
MaryJo.Yantis@UCHSC.edu
Gary Zerbe, Ph.D.
University of Colorado Cancer Center
4200 E. 9th Ave.
Denver, CO 80262
303-315-7608
303-315-3304 Fax
Gary.Zerbe@UCHSC.edu
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