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

CANCER
RESEARCH                                  Progress Brings Hope                                                  Spring 2010

Welcome Message from the Director
To start off the Spring 2010 issue of Cancer Research, I am happy to report on the highly successful visit of our Cancer Center External Scientific Advisory Board, held on April 7. All of our presentations were extremely well-received; our Program and Translational Working Group Leaders each did a fantastic job presenting and promoting the research efforts of all of our members. The ESAB was duly impressed with our progress in the past year. We have completed many mission-critical tasks in a short time with limited funding.
The energy and enthusiasm in our center continues to grow. Our Annual Scientific Retreat in November was outstanding and our CCSG Progress Report, submitted in December, was extremely well-done. Our members and staff in all areas are performing above and beyond; we are exceeding expectations in all facets of our research and clinical enterprise. This is a world-class Cancer Center and each and every one of us is making a significant impact on cancer research, education and treatment in multiple areas in many ways.  

Shared Resource Highlight: Genomics High Throughput Facility
Website:              http://www.cancer.uci.edu/resources/genomic.html
Contacts:            Director: Suzanne Sandmeyer, Ph.D., 949.824.7571, sbsandme@uci.edu
Facility Manager: Denis Heck, 949.824.6023, jdheck@uci.edu
Finance Manager: Janet Ko, 949.824.9979, jko@uci.edu
Location:             340 Sprague Hall
The UC Irvine Genomics High-Throughput Facility (GHTF) offers high quality microarray-based expression, SNP and CNV analyses utilizing the Affymetrix GeneChip System. The full service package includes post-extraction RNA processing, hybridization, scanning, and basic statistical analysis of expression microarray results. Data analysis is further facilitated by interactions and support functions provided the Institute for Genomics and Bioinformatics (IGB). Dr. Baldi, Director, supervises a Bioinformatics Core which is available to consult in advance with investigators on genomics experiments and provide analysis support for microarray and HTS work from the GHTF. Aspects of these analyses related to epidemiological and genetic variation and mapping studies also include consultations with members of the Biostatistics Core.

The GHTF recently installed and activated a GAIIx Genome Analyzer 2nd-generation DNA Sequencer from Illumina. The massively parallel, high-throughput GAIIx DNA Sequencer has been operational and continuously running  end-user's sample libraries for a couple of months. The associated ClusterStation (for preparing DNA libraries to be sequenced on the GAIIx) and the Paired-End Module (which allows library samples to be sequenced from both ends of the DNA fragments while on the GAIIx) are also fully functional. Additionally, to aid in the upfront construction of the input DNA libraries, the GHTF installed the Covaris S2, which shears genomic DNA into short fragments with uniform and consistent size fractions, and an Invitrogen Qubit, a highly sensitive fluorometer for accurately quantifying small amounts of DNA or RNA within the Facility. Stand alone services based on these last two instruments are offered.

The GHTF has contributed significantly to the success of several cancer center members. Dr. Bogi Andersen (GFS) has made extensive use of the Facility’s resources to support his NIH R01-funded studies of ‘Epithelial differentiation in cornea’ and ‘Gene regulatory network in epidermis’. Dr. Dan Mercola (CA) and his team rely heavily on the support from the shared resource for their multi-institutional ‘Strategic Partners for the Evaluation of Predictive Signatures of Prostate Cancer’ (SPECS) consortium.

Recent high profile publications and presentations

  1. Acharya MM, Christie LA, Lan ML, Donovan PJ (DB), Cotman CW, Fike JR, Limoli CL (CA). Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells. Proc Natl Acad Sci U S A 106, 19150-19155 (2009).

Cranial irradiation remains a frontline treatment for the control of brain tumor growth (for example, most patients with advanced or aggressive glioblastoma receive radiation therapy), and this treatment often leads to various degrees of cognitive dysfunction. Depletion of stem/precursor cell pools in the brain is postulated to be at least partially responsible for these often-unavoidable cognitive deficits. In this study, athymic nude rats subjected to head only irradiation were transplanted 2 days afterward with human embryonic stem cells (hESC) into the hippocampal formation and analyzed for stem cell survival, differentiation, and cognitive function. Animals receiving hESC transplantation exhibited superior performance on a hippocampal-dependent cognitive task 4 months postirradiation, compared to their irradiated surgical counterparts that did not receive hESCs. A high proportion of stem cell survival was demonstrated at 1 and 4 months post transplant, the cells had migrated to distant appropriate sites throughout the dentate gyrus, and had assumed neuronal morphology within this neurogenic niche. The results demonstrate the capacity of hESCs to moderate radiation-induced normal tissue injury, and suggest that strategies such as hESC transplant may provide useful interventions to reduce the adverse effects of irradiation on cognition. See a feature story from UCI website at http://uci.edu/features/2009/11/feature_radiationstemcells_091116.php.

  1. von Gruenigen VE, Huang HQ, Gil KM, Gibbons HE, Monk BJ (CPC), Rose PG, Armstrong DK, Cella D, Wenzel LB (CPC): Assessment of factors that contribute to decreased quality of life in Gynecologic Oncology Group ovarian cancer trials. Cancer 115, 4857-4864 (2009).

It is abundantly clear that cancer chemotherapy severely impacts patients’ quality of life (QoL). Measurement tools, such as the FACT survey, quantify 4 domains of physical, functional, social, and emotional well being (PWB, FWB, SWB, EWB, respectively). This study quantified the responses of women receiving chemotherapy, and compared those with overall FACT scores in the lowest quartile (Q1) with those in the upper 3 quartiles (Q2-Q4). A significantly greater proportion of women in Q1 versus Q2-Q4 selected the 2 worst categories for several physical symptoms (nausea, pain, feeling ill, and being bothered by the side effects of treatment). For FWB, significant differences included being able to work, being content with the quality of their life, and sleeping well. For EWB, there were significant differences in feeling nervous and worrying about dying. A large proportion of women receiving chemotherapy for ovarian cancer reported QoL issues that are potentially amenable to clinical interventions, such as symptom management and psychosocial support, which Dr. Wenzel and her colleagues focus on providing for cancer patients. Prior to publication, these results were presented at the 2008 Society of Gynecologic Oncologists Annual Meeting, in Tampa, Florida.

  1. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA, Vu C, Lilly MB (CA), Mallya S, Ong ST, Konopleva M, Martin MB, Ren P, Liu Y, Rommel C, Fruman, DA (GFS). Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Medicine 16, 205-213 (2010).

Dr. Fruman and colleagues showed that small molecule inhibitors of PI3K and mTOR are effective in the inhibition of proliferation and function of leukemia cells, without detrimental effects on normal lymphocytes and hematopoietic stem cells. The inhibitor PP242 kills human leukemia cells in vitro, delays leukemia onset in vivo, and enhances activity of tyrosine kinase inhibitors currently used in leukemia treatment. This is a major advance in development of new therapies for chronic myelogenous leukemia and other blood cancers where PI3Kinase and Bcr-Abl play key roles in cell transformation. See http://uci.edu/features/2008/09/feature_fruman_080922.php for more.

Congratulations to the following grant awardees
Dr. Bruce Tromberg, co-leader of the Onco-Imaging and Spectroscopy Research Program and Director of the Beckman Laser Institute, was awarded $1,882,945  (total costs for 3 years, 2010-2012, R01CA142989) from the National Cancer Institute for a new grant ‘DEVELOPING DOSI TECHNOLOGY FOR MONITORING RESPONSE TO BREAST CANCER CHEMOTHERAPY’. Tromberg’s group is developing new quantitative imaging methods to monitor and predict breast cancer response to neoadjuvant chemotherapy, both prior to and as early as possible during the course of treatment. The new Diffuse optical spectroscopic imaging (DOSI), allows patients to be followed from baseline through treatment and surgery with a cost-effective, bedside, handheld scanning probe. In preliminary patient studies, DOSI quantitative functional endpoints effectively predicted tumor response to chemotherapy within the first week of a two - four month treatment regimen. This work will optimize and improve functionality, standardize clinical measurement and analysis procedures, and evaluate whether DOSI can be used with equivalent overall performance by different operators. The long-term goal is to identify quantitative clinical endpoints that can be used to inform medical decisions on chemotherapy regimen, duration, and timing of surgery. See related article on a hand-held laser scanner developed by Tromberg’s group at http://uci.edu/features/2010/02/feature_breasttumor_100216.php

Drs. John Lowengrub (CA), Arthur Lander (DB) and Eva Lee (CA), were awarded a Grand Opportunities RC2 grant of $2,033,332 (total costs for two years 2009-2011, RC2CA148493) in ARRA funds from the National Institutes of Health to study ‘FEEDBACK, LINEAGES AND CANCER: A MULTIDISCIPLINARY APPROACH’. The group will develop mathematical models of how tumors develop over time-size, shape, growth rate, stem cell fraction, etc.-in order to infer specific information about the kinds of control processes that operate (or recently operated) within the tumor and its surrounding environment. This information will provide insight into how different types of tumors develop, as well as patient-specific information about prognosis and the effects of therapy. The ability of these models to reproduce and predict the behaviors of real tumors will be assessed using established animal models of breast cancer, in which luminescent and fluorescent imaging techniques are used to follow tumors, and their stem cells, over time. This will enable the validation of particular model architectures, or suggest methods for their refinement, and allow the determination of control strategies at work in tumors that can be exploited to provide a leap forward in both personalized medicine and cancer care. What makes this project a "grand opportunity" is the pursuit of rapid progress through a highly multidisciplinary team that will draw on new advances in the areas of cell lineage behaviors, cancer stem cells, three-dimensional mathematical and computational modeling, and machine-learning. See http://uci.edu/features/2009/06/feature_mathtumor_090603.php for a related story on this topic.

Dr. Peter Donovan (DB) was awarded  $3,339,332 (total costs for 3 years, 2009-2012) from the California Institute for Regenerative Medicine to continue training the next generation of stem cell researchers through the ‘UCI CIRM TRAINING GRANT’. The eight pre-doctoral and four post-doctoral CIRM Scholars participate in research training in the labs of faculty stem cell mentors, including cancer center members Drs. Anderson (GFS), Donovan (DB), Limoli (CA), Nalcioglu (OIS), Sassone-Corsi (GFS), Thompson (DB) and Wallace (CA). The research training environment provided for Scholars encompasses many areas of stem cell biology including the role of stem cells in cancer. The potential therapeutic use of normal stem cells to treat cancer and alleviate treatment side-effects, as well as the distinctions between normal stem cells and cancer stem cells, are topics in the core courses ‘Basic Biology of Stem Cells’ and ‘Clinical Applications of Stem Cells’. See http://uci.edu/features/2009/12/feature_prop71anniversary_091217.php.

Thanks to Cancer Center members
Many of our members went to extraordinary lengths to prepare for and facilitate three smooth and successful recent events: 1) Annual Scientific Retreat, November 6-7, 2009; 2) CCSG non-competing renewal, submitted November 30, 2009; and, 3) ESAB site visit on April 7, 2010. Thanks for all of your outstanding efforts!
Thanks also for your continued engagement as we prepare for our upcoming competing renewal application.

Editor’s corner
At the recent AACR meeting in Washington, DC, during a discussion of science policy and the NCI budget, the question was raised, ‘how much funding is needed for the NCI’? For FY2010, the NCI budget was just over $5.1 billion, with an additional $1.267 billion in ARRA funding. President Obama’s FY 2011 budget request for the NCI is $5,264,643,000. Up some $160 million, but well short of the $1.1 billion increase realistically justified and requested by the NCI to hasten our research progress against cancer. Would $6 billion be enough, or merely just better? Consider this: according to the USA Today’s Salaries Database, $6 billion would be enough to fund the salaries of all the MLB and NFL teams for a year. Thirty baseball teams and 32 football teams. How many salaries? 65 NCI-designated cancer centers. How many dedicated cancer researchers and, more importantly, deserving cancer patients? What could you do with $6 billion?

Comments and suggestions for future news items to Randy Berg (rberg@uci.edu).