2008 AACR-Prevent Cancer Foundation Award Recipient
Frank L. Meyskens, Jr., M.D.
Director, Chao Family Comprehensive Cancer Center
Associate Vice Chancellor of Health Sciences,
College of Health Sciences Professor of Medicine and Biological Chemistry
University of California
Dr. Frank L. Meyskens, Jr. is recognized for his innumerable contributions to the fields of cancer prevention and control over the last 30 years. He has published over 100 peer-reviewed laboratory and clinical manuscripts on this topic.
Dr. Meyskens was among the first to recognize the potential of retinoids as preventive and therapeutic agents, and he led the development of topical all-trans-retinoic acid for the chemoprevention of CIN through pilot and Phase I, II and III trials. His positive Phase III study of retinol in chronic myelogenous leukemia promoted the idea that retinoids could affect the natural history of this preneoplastic condition, pre-saging the successful development of all-trans retinoic acid's for acute promyelocytic leukemia.
In parallel with these activities focused on retinoids, Dr. Meyskens, along with his colleague Dr. Ann Kennedy, has been responsible for the clinical development of the Bowman-Birk Inhibitor (BBIC) as a chemopreventive agent for oral leukoplakia. The promising results of a Phase IIa trial were reported in Clinical Cancer Research in 2000, and he is currently completing a randomized Phase IIb trial of BBIC in oral leukoplakia patients.
Perhaps the most noteworthy of his accomplishments in cancer prevention and control to date was his leadership in the development of alpha-difluoromethylornithine (DFMO) as a chemoprevention agent in humans. Dr. Meyskens was the Principal Investigator of a large Phase IIb trial of DFMO plus sulindac versus placebo in patients with prior colorectal adenomas that was transitioned to a Phase III study in 2004. The results of that trial demonstrated a remarkable 70% reduction in the risk of adenoma recurrence, and a 90% reduction in the risk of recurrence of an advanced adenoma. Thus, this trial demonstrated the highest level of efficacy seen in a clinical chemoprevention trial to date and established the clinical premise for combinatorial approaches to chemoprevention. Extending this work beyond those at risk for colorectal neoplasia, Dr. Meyskens also served as a senior member of the team which conducted a unique trial to measure the effect of DFMO on prostatic tissue in men at familial risk. The results were recently published in Cancer Epidemiology, Biomarkers and Prevention showing reduction in prostate volume and PSA levels, as well as changes in other parameters.
In addition, Dr. Meyskens has re-examined the scientific basis for the etiology of melanoma. Based on 15 years of detailed laboratory work, he proposed a new conceptual framework for melanoma etiology, prevention, and treatment. Most recently, he has provided a major, new insight into the non-UVR causation of melanoma with suggestions for potential preventive strategies.
Of particular note, Dr. Meyskens has published many seminal "thought" papers that have moved the field of cancer prevention forward. Perhaps, the most influential and important papers in the past decade considered the many challenges associated with the identification and development of markers as predictors of preventive effectiveness.
Dr. Frank L. Meyskens has excelled in both the basic and clinical science of cancer chemoprevention, thereby greatly enhancing its legitimacy and its translational potential to affect meaningful reductions in the burden of cancer worldwide.
2008 AACR Distinguished Lectureship in Breast Cancer Research
Joan Massagué, Ph.D.
Alfred P. Sloan Chair, Cancer Biology and Genetics Program
Investigator, Howard Hughes Medical Institute
Memorial Sloan-Kettering Cancer Center
New York, NY
The AACR honors Dr. Joan Massagué for series of remarkable and continuous discoveries made over more than two decades in defining the mechanisms by which signals initiated by transforming growth factor-b (TGF-b) are conveyed from their receptors on the cell membrane to the nucleus to affect cell proliferation, differentiation, and cancer. He is also recognized for his most recent studies that identified genes that define metastatic tissue tropism, providing a firm genetic basis for understanding the ability of breast cancer cells to colonize either the lung or bone.
Dr. Massagué's major contributions began with his identification and characterization of TGF-b receptors. Using biochemical cross-linking approaches, he identified two major forms of the receptor (Type I and Type II), which were coexpressed on epithelial cells. This receptor system mediated the many effects of the ligand on cell differentiation, adhesion, remodeling of extracellular matrices, and inhibition of proliferation. TGF-b's pleiotropic effects were circumvented in mutant cells lacking Type I or II receptors, but their responsiveness to ligand could be restored by complementation between different. This indicated that the Type I and II receptors act in concert to convey TGF-b-induced signals. Working together with Robert Weinberg, Massagué found that TGF-b receptors, while present in normal retinal cells, were absent in retinoblastomas, thereby providing a mechanism by which tumor cells escape negative growth regulation. Intriguingly, growth inhibition by TGF-b was linked to suppression of retinoblastoma protein (RB) phosphorylation, providing direct reinforcement for the then emerging idea of Ludlow and Livingston that RB was regulated in this manner.
In attempting to understand how cytokines of the TGF-b and BMP families control gene expression, the Massagué laboratory identified a family of SMAD proteins that act both as signal transducers and transcriptional activators. Members of the SMAD complex are activated by receptor kinase-mediated phosphorylation. A flurry of subsequent studies indicated that SMADs are potent integrators of TGF-b-induced biologic responses across the genome. As both activated and repressed TGF-b-responsive genes utilize the same SMAD proteins and DNA binding elements, specificity depends upon a variety of cell type-specific coactivators and corepressors and on other non-canonical regulators.
Springing from surprising observations that TGF-b can function as a pro-metastatic cytokine, Massagué undertook studies to define the basis for osteolytic bone metastasis of breast cancer cells. His laboratory subsequently used in vivo selection procedures and bioimaging, detailed transcriptome analyses, and both functional and clinical criteria to define multigenic gene expression programs that determine the ability of breast cancer cells to metastasize to bone. Intriguingly, organ-specific metastatic signatures help to define the underlying nature for the preferential colonization of these different tissues. Although some of the implicated genes confer growth advantages both in primary tumors and in the altered metastatic microenvironment, others are entirely distinct from those that define poor-prognosis gene expression signatures.
These investigations have highlighted tractable approaches for studying the metastatic behavior of cancer cells and have led to the conclusion that the genetic "seeds" for metastasis may sometimes be identified ab initio in primary malignancies even before there is any evidence of their dissemination. Many "metastasis genes" encode extracellular proteins not previously implicated in the process, and some, when engineered to be overexpressed in the primary tumor can facilitate angiogenesis, migration and invasion.
In turning his career full circle, Dr. Massagué's work has revealed that TGF-b primes breast cancer cells for metastasis to the lung by inducing an angiopoietin that facilitates the trans-endothelial passage of tumor cells.
Dr. Massagué's work is a dramatic example of the continuing importance of the focused pursuit of basic problems in biology for advancing our understanding of cancer and for developing new approaches to diagnosis and treatment. Based on these exceptional contributions, we feel privileged to recognize your long dedication to this field by naming you the recipient of the first AACR Distinguished Lectureship in Breast Cancer Research.
Dr. Massagué obtained his Ph.D. in Biochemistry from the University of Barcelona. In 1989, Dr. Massagué was recruited to Memorial Sloan-Kettering Cancer Center where he rose through the academic ranks. He currently serves as Professor, Weill-Cornell Graduate School; Investigator, Howard Hughes Medical Institute; and Alfred P. Sloan Chair, Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center.
2008 AACR Outstanding Investigator Award in Breast Cancer Research funded by Komen for the Cure®
Douglas Easton, Ph.D.
University Professor of Genetic Epidemiology & Director,
CR-UK Genetic Epidemiology Unit
Department of Public Health & Primary Care
University of Cambridge
Strangeways Research Laboratory
The AACR honors Dr. Douglas Easton for his exemplary international consortium studies in breast cancer that have elucidated the genetic epidemiology of BRCA1 and BRCA2, and which have recently provided definitive evidence for polygenic predisposition. As a result, this has led him to develop risk models that are in daily clinical use world-wide. Easton is furthered honored for the establishment of the Breast Cancer Linage Consortium, which has provided definitive evidence for the localization of a breast cancer susceptibility locus on BRCA1 and provided the first estimates of the breast and ovarian cancer risks in BRCA1 mutation carriers.
Most recently, Dr. Easton has been at the forefront of using new genome-wide arrays to identify cancer susceptibility loci. With his colleagues in Cambridge, he devised, conducted and analyzed the first genome-wide association study in breast cancer. This led to definitive identification of five breast cancer susceptibility loci, none previously associated with breast cancer: FGFR2, TNRC9, MAP3K1, LSP1 and a locus on 8q. Subsequently, his group, in collaboration with the CIMBA consortium, showed that the susceptibility variants in these loci were also associated with an increased risk of breast cancer in BRCA2 mutation carriers, but that only one (TNCR9) was associated with risk in BRCA1 mutation carriers. This result is consistent with other analyses in BCAC, which showed that the TNCR9 locus predisposes to both ER+ve and ER-ve breast cancer, whereas the other loci predispose predominantly to ER+ve disease. These observations indicate that these low penetrance variants may become important in counseling women who are BRCA mutation carriers and will be important for risk stratification in the general population.
Dr. Easton received his Bachelors of Arts and Masters of Arts in Mathematics from the University of Cambridge. He received his Ph.D. in Genetics Epidemiology from the University of London. In 1980, Dr. Easton was recruited to a Research Fellow position and rose through the academic ranks at the University of Cambridge. He currently serves as Director Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory; Professor in Genetic Epidemiology, Department of Public Health and Primary Care at the University.
Dr. Easton's many contributions have stimulated-and continue to stimulate-important directions of research in the field of breast cancer prevention.