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Baylor College of Medicine Breast Cancer SPOREC. Kent Osborne, M.D., Principal Investigator
General AbstractTranslational research, bringing new laboratory findings quickly to improve prevention, treatment, quality of life, and survival for breast cancer patients, has been the focus of the team now forming the Baylor Breast Center for over 25 years. During the first years of our SPORE, our tumor bank which made much of this rapid translation possible became a national resource, while basic cell and molecular biology research suggested new clinical implications for endocrine and chemotherapy resistance, breast cancer prevention, metastasis, and development of premalignant lesions. Developmental projects ranged even further in seeking new translational possibilities. In this SPORE renewal, we build on the results developed in our earlier work and on new findings and new technologies, in five projects and several supporting components. (1) Targeting HER2 with agents such as trastuzumab has become an important treatment, but resistance often develops. We will explore and take to clinical trials our promising preclinical evidence that more complete blockade of the complex HER network or of its cross-talk with the estrogen receptor may overcome this resistance. (2) Based on our data suggesting that a small subpopulation of resistant tumor cells with stem-cell-like properties may be the source of tumor re-growth after apparently successful chemotherapy, we will investigate this potential "cancer stem cell" population and begin trials of treatments targeting these cells along with the more numerous, more differentiated tumor cells for more complete and enduring responses. (3) Prevention trials have shown that SERMs like tamoxifen or raloxifene can greatly reduce ER-positive but not ER-negative breast cancer in high-risk women. Now we will apply our prevention experience with RXR agonists such as bexarotene to develop preclinical and clinical combinations with SERMs to prevent both ER-positive and ER-negative breast cancer. (4) Surprising new clinical and laboratory data suggests that overexpression of the androgen receptor may be an important cause of resistance to endocrine therapy with either tamoxifen or aromatase inhibitors. We will seek the mechanisms behind this interaction, and will initiate a clinical trial designed to reverse this resistance with an already-approved AR antagonist. (5) The IGF pathway has been shown to be important in breast cancer development and progression, but therapeutic targeting is complicated by high cross-reactivity with the insulin receptor. We will investigate the efficacy of a new, specific IGF-I receptor antibody and explore strategies to lessen toxicities associated with collateral insulin receptor blockade by other IGF pathway targeting approaches. Though parts of our unique breast Tissue Resource were lost in the floods of 2001, much remains, and new accessions are further enhancing this critical resource. Biostatistics, Pathology, and Administrative Cores also give key support to this SPORE. Our highly successful Developmental Projects and Career Development programs will continue to encourage new ideas and new investigators in translational breast cancer research. Our new Dan L. Duncan Cancer Center provides valuable direct support and collaboration for this SPORE effort.
Project 1: Targeting the HER2 Pathway: Mechanisms of Resistance and Strategies to Overcome ThemRachel Schiff, Ph.D., Project Leader Trastuzumab has proven to be a very effective therapy for HER2-positive breast cancer, but de novo or acquired resistance limits its long-term value. New observations from our laboratory suggest several hypotheses on the mechanisms of resistance to trastuzumab and other therapies targeting the HER network. First, our results suggest that this resistance might stem from incomplete blockade of the signals generated from the various HER-family dimer pairs in the network input layer. Using a limited number of HER2-overexpressing xenograft models we have found that combined drug therapies designed to more completely block these heterodimers can overcome resistance to single agents and are even capable of eradicating many of these tumors in mice. Our preclinical models and preliminary patient data also suggest alternative mechanisms for resistance to HER-directed therapy that involve the estrogen receptor in some tumors and the MUC4 mucins in others. Here we propose a series of preclinical studies and an early phase clinical trial to begin to test these hypotheses. Specifically we will: 1) Confirm our preliminary data that resistance to single-agent HER-targeted therapy can be overcome by various combinations of trastuzumab, lapatinib, and pertuzumab, designed to more completely block signaling from the HER network input layer, in a large panel of HER2-amplified breast cancer cell lines, and to identify and establish models resistant to these single and combined antiHER2 drugs for later studies; 2) Determine using these various preclinical HER2-positive models whether upregulation of ER or ER signaling to an alternative survival pathway can be induced by HER blockade as a resistance mechanism, and whether simultaneous targeting of ER and HER2 is then necessary for optimal treatment; 3) Investigate whether upregulation of MUC4 causes resistance to HER-targeted therapy in our preclinical in vivo model system, thereby providing a new potential diagnostic and treatment target to investigate in human samples; 4) Lead a multi-institutional phase 2 neoadjuvant clinical trial of lapatinib combined with trastuzumab, with serial tissue sampling to assess molecular mechanisms of action and resistance, in order to begin to translate our exciting preclinical findings to patients. This work will facilitate new strategies to circumvent resistance to HER-targeted therapy for improved patient survival.
Project 2: Treatment Resistance Pathways and Targeting Residual CancersJenny Chang, M.D., Ph.D., Project Leader Systemic therapies are effective initially in controlling and reversing tumor growth. However, residual cancers will invariably re-grow despite this initial response. Historically, investigation of treatment resistance has focused on the identification of acquired genetic alterations in bulk tumor epithelial cells that confer resistance to specific agents, or to multiple agents. But our recent data supports the existence of a small but distinct subpopulation of cancer cells present in the original tumor that are greatly enriched in residual cancers after conventional therapies. These residual cancer cells are characterized by their relative quiescence and resistance to therapy, yet they possess enhanced self-renewal capacity like that of stem cells. We therefore hypothesize that a unique subpopulation of cancer cells present in the original tumors are intrinsically resistant to conventional therapies, and are responsible for tumor initiation and cancer re-growth. To test our hypothesis, we propose: (1) To determine whether treatment-resistant breast cancers from our neoadjuvant trials are enriched for subpopulations of cells with self-renewal and tumor-initiating capacity. We will use cell surface markers and fluorescent vital dye retention to identify these cells and purify them by FACS. Self-renewal and tumorigenicity will be assessed by in vitro mammosphere (MS) assays and xenograft transplantation, respectively. (2) To define the regulatory genes and signaling pathways responsible for treatment resistance and self-renewal in human breast cancers after conventional chemotherapy. This will be done using mRNA and BAC methylation microarrays to determine gene expression and epigenetic similarities among label-retaining MS-initiating cells, CD44+/CD24- putative “breast cancer stem cells”, and chemoresistant residual cancer cells, and differences from differentiated primary invasive breast cancer cells. (3) To determine whether suppression of self-renewal and treatment resistance pathways can improve existing cancer therapies using MS-formation assays as well as our novel primary xenograft mouse models in “animal clinical trials”, leading to human trials targeting this tumor re initiating subpopulation directly. If our hypothesis is correct, then relapse after apparently successful therapy is due to the persistence of these resting, therapy-resistant tumor cells, thereby allowing tumor re-initiation. If so, approaches for anti-cancer drug development must be changed fundamentally to target these rare tumor-initiating cells, rather than only cells of the bulk tumor as has been done to date.
Project 3: Combination Chemoprevention: Prevention of Both ER-positive and ER-negative Breast CancerPowel H. Brown, M.D., Ph.D., Project Leader Prevention of breast cancer using medical therapy (chemoprevention) is now possible. Clinical trials have demonstrated that treatment of normal women at high risk of breast cancer with anti-estrogen drugs (selective estrogen receptor modulators, or SERMs) can substantially reduce their risk of developing breast cancer. However, SERMs are frequently not used by high risk women because they are not 100% effective and because chronic therapy with anti-estrogens has significant side effects. In addition, while long-term anti-estrogens reduce the risk of ER-positive breast cancer, they do not reduce ER-negative breast cancer. Thus, more effective and less toxic strategies to prevent all types of breast cancer are needed. We have previously shown that RXR-selective retinoids (“rexinoids”) prevent the development of ER-negative breast cancer in preclinical models in mice, and that the combination of SERMs and rexinoids is particularly effective. We have also conducted clinical trials using SERMs or rexinoids (as single agents) in high risk women and have demonstrated that these agents are tolerable. Here we will test the hypotheses that both ER-positive and ER-negative breast cancer can be prevented by combining drugs with different mechanisms of action, that by combining these drugs we will induce apoptosis in premalignant mammary tissue, and that short-term use of combined preventive agents will result in effective prevention with reduced side effects. (1) We will investigate whether chronic therapy with the SERM tamoxifen and the rexinoid bexarotene will totally prevent breast cancer in the p53-null mouse model (in which both ER-positive and ER-negative breast cancers develop) and determine whether this combination therapy induces apoptosis in precancerous breast cells. (2) We will investigate whether short-term treatment with tamoxifen and bexarotene will effectively prevent the development of breast cancer, and we will investigate the mechanism by which this short-term treatment can provide long-lasting protection. (3) We will conduct a Phase II clinical trial in premenopausal women at increased risk of breast cancer using the combination of tamoxifen plus bexarotene to determine whether short-term treatment in high risk women will induce apoptosis or suppress proliferation of mammary epithelial cells. These studies will lay the foundation for testing this combination of an anti-estrogen and a rexinoid in women at risk of breast cancer in future Phase III breast cancer prevention trials.
Project 4: Role of Androgen Receptor in Breast Cancer ProgressionSuzanne A.W., Fuqua, Ph.D., Project Leader The androgen receptor (AR) is known to be expressed in the majority of estrogen receptor (ER) alpha-positive human breast tumors. By gene expression profiling, we discovered elevated AR RNA in clinical breast tumors resistant to antiestrogen therapy with tamoxifen (Tam). We have shown that overexpression of AR causes ER alpha-positive MCF-7 breast cancer cells to become resistant to the growth-inhibitory effects of Tam and to estrogen withdrawal, which models the therapeutic action of aromatase inhibitors [AIs]). This endocrine resistance could be reversed by the AR antagonist bicalutamide, or by AR knockdown. Furthermore, in AR-overexpressing breast cancer cells, Tam induced rather than repressed ERalpha’s transcriptional activity, and this could also be reversed by bicalutamide. We therefore hypothesize that AR overexpression is a novel mechanism of resistance to ER-targeted therapies. We have developed this translational study to extend these findings, to determine how AR causes resistance to Tam and AIs and thus identify potential predictive markers for resistance and possible intermediate targets for reversing resistance, and finally to test this hypothesis in an initial clinical trial using bicalutamide to restore response in breast cancer patients whose tumors become resistant to Tam or AI treatment. Our proposed Aims are: (1) To determine the contribution of AR crosstalk with growth factor receptors and ER alpha in the resistant phenotype associated with AR overexpression using various signal transduction inhibitors and cell biological assays. (2) To determine how AR overexpression causes Tam-mediated nuclear ER transcriptional activation, exploring genomic AR actions. (3) To examine how AR overexpression affects survival pathways during estrogen deprivation with an AI. (4) To determine whether the AR antagonist bicalutamide can reverse endocrine resistance in breast cancer patients progressing on Tam or an AI in a Phasei/II clinical trial. These studies will employ techniques to explore the molecular mechanisms of AR action in breast cancer cells, which is an understudied area. We will identify whether specific components of the AR signaling pathway can be exploited to reverse endocrine resistance. We anticipate that AR will become an important new marker of endocrine resistance, and with the availability of an FDA-approved agent to block its effects (bicalutamide), we can rapidly translate our results into a possible new strategy for maintaining the benefits of endocrine therapy in breast cancer patients.
Project 5: Targeting the IGF Pathway for Treatment of Breast CancerAdrian V. Lee, Ph.D., Project Leader The insulin-like growth factor receptor (IGF-IR) is hyperactive and overexpressed in many breast cancers, and preclinical data have validated IGF-IR as a therapeutic target — several IGF-IR inhibitors have recently entered clinical trials. We have shown that a new IGF-IR tyrosine kinase inhibitor (TKI) can reverse IGF-IR-mediated transformation in vitro and block breast cancer xenograft growth in vivo. However, development of anti-IGF-IR TKIs has long been hindered by concerns about toxicity due to blockade of the highly similar insulin receptor (InsR). Indeed, all IGF-IR TKIs developed thus far show relatively equal potency against InsR. In contrast, monoclonal antibodies that specifically block IGF-IR, without cross-reacting with InsR, have recently been developed, and many show preclinical activity. We are participating in a multi-institutional Phase 2 study of the anti-IGF-IR antibody CP-751,871 in combination with the aromatase inhibitor exemestane as first-line treatment in metastatic breast cancer. However, two critical questions remain regarding the targeting of IGF-IR. First, there are no validated biomarkers that predict response to anti-IGF-IR therapy. Second, it is not clear whether InsR, which can signal to many of the same pathways as IGF-IR, and can form IGF-IR/InsR hybrid receptors, might need to be blocked. We hypothesize that biomarkers of IGF action identified in breast cancer cells will be modified in patient biopsies following treatment with the anti-IGF-IR-specific antibody CP-751,871, and may identify patients who will respond to IGF-IR targeted therapy. However, we predict that the greatest response may require targeting of both IGF-IR and InsR. To test our hypotheses we propose the following specific aims: 1) Identify biomarkers of IGF-IR activity in breast cancer cell lines, and then determine if these biomarkers are altered in patient biopsies from clinical trials of the new IGF-IR blocking antibody CP-751,871. 2) Determine the function of InsR and hybrid IGF-IR/InsR in breast cancer cell lines, and whether targeting of both IGF-IR and InsR is more effective than targeting IGF-IR alone. 3) Test whether intermittent, rather than continuous, dosing of an IGF-IR/InsR TKI (BMS-536924) is effective at inhibiting breast cancer growth, and determine combinations with other therapies that provide synergistic benefit. Our long term goal is to understand the role of IGF-IR in breast cancer, and thus advance the clinical development and implementation of IGF-IR inhibitors as effective therapies in breast cancer.
Core A: National Tissue ResourceCarolina Gutierrez, M.D., Core Director This is a continuation of an existing, well-functioning, and absolutely essential Core. Over its lifetime, Core A (National Tissue Resource) has provided a very large number of tissues to SPORE and non-SPORE investigators alike, nationally and even internationally. During our first 9 years, from 1993 through 2001, a total of 10,866 tumor samples were delivered to 78 projects. Investigators in this SPORE accounted for only about 40% of that activity — more than 6,000 specimens were provided to 59 different investigators outside the SPORE. Since the last submission (2002 to 2006), the Core has provided 5,057 specimens (with an additional 1320 pending distribution) to 34 projects involving 17 different principal investigators. A large fraction of distributions continue to go to investigators outside of our own SPORE. At least 25 full length manuscripts directly related to use of specimens and/or data from our SPORE tissue resources have been published since the last submission. The continuing objectives of the National Tissue Resource Core are to provide centralized support for tissue banking, quality assessment, and distribution efforts within the Breast SPORE by managing and distributing tissue and data from legacy inventories to qualified researchers; by collecting, managing, and distributing newly acquired breast cancer materials to qualified researchers; by assisting in acquisition, management, and distribution of clinical trial associated material; and by collection of additional clinical and follow-up data on appropriately consented subjects represented in the collections. Although guidelines state that “each SPORE must have a dedicated core for collection and distribution of human cancer specimens”, Core A greatly surpasses this minimum requirement — it is critical for the research activities proposed in this SPORE, and also has been and will continue to be an important research resource to other scientists within and outside Baylor College of Medicine who are engaged in translational breast cancer research.
Core B: Biostatistics and Data ManagementSusan G. Hilsenbeck, Ph.D., Core Director This is a continuation of an existing, well-functioning and absolutely essential Core. During the previous funding period, the Core provided extensive biostatistical and data management support to all five projects, to both the Pathology Core and the Tumor Bank Core, and to several of the Developmental Projects, resulting in more than 30 coauthored publications, many in high impact journals. All projects in our new SPORE application will require substantial statistical support for a range of preclinical and clinical experiments. In our experience, centralized biostatistical support ensures that the biostatisticians are completely familiar with all aspects of the Projects and Cores. This provides continuity, increases efficiency, and ensures that appropriate methods are applied. The specific aims of the Core B (Biostatistics and Data Management) are to: (1) Provide comprehensive biostatistical and bioinformatical consultation, data analysis and reporting; (2) Provide comprehensive support for conduct and analysis of clinical trials, including data quality control and monitoring, interim monitoring and analysis of data, final analysis, and reporting; (3) Develop and maintain databases and database applications in support of Projects and Cores. The SPORE benefits greatly from having a dedicated and experienced team of analysts with a range of skills. For example, analysis of microarray experiments is especially demanding and complex and will require both biostatistical and bioinformatic expertise. Core analysts are active participants in all aspects of the SPORE. Sample size considerations, experimental designs, and overviews of planned analyses for all projects were prepared in collaboration with the Core, and are provided within each project and specific aim. In addition, deep understanding of Project and Core data and analysis needs, in turn, drives database development, ensuring that database solutions meet the broad as well as project-specific needs of the SPORE. Core personnel can also help the investigators design new studies and test new hypotheses that may arise by cross-fertilization of these related projects. Finally, Core leaders are highly experienced biostatisticians, who have longstanding collaborative relationships with all SPORE investigators and other Core leaders, and who are members of the Biostatistics Shared Resource of the Dan L. Duncan Cancer Center at Baylor College of Medicine, thus facilitating a close integration with the Cancer Center.
Core C: PathologyCarolina Gutierrez, M.D., Core Director This is a continuation of an existing, productive, well-functioning, high volume Core with expert staff and state-of-the-art equipment essential for all five major projects and certain developmental projects outlined in this renewal application. Over the past four years the Core completed 825 work orders, developed 50 new immunohistochemical assays, prepared nearly 3500 paraffin blocks, processed 356 specimens into tissue arrays, performed 3500 immunohistochemical assays, and contributed to 32 published manuscripts. The objectives of the Pathology Core are to provide comprehensive histopathological support and pathology expertise to all SPORE projects. Services include tissue preparation, staining, laser capture microdissection, confocal microscopy, immunohistochemistry, and preparation of tissue arrays for both human and mouse specimens. Overall this Core will process 3590 human and animal tissue samples, and process and interpret 8935 slides for the proposed projects. This Core is essential to ensure quality and cost efficiency, and it has the necessary laboratory space, equipment, experienced histotechnologists, and expert pathologists to successfully manage this work.
Core D: AdministrationC. Kent Osborne, M.D., PI and Core Director Our Breast SPORE consists of five full research projects as well as developmental projects, career development, and specialized core resources. An Administrative Core is needed to efficiently utilize administrative personnel and to provide common services for these projects and cores. Dr. C. Kent Osborne, as Principal Investigator of the SPORE, will direct this Administrative Core. The Core provides a pool of services which are common to all components of the SPORE, including: administrative processing of review and funding of Developmental Projects, recruitment of Career Development candidates, financial administration of grant funds and the Director’s discretionary funds, organization of conferences and seminars, manuscript preparation, coordination of travel, report preparation, general clerical support, processing of IRB protocols, and assurance of compliance with all NIH and institutional grant regulations. The Core will also coordinate the services of our Internal Advisory Committee and Advocates Committee, and arrange for the visits of our External Advisory Committee members to review our progress and make recommendations. In summary, consolidation of common support and administrative functions relieves individual projects of many minor but important tasks, and assures quality control in record-keeping, services, and compliance issues. Core personnel are highly experienced, and the Core provides well-organized and cost-effective support to all components of the SPORE.
Developmental Research ProgramGary C. Chamness, Ph.D., Program Director In order to enable SPORE investigators to rapidly develop new research opportunities which could translate into early benefits for breast cancer patients, and to allow for exploration of new techniques which may require substantial efforts but which are nevertheless not ready for full scale multi-year research funding, we have devoted considerable effort and resources to this SPORE Developmental Research Program. The Executive Committee, together with the advocate members and the Internal Advisory Committee, selects proposals for funding as Developmental Projects, based on their scientific merit and relevance to SPORE translational goals. Through the funding of pilot projects, we broaden the scope of research, and allow exploration of high-risk ideas that have the potential for high yields in treatment, prevention, or basic biology of breast cancer. We also attract new investigators with a wide variety of special expertise to apply their expertise to problems and questions in breast cancer research, and we catalyze productive collaborations in which individual skills and approaches combine to create progress that no single investigator could achieve alone. It is important to point out that, although only $50,000 per year is requested from SPORE funds for this program, the Dan L. Duncan Cancer Center is contributing an additional $50,000 per year in recognition of the value of this outreach effort to cancer research in general. During the first 15 years since our Breast SPORE was initiated in 1992, we funded 70 developmental projects, leading to 85 publications and providing essential preliminary data for 50 funded grants plus 8 more pending. This mechanism complements the larger and longer-term regular research projects, offering a degree of flexibility which leads to enhanced productivity for the SPORE as a whole.
Career Development ProgramGary C. Chamness, Ph.D., Program Director The purpose of this Career Development Program is to support promising investigators who will participate in translational breast cancer research projects. There are one to two awardees at any one time, who may be either MD's or PhD's. Candidates are selected based on their previous accomplishments and their potential and desire to pursue a career in academic breast cancer research. While our primary focus is to support promising young investigators at the junior faculty level, it is possible that more established investigators may also be appropriate for support. The general outline of each awardee’s research will have been discussed by the applicant and the Selection Committee as a part of the selection process, and a principal mentor from the Program Faculty will be agreed upon. Awardees will receive further guidance from the Executive Committee and the selected mentor in developing their translational research projects throughout the award period. They will also participate in an extensive set of seminars, professional development courses, and clinical opportunities. The research environment at the Baylor Breast Center is ideal for supporting translational activities. Scientific excellence in breast cancer research continues to be reaffirmed by the award of both individual and collaborative grants, while both national and local programs of clinical investigation are well established at the Baylor Breast Center and can serve to assist in the translation of research findings into clinical practice. This is an ideal environment for enhancing and focusing the careers of outstanding investigators on productive translational research in breast cancer.
LIST OF CURRENT INVESTIGATORSC. Kent Osborne, M.D. (Professor and Director of the Breast Center at Baylor) Powel H. Brown, M.D., Ph.D. (Professor) Gary C. Chamness, Ph.D (Professor) Jenny Chang, M.D. (Professor) Suzanne A.W. Fuqua, Ph.D. (Professor) Carolina Gutierrez, M.D. (Assistant Professor) Susan G. Hilsenbeck, Ph.D. (Professor) Jian Huang, M.D. (Assistant Professor) Adrian V. Lee, Ph.D. (Associate Professor) Michael Lewis, Ph.D. (Assistant Professor) Daniel Medina, Ph.D. (Professor) Gordon Mills, M.D., Ph.D.(Professor) Mothaffar Rimawi, M.D. (Assistant Professor) Rachel Schiff, Ph.D. (Associate Professor) Nancy Weigel, Ph.D. (Professor) |
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