Chao Family Comprehensive Cancer Center
Message from Dr. Frank L. Meyskens, Director

CANCER
RESEARCH                                  Progress Brings Hope                                                 Fall 2010

Welcome Message from the Director
The Annual Cancer Center Scientific Retreat, held November 12 and 13, was one of the very best in recent years. Speakers from all programs were excellent; it is difficult to choose any as a highlight. Scientific highlights did include talks from seed grant recipients Drs. Aimee Edinger and David Fruman, fantastic clinical research presentations by Drs. Jason Zell and Sara Jordan, and Dr. Martin Jadus’ presentation of work described below. A special feature this year was a panel discussion that included Drs. R. Clayman (Dean of the School of Medicine), P. Casali (Director of the Institute for Immunology, and Senior Associate Dean for Research and Graduate Studies, School of Medicine), P. Donovan (Director of the Sue and Bill Gross Stem Cell Research Center), D. Cooper (Director of the Institute for Clinical and Translational Science), A. Lander (Director of the Center for Complex Biological Systems), G.P. Li (Director of Cal IT2), and L. Marsh (Director of the Developmental Biology Center). The focus was on integration of efforts between the Cancer Center and the various university centers and institutes, which will help to ensure that the Cancer Center’s oversight, planning and evaluation are in strategic alignment and well-integrated with the Institution’s strategic initiatives.

We have recently had a reorganization in Cancer Center Senior Leadership. Dr. Hoda Anton-Culver, our longstanding co-leader of the Cancer Prevention and Control Research Program and Associate Director of the Population Sciences Division, has stepped aside from these positions, in order to focus on breast cancer and other research endeavors. Please join me in thanking Hoda for her many years of dedicated service to the cancer center in these leadership roles. Dr. Christine McLaren has accepted the role of co-leader for the program, renamed Population Sciences and Prevention. She has done a superb job in a short period of time in reorganizing the program, including presentation of a strong and extensive report for this year’s progress report submission. Dr. Dan Gillen, a superb statistician who has been very involved in the Cancer Center, has accepted the position of Director of the Biostatistical Shared Resource in Dr. McLaren’s place. He brings new and energetic leadership to this vital shared resource and we look forward to working with both of them in these new capacities. Finally, Dr. Dan Mercola, a SPECS- and EDRN-funded investigator, has been asked to join the Senior Leadership Council in the capacity of Special Scientific Assistant to the Director. His mandate in this role is to establish a Center for Personalized Medicine, and we look forward to this vision becoming a reality under Dan’s care and guidance.

Lastly, thanks are due to all members, program leaders, shared resource managers and directors, and especially Jacqueline Tidball, Randy Berg, Mark Walsh, Jacqueline Orozco, and Cynthia Mann for your energy and efforts in preparing the annual CCSG progress report, which was submitted at the end of November. This year’s report was particularly well-prepared, which bodes well for our competing renewal to be written in the coming year. As we head full-steam into the holidays, we sincerely hope that you had an enjoyable Thanksgiving, and that your Christmas celebrations are filled with wonderful experiences, friends and family. Best wishes for the New Year!

Shared Resource Highlight:
Website: Clinical Research Office
Director: Dr. David Hsiang
Facility Manager: Margarita Torres
Finance Manager: Jacqueline Orozco
Location: Fourth floor of the Clinical Cancer Center (building 23), and Administrative Complex (building 56)

The Clinical Research Office supports cancer center members through all stages of cancer-related clinical research studies, including: clinical trial protocol development and approval; subject enrollment, protocol management, data collection and management; screening and accrual support services; and, performing quality assurance, research compliance and adherence checks through internal audits. The CRO works with cancer center senior leaders, program leaders and investigators to prioritize and coordinate clinical trials, aiming to achieve an adequate protocol portfolio that meets the needs of the cancer center patient population and the clinical focus of cancer center members, as well as the priorities of the institution, cooperative groups (e.g., GOG, SWOG, NSABP) and other sponsors (e.g., pharmaceutical). The CRO works in close collaboration with our UC Irvine Medical Center colleagues, especially the Office of Clinical Research and Trials (OCRT) and the Institute for Clinical and Translational Science (ICTS), to provide high-quality services to cancer center members and patients. The CRO has spearheaded the implementation of the OnCore clinical trials management system (CTMS). OnCore includes several modules that improve patient safety, reduce administrative delays, provide greater data organization and access, allow integration to budgets and billing, as well as other features. We will soon move into implementation phase three, which will introduce the OnCore Financials Console, as well as a bidirectional interface with the UC Irvine Medical Center Electronic Medical Record, adding functional integration that will allow for notification of individual patient study eligibility.

The CRO directly supports the clinical research programs led by cancer center members in all programs, covering almost all disease sites and all phases of clinical trials. Accrual to phase I and phase II trials continues to be strong. Total accrual for 2009 was 292 patients, including 78 in prevention trials and 214 in therapeutic. For 2010 (up to 09/31), we have enrolled 86 subjects on prevention trials and 172 to therapeutic, for a total of 258 patients. In 2010 the total number of accruals for phase 1 studies is already at 72, compared with 57 for all of 2009. Accrual to phase I trials accounts for 44% of total therapeutic accruals for 2010, up from 27% in 2009. We also expect an increase in total accrual to phase 2 trials in 2010 (currently at 153) compared with 160 for all of 2009.

The CRO managed Dr. Ou’s (PSP) study, “Phase 1 Safety, Pharmacokinetics and Pharmacodynamic Study of Pf-02341066, a C-MET/HGFR Selective Tyrosine Kinase Inhibitor, Administered Orally to Patients with Advanced Cancer” (UCI 07-40), which was published earlier this year in the New England Journal of Medicine (Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer, NEJM 363, 1693-703). Another high profile study is UCI-07-61: “A Phase II Study of Breast Cancer Treatment Using Weekly Carboplatin + Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting” (R. Mehta (OIS), PI). The trial has continued toward its accrual target (57 consented and 52 patients treated), and MRI evaluation results are to be presented at the San Antonio Breast Cancer Symposium (Dec 8-12, 2010). Finally, Dr. M. Lilly (CA) is leading a multi-center trial, UCI-06-60: “A Phase II Trial of Dasatinib (Sprycel®) in Subjects with Hormone-Refractory Prostate Cancer, Previously Treated with Chemotherapy: BMS CA180-0097”. This trial assessing efficacy of the src kinase inhibitor Dasatinib for hormone-refractory prostate cancer patients who have failed one round of chemotherapy is one of only two such studies currently underway in the US. The initial accrual goal was completed in spring of 2010, data is under interim analysis, and a manuscript is in preparation. The CRO facilitated trials that were the basis of 20 publications in 2010. The CRO was also the focus of 3 administrative supplement grants awarded this year, bringing in $140,000 in NCI funding.

Recent high impact publications
Martin Jadus (GFS), Alex McPherson (CSB) and colleagues: ‘Glioma cells display complex cell surface topographies that resist the actions of cytolytic effector lymphocytes’; J Immunol 185, 4793-4803. In this ongoing collaboration, Drs. Martin Jadus and Alex Mcpherson used atomic force microscopy to characterize the surface of glioma cancer cells, including primary glioma cells from cultured neurospheres. Their findings uncover a remarkable surface topology with numerous microvilli and filopodia. The article, which was highlighted on the cover of the Journal of Immunology, showed that cells with this surface topology are more resistant to killing by cytotoxic T cells than their non-villi counterparts. The collaboration began with an exchange of ideas at the 2005 Cancer Center Annual Scientific Retreat.

Tom Poulos (CSB): ‘Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir’; PNAS 107, 18422-18427. HIV-infected patients are usually given complex drug formulations, often including the drug ritonavir. It is a HIV protease inhibitor that also potently inactivates cytochrome P4503A4 (CYP3A4), the major human drug-metabolizing enzyme. In blocking P4503A4, ritonavir increases plasma concentrations of other anti-HIV drugs, which are normally broken down by P4503A4, and thus reach their targets in higher doses. One problem is that ritonavir itself is destroyed by other P450s. Poulos and his group have solved the crystal structure of ritonavir complexed to P4503A4. This information provides a molecular blueprint on how to design more effective compounds that can block P4503A4, while not being degraded themselves by other P450s, further enabling other drugs to escape P450 metabolism. The development of such novel agents can have wide ranging therapeutic benefits including cancer chemotherapy.

Tony Long, with extensive support from our GHTF shared resource: ‘Genome-wide analysis of a long-term evolution experiment with Drosophila’; Nature 467, 587–590. Whole-genome resequencing data from Drosophila melanogaster populations made use of the next-generation high throughput sequencing service available through our GHTF. The experiment was designed to ask whether evolution in flies, and by inference other sexually reproducing species, follows the same patterns as asexual bacteria and yeast. The team studied single nucleotide polymorphisms in populations of flies that had been selected over 600 generations for accelerated development, and which develop from egg to adult ~20% faster than flies of ancestral control populations. They observed little allele frequency differentiation between replicate populations within a selection treatment. Signatures of selection were qualitatively different than what has been observed in asexual species. The conclusion is that, at least for life history characters such as development time, evolution of sexual organisms is not associated with ‘classic’ sweeps whereby newly arising, unconditionally advantageous mutations become fixed in the population. See also the feature story on the UC Irvine website (http://www.uci.edu/features/2010/11/feature_fruitflies_101101.php).

Paolo Sassone-Corsi (GFS): ‘The histone methyltransferase MLL1 permits the oscillation of circadian gene expression’; Nature Struct Mol Biol, published online 28 November 2010. Enzymes involved in chromatin remodeling exert coordinated activity to govern nuclear events. Chromatin remodeling appears to be crucial in diverse processes, including cancer progression, normal development and molecular clock function. The prevailing model of a molecular clock is based on interlocked transcriptional-translational feedback loops, which includes chromatin remodeling. This study focused on the rhythmic changes in Lys4 (K4) trimethylation of histone H3, a function of the mammalian homolog of Drosophila trithorax, MLL1. H3K4 trimethylation by MLL1, in a complex with CLOCK–BMAL1, appears to be required to establish a permissive chromatin state for circadian transcription. This control of epigenomic changes by MLL1 establishes a paradigm of regulation by cyclic, time-controlled activities of chromatin remodeling. Implications of this work range from the mechanisms of carcinogenesis to development of novel cancer therapeutics.

Jason Zell (PSP), Christine McLaren (PSP), Frank Meyskens (PSP): ‘Ornithine Decarboxylase-1 Polymorphism, Chemoprevention With Eflornithine and Sulindac, and Outcomes Among Colorectal Adenoma Patients; J Natl Cancer Inst 102: 1513-1516. It was previously known that individuals homozygous for the minor A allele of the ornithine decarboxylase-1 (ODC1) gene have reduced risk of colorectal adenoma recurrence compared with those with the major G allele. This study further investigated associations between ODC1 genotype, tissue polyamine responses, and toxicity after treatment with eflornithine and sulindac, using patient data from a multicenter phase III clinical trial of colorectal adenoma prevention. A statistically significant interaction between ODC1 genotype and adenoma recurrence was found; individuals homozygous for the G allele had reduced adenoma recurrence following eflornithine and sulindac treatment, compared with those with one or two A alleles. Thus, while the minor A allele protects individuals against colorectal adenoma recurrence (especially in association with aspirin use), carrying two copies of the G allele reduces the risk of recurrence after treatment with eflornithine and sulindac. A major impediment to the translation of cancer chemoprevention research into clinical practice has been marginal agent efficacy and toxicities that exceed benefit. This study suggests that ODC1 genotype may be a marker for both treatment benefit and toxicity.

Congratulations
Dr. Dan Mercola (CA) was awarded U01 CA152738-2 ($565,168 annual direct costs), ‘The Prostate Cancer tumor microenvironment exhibits differentially expressed genes useful for diagnosis’. With this award, he is now a Principal Investigator in the NCI Early Detection Research Network (EDRN). The grant will fund a prospective clinical trial involving 900 men undergoing prostate biopsy, which aims to determine the prognostic and predictive ability of a stromal gene signature that Dr. Mercola’s team derived from previous gene expression array studies. His work featured on the UC Irvine School of Medicine website (http://www.uci.edu/features/2010/11/feature_prostate_101122.php).

Dr. Daniele Piomelli (CSB) received a prestigious DP1 award 1DP1DA031387 from NIH/NIDA ($500,000 annual direct costs), ‘Optimization and Preclinical Development of FAAH Inhibitors for Smoking Cessation’. The project follows on previous work showing that pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), blocks nicotine self-administration and prevents nicotine-induced reinstatement in a primate model of nicotine addiction and relapse to nicotine use. The goal is to identify, optimize and develop novel FAAH inhibitors for smoking cessation all the way through to IND application and approval. As smoking is a major risk factor and cause of several cancers in addition to lung, this work holds promise to make a seminal contribution to cancer prevention.

Editor’s corner
To accompany this issue’s highlight of the CRO, it is prudent to focus here on the ongoing national dialogue about the rethinking, redesign and reorganization of clinical cancer research and clinical trials. New NCI guidelines and targets for activation of clinical trials have recently been developed (http://www.cancer.gov/ncicancerbulletin/040610/page4). They are intended to reduce the time it takes to open new trials, in particular the large cooperative group trials that sometimes take several years to open. The Institute of Medicine recently conducted an extensive review and reported on ‘A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program’. The goals of streamlining the process and reducing the activation energy required to open a new trial may be aided by application of new and alternative approaches to clinical trials, including the adaptive designs and Bayesian statistics exemplified in the I-SPY2 breast cancer trials (http://www.gemini-grp.com/ISPY/NatureArticle.pdf). It is hoped that, together, these and other factors will reduce the time it takes to begin and complete clinical trials, as well as increasing the fraction of trials that are successes and the number of new therapies approved for clinical use to help improve the lives of cancer patients. Watch for big changes in the cancer clinical trials process in the near future. –Randy Berg, Ph.D

Comments and suggestions for future news items to Jacquie Tidball (tidball@uci.edu)