Third Annual AACR Margaret Foti Award for
Leadership and Extraordinary Achievements in Cancer Research
Anna D. Barker, Ph.D.
Deputy Director, and Deputy Director for Strategic Scientific Initiatives
National Cancer Institute
The American Association for Cancer Research established this Award in 2007 in honor of Margaret Foti, Ph.D., M.D. (h.c.) for her exemplary leadership of the AACR as its Chief Executive Officer; for her sustained, outstanding work in fostering research, scholarly communications, education and training, science policy, and public education; and for her extraordinary dedication and contributions to the conquest of cancer. The Award recognizes a true champion of cancer research, an individual who embodies the sustained commitment of Margaret Foti to the prevention and cure of cancer. The Award is given to an individual whose leadership and extraordinary achievements in cancer research or in support of cancer research have made a major impact on the field. Such achievements include extraordinary contributions to the acceleration of progress in cancer research, raising national and/or international awareness of cancer research, or other substantive demonstrations of a sustained commitment to the conquest of cancer.
Dr. Anna D. Barker has demonstrated an exemplary commitment to cancer research, specifically in the leadership and management of research and development, technology transfer, and new product development in both the non-profit and private sectors. It is noted that she has been a visionary and always at the forefront of encouraging the adoption of new technologies such as cancer genomics, nanotechnology, systems biology, information technology, and the physical sciences into cancer research. In addition, throughout her amazing career, she has been a staunch advocate for increased federal funding for research and has demonstrated innovative leadership in supporting as well as interacting with cancer survivors and patient advocates.
Prior to entering the biotechnology sector, Dr. Barker was a senior executive at Battelle Memorial Institute for 18 years where she developed and led a large group of scientists and technical staff working in the areas of drug discovery and development, pharmacology, and biotechnology, including several NCI-sponsored research programs. In the private sector she co-founded and served as the CEO of a public biotechnology company, which was focused on therapeutics discovery and development; and she subsequently founded and served as the CEO of a private company dedicated to the transfer and deployment of technologies to prevent, diagnose, and treat cancer.
Dr. Barker is currently Deputy Director of the National Cancer Institute (NCI), and she has concentrated many of her efforts in this position on strategic scientific initiatives, advanced technologies and key partnerships. In her role as Deputy Director, she plans and coordinates the implementation of integrative, multi-disciplinary, and multi-sector programs to accelerate the development and translation of new knowledge and advanced technologies into effective interventions to prevent, detect, and treat cancer. Under her leadership, the NCI launched new programs in bioinformatics, nanotechnology (Nanotechnology Alliance for Cancer), genomics (The Cancer Genome Atlas) proteomics, biospecimen science and the most recently trans-disciplinary Physical Sciences-Oncology Centers to enable cancer research.
Dr. Barker is also known for her leadership in cancer research advocacy. Of particular note is her position as co-Chairperson of THE MARCH-Coming Together to Conquer Cancer Research Task Force, an unprecedented grass-roots movement and historical national event, which sought to detail the scientific rationale and need for a significant, immediate increase in the Nation's investment in cancer research. Dr. Barker has also held memberships on the NCI Board of Scientific Counselors for the Division of Cancer Etiology and served as Chairperson of the Cancer Center Support Review Study Section. She was a founding member of C-Change, two-term member of the Board and Chairperson of the C-Change Cancer Research Team; a member of the DOD Breast Cancer Research Program Integration Panel, and a past chairperson of the BCRP Integration Panel. She is the founding co-chair and NCI liaison to the FDA-NCI Interagency Oncology Task Force.
Dr. Barker has served in several capacities for the American Association for Cancer Research, including as a member of the Board of Directors and chairperson of the Public Science Policy and Legislative Affairs Committee for ten years. She was also responsible for establishing the AACR Scientist↔Survivor Program in 1999, and remains actively involved in this innovative program today. Dr. Barker has been a member of the AACR since 1978.
Sixth Annual AACR Award for Lifetime Achievement in Cancer Research
Joseph F. Fraumeni, Jr., M.D., M.Sc.
Director, Division of Cancer Epidemiology and Genetics
National Cancer Institute
National Institutes of Health
The AACR Lifetime Achievement Award was established in 2004 to honor an individual who has made significant fundamental contributions to cancer research, either through a single scientific discovery or a body of work. These contributions, whether they have been in research, leadership, or mentorship, must have had a lasting impact on the cancer field and must have demonstrated a lifetime commitment to progress against cancer.
Dr. Joseph F. Fraumeni, Jr. is honored for his seminal research contributions in understanding the causes of human cancer and in preventing its occurrence. Through his innovative studies of high-risk populations, he has identified and characterized genetic and environmental determinants of cancer, developed novel approaches to etiologic research, and provided new opportunities for prevention.
During his luminous career, Dr. Fraumeni combined clinical, biological, and epidemiological approaches into a comprehensive and integrative strategy that has provided enduring contributions to cancer research and public health. His interest in genetic susceptibility began with the investigation of familial aggregates of various cancers and the discovery of cancer-malformation syndromes (e.g., congenital aniridia and other anomalies with Wilms tumor) based on surveys of childhood cancer conducted with Robert W. Miller. Dr. Fraumeni's interdisciplinary approach to research causation is perhaps best illustrated by the discovery in 1969 and subsequent pursuit (with Frederick P. Li) of a familial multiple-cancer syndrome featuring a genetic predisposition to breast cancer, sarcomas, and a variety of other neoplasms in children and young adults. Now known as Li-Fraumeni syndrome (LFS), this striking constellation of multiple cancers dispelled the prevailing dogma that familial predisposition is always tumor-specific, and suggested that genetic susceptibility pathways may be shared by different forms of cancer. In collaboration with cellular biologists, he described a radiation-resistant phenotype in cells from LFS family members, presaging the apoptotic role of the gene that was eventually identified.
The search for genetic underpinnings of LFS eventually led to collaborative studies in Stephen Friend's laboratory at Harvard where germline mutations in the p53 tumor suppressor gene were discovered. This finding stimulated new avenues of molecular research, particularly since somatic alterations of the p53 gene are involved in a large proportion of cancers in the general population. LFS has also served as a prototype for predictive genetic testing programs aimed at detecting inherited cancer-predisposing mutations in healthy individuals.
Another central theme of Dr. Fraumeni's research has been the search for lifestyle and other environmental risk factors for cancer. Toward this end, Dr. Fraumeni led the development in 1975 of the first U.S. Cancer Mortality Atlas, which displayed computer-generated and color-coded maps pointing to clusters of high-rate counties where carcinogenic exposures may be more prevalent. This strategy enabled Dr. Fraumeni and his colleagues to design epidemiological studies to identify carcinogenic hazards, including smokeless tobacco use in relation to oral cancer in the rural South, shipyard asbestos exposures to lung cancer along coastal areas, agricultural herbicides to lymphoma in farming communities, work in the furniture industry to sinonasal cancer in the southeast, and high levels of arsenic in drinking water to bladder cancer in the northeast. These findings often led to cancer control measures, such as education campaigns and advertising/labeling regulations aimed at smokeless tobacco.
Publication of the U.S. cancer maps was followed by the development of similar atlases in at least 35 nations. Most striking were the geographic patterns of cancer in China, where Dr. Fraumeni forged collaborations with Chinese scientists in a series of epidemiologic studies and prevention trials conducted in areas with extraordinarily high rates of cancer. These studies uncovered, for example, the impact of indoor air pollution from cooking oil vapors and coal combustion products in the development of lung cancer among non-smoking women in poorly ventilated homes; the protective effect of antibiotic eradication of Helicobacter pylori in the precursor stages of stomach cancer; and the reduced risk imparted by vitamin and mineral supplements in esophageal dysplasia and cancer.
In other studies, Dr. Fraumeni has sought reasons for the rising incidence rates and racial disparities for various cancers in the U.S., such as the remarkable recent increase in esophageal adenocarcinoma among white men (e.g., reflux, obesity) and the striking excess of esophageal squamous cell carcinoma among African American men (e.g., alcohol, smoking, dietary deficiencies).
Occupational cancer has long been a special interest of Dr. Fraumeni, who was the first to implicate inorganic arsenic as a respiratory carcinogen based on his landmark study of non-ferrous smelter workers. This finding provided the impetus for regulatory agencies to set limits on occupational exposure to arsenic. Another focus of Dr. Fraumeni's research has been the surveillance of cancer risks associated with certain pharmaceutical compounds, including immunosuppressive, cytotoxic and hormonal medications, which have provided clinical data for risk-benefit analyses as well as mechanistic insights into carcinogenesis.
Dr. Fraumeni's recent work has centered on the integration of genome-wide scans and other emerging technologies into large-scale epidemiologic studies designed to investigate the role of common genetic variants and environmental exposures, plus their interactive effects in cancer etiology and progression. He has been a leader in developing the molecular epidemiology platforms and international consortial strategies needed to accelerate a fuller understanding of cancer causation. These studies have already uncovered novel genetic variants associated with the risk of breast, prostate, and other cancers, and are setting the stage for further molecular and epidemiologic research that is likely to inform new clinical and public health approaches to cancer prevention and control.
The research contributions of Dr. Fraumeni are documented in over 800 scientific publications and books, including multiple editions of the definitive textbook (co-edited with David Schottenfeld) entitled Cancer Epidemiology and Prevention. While pursuing his own research, Dr. Fraumeni provided the leadership at the National Cancer Institute to create one of the premier cancer epidemiology research programs in the world. As an extension of his strong commitment to mentoring, he developed a distinctive fellowship program to train the next generation of scientific leaders in epidemiology, genetics, statistics and related fields.
In recognition of his research accomplishments, Dr. Fraumeni has been elected to membership in the National Academy of Sciences, the Institute of Medicine, and the Association of American Physicians.
Eighth Annual Kirk A. Landon-AACR Prize for Basic Cancer Research
Peter A. Jones, Ph.D., D.Sc.
Director of The USC/Norris Comprehensive Cancer Center
Distinguished Professor of Urology, Biochemistry and Molecular Biology
University of Southern California
Los Angeles, CA
Stephen B. Baylin, M.D.
Deputy Director, Oncology Center
The Sidney Kimmel
Comprehensive Cancer Center at
John Hopkins University
The Kirk A. Landon-AACR Prize was established in 2002 to heighten the attention of scientists and members of the general public to landmark scientific achievements in the continuing effort to prevent and cure cancer. The Prize is awarded to an outstanding scientist who has made seminal cancer research discoveries in basic cancer research at the cutting edge of scientific novelty and significance. The Prizes are intended to honor an individual scientist for his or her research; however, in extraordinary circumstances, two individuals may be selected to share either of these Prizes when their research is closely related in subject matter and has resulted in prize-worthy work.
Drs. Peter A. Jones and Stephen B. Baylin have revolutionized cancer research by developing and demonstrating the concept of a major epigenetic component to neoplasia. This true paradigm shift has already resulted in significant improvements in cancer diagnosis and therapy, thanks largely to their efforts.
Dr. Jones' first fundamental observation in epigenetics is described in a trio of papers where it was demonstrated that the nucleoside analogues 5-azacytidine and 5-aza-2'-deoxycytidine can induce multiple differentiation phenotypes (e.g. fibroblast to muscle) in stably immortalized cells by inhibition of DNA methylation. This observation was the first unequivocal demonstration of the power of DNA methylation in stably modulating gene expression, including in transformed cells. It opened the way for numerous subsequent experiments in DNA methylation and beyond. Most relevant to cancer research was the drug-induced reversal of tumor-suppressor gene (TSG) silencing and of the neoplastic phenotype. In many ways, these early experiments were the precursors for the current successes in reprogramming cells (including cancer cells) by nuclear transplantation and by transcription factors.
Spurred by the azacytidine data, Dr. Jones moved on to a comprehensive study of DNA methylation in cancer and was one of the very first investigators to turn to this issue. In the 1980's he showed how DNA methylation was altered in a complex way (both hyper and hypomethylation) in aging and neoplastic cells and could be affected by carcinogens - an observation that is only now receiving its due attention. Dr. Jones' lab also showed that deamination at methylated cytosines was an important cause of mutations in cancer. In the 1990's, his lab showed in exquisite detail how promoter specific DNA methylation can silence TSGs, and he begun a series of studies aimed at understanding the mechanisms of DNA methylation associated silencing from histone modifications to nucleosome positioning. More recently, he was the first to appreciate how microRNAs could themselves be epigenetically regulated and subjected to DNA methylation associated silencing in cancer.
Dr. Baylin is most recognized for the observation of tumor-suppressor gene (TSG) silencing by DNA methylation in cancer. His insight came from studies of the differentiation-related calcitonin gene, where he observed frequent hypermethylation in cancer, and proposed that this could be an alternate mechanism of TSG silencing. Working against considerable skepticism, he went on to show that this was true for most TSGs in cancer.
Most importantly, he made the key observations that mutations and promoter methylation of TSGs was mutually exclusive suggesting equivalent selection pressure for the two events, and reversing TSG methylation functionally restored silenced pathways. He was the first to propose that within deleted regions, TSGs can be identified based on aberrant DNA methylation and subsequently showed this for the HIC1 gene. His lab demonstrated recently that aberrant DNA methylation is much more common than mutations in some cancers. He has extensively explored the relations between DNA methylation and other silencing marks including histones and polycomb occupancy, and, along with other investigators, has proposed a stem cell origin for aberrant epigenetic marks in cancer.
To judge Drs. Jones' and Baylin's impact on medicine, it is instructive to review the fate of the two drugs 5-azacytidine and 5-aza-2'-deoxycytidine. Initially developed as cytotoxic agents, they entered clinical trials in the 1970's and were largely abandoned. The discovery by the Jones laboratory of their role as targeted anti-DNA methylation agents, together with the realization by the Baylin and Jones laboratories that DNA hypermethylation was a key driver of neoplasia revived interest in the drugs, to the point of their FDA approval in the past two years. They have been shown to prolong the lives of patients with leukemia, and these advances were made possible by the work of Drs. Jones and Baylin.
Eighth Annual Dorothy P. Landon-AACR Prize for Translational Cancer Research
Charles L. Sawyers, M.D.
Chairperson, Human Oncology and Pathogenesis Program
Memorial Sloan-Kettering Cancer Center
New York, NY
Investigator, Howard Hughes Medical Institute
The Dorothy P. Landon Prize was established in 2002 to heighten the attention of scientists and members of the general public to landmark scientific achievements in the continuing effort to prevent and cure cancer. This Prize is awarded to an outstanding scientist who has made seminal cancer research discoveries in translational cancer research at the cutting edge of scientific novelty and significance.
Dr. Charles L. Sawyers is recognized for discovering the mechanism of resistance to the kinase inhibitor imatinib (Gleevec) in patients with chronic myeloid leukemia (CML). This led to the recognition that neoplasms can escape oncogene-directed therapy through mutation of the drug target (e.g., BCRABL in CML). This has had broad implications for other kinase targets in other diseases, such as drug-resistant EGF receptor mutations in lung cancer. Dr. Sawyers has also made significant contributions to targeting prostate cancer.
Dr. Sawyers addressed the question of how the BCR-ABL fusion protein causes CML beginning with his postdoctoral training with Dr. Owen Witte. He made the first functional connections between BCR-ABL and the downstream effectors Myc and Ras, and MAP kinase pathways. He first interacted with Dr. Brian Druker based on mutual interest in the BCR-ABL substrate CrkL that they later optimized as a readout for BCR-ABL kinase activity in patients.
This interaction formed the basis for their later collaboration on imatinib. Drs. Sawyers, Druker, Talpaz and Kantarjian worked very closely with Drs. Nick Lydon and Alex Matter of Ciba-Geigy Pharmaceuticals (later Novartis) on various clinical developments strategies and wrote the phase I clinical study for CML that ultimately led to drug approval by the FDA. Subsequently, Dr. Sawyers discovered that mutations in BCR-ABL can explain resistance to imatinib in CML, which established a paradigm for resistance to tyrosine kinase inhibitors that held true for other targets. Based on functional assays using mutant forms of BCR-ABL, his laboratory predicted the activity of dasatinib in imatinib resistant CML. Together with Dr. Talpaz, he then led the clinical studies that resulted in FDA approval of dasatinib in imatinib-resistant CML.
In parallel with his work in leukemia, Dr. Sawyers developed a leading research program in prostate cancer which is currently focused on defining the mechanism of resistance to hormone therapy. After establishing a series of novel xenograft models that mimic the progression from hormone-sensitive to hormone-refractory cancer he conducted a global gene expression profiling survey that implicated increased levels of the androgen receptor (AR) as the key driver of hormone refractory progression.
Through functional studies Dr. Sawyers conclusively showed that increased AR is both necessary and sufficient to confer resistance to hormone antagonists. He also made the unexpected finding that antagonists behave as agonists in the setting of increased AR levels, providing an explanation for the clinical phenomenon of antiandrogen withdrawal syndrome as well as a critical clue toward the design of novel antiandrogens.
Recently, Dr. Sawyers has exploited this observation to discover second generation antiandrogens that retain activity in cells with increased AR levels. This work, in collaboration with chemist Dr. Michael Jung at UCLA resulted in a series of novel nonsteroidal antiandrogens with greater potency than currently used drugs due to higher affinity for the androgen receptor as well as induction of a conformational change in AR that impairs DNA binding activity at promoter/enhancer elements of canonical AR target genes.
Twelfth Annual Pezcoller Foundation-AACR International Award for Cancer Research
Napoleone Ferrara, M.D.
South San Francisco, CA
The Pezcoller Foundation-AACR International Award was established in 1997 to annually recognize a scientist who has made a major scientific discovery in basic cancer research or who has made significant contributions to translational cancer research; who continues to be active in cancer research and has a record of recent, noteworthy publications; and whose ongoing work holds promise for continued substantive contributions to progress in the field of cancer.
Dr. Napoleone Ferrara is honored in recognition of his groundbreaking research in the mechanisms of tumor angiogenesis, which ranges from pioneering basic science to creating novel therapies.
In 1989, Dr. Ferrara and his colleagues reported the isolation and cloning of vascular endothelial growth factor (VEGF) and then characterized this molecule as a major regulator of angiogenesis involved in a variety of physiological processes, including embryonic development, reproductive functions and skeletal growth. Dr. Ferrara also demonstrated that VEGF is an important mediator of tumor angiogenesis. The development of a humanized anti-VEGF antibody (bevacizumab) stems from his exemplary scientific work and is the first molecule proven clinically effective in targeting angiogenesis. Since 2004, bevacizumab has attained FDA approval for the treatment of metastatic colon, lung and breast cancer, the three leading causes of cancer deaths in the United States. Dr. Ferrara's studies on the role of VEGF in intraocular neovascularization also led to the clinical development and FDA approval of an anti-VEGF antibody fragment - ranibizumab - as a novel and effective therapy to prevent blindness in patients with wet age-related macular degeneration.
Today, Dr. Ferrara continues his innovative research. He is pursuing the investigation of VEGF and its receptors as well as studying novel mechanisms of regulation of angiogenesis. As part of this line of research, he identified endocrine gland vascular endothelial growth factor (EG-VEGF), a molecule that forms new blood vessels selectively in endocrine-system tissues. Most recently, his laboratory has been investigating the mechanims of tumor escape to anti-VEGF therapy and identified factors produced by tumor-infiltrating myeloid cells and fibroblasts as novel mediators of VEGF-independent angiogenesis and, potentially, as therapeutic targets.
Third AACR Princess Takamatsu Memorial Lectureship
Curtis C. Harris, M.D.
Chief, Laboratory of Human Carcinogenesis
National Cancer Institute
The AACR Princess Takamatsu Memorial Lectureship was established and first presented in 2007 in honor of the late Princess Takamatsu of Japan. During her extraordinary life, Her Imperial Highness Princess Takamatsu expended tremendous efforts toward the public and humanitarian cause of the eradication of cancer. She is regarded as an honored and respected figure in Japan, the United States, and within the international cancer research community as a whole.
The Lectureship will recognize an individual scientist whose novel and significant work has had or may have a far-reaching impact on the detection, diagnosis, treatment, or prevention of cancer, and who embodies the dedication of the Princess to multinational collaborations.
Dr. Curtis C. Harris is honored for his outstanding research accomplishments, his several decades of scientific collaborations with Japanese scientists, and his early and continuing efforts to forge friendship between the Japanese and US scientific communities.
The research of Dr. Harris has provided major elements of the scientific foundation for the molecular epidemiology of cancer. He pioneered the development of in vitro models using human tissues and cells to compare metabolic pathways of chemical carcinogen activation and detoxification in humans and laboratory animals. From his studies, quantitative and qualitative differences in carcinogen metabolism, carcinogen-DNA adduct formation, and DNA repair were identified, found to have an inherited basis, and shown to play a critical role in cancer susceptibility to environmental carcinogens. Dr. Harris showed that chemical carcinogens in tobacco smoke or oncogenes induce neoplastic transformation of human bronchial epithelial cells in the laboratory. Dr. Harris also is internationally recognized for his cellular and molecular studies of asbestos-induced human pleural mesothelioma and lung carcinogenesis.
Dr. Harris significantly contributed to the discovery that mutation of the p53 tumor suppressor gene is the most common genetic lesion in human cancers. The characterization of mutational spectra of the p53 gene in human tumors provides unique and critical molecular links between environmental carcinogens and specific human cancers. Dietary exposure to the mycotoxin aflatoxin B1 is positively correlated with a specific codon 249 mutation in hepatocellular carcinoma, and a dose-response relationship exists between tobacco smoking and G to T transversions in lung cancer. Additionally, the p53 mutation spectra in lung cancer associated with environmental radon differs from that observed in tobacco smoke-induced lung cancer. Drs. Harris and Monica Hollstein established the p53 mutation database in 1990 that has grown to be the world's largest mutation database with more than 15,000 entries of tumors with p53 mutations.
Third Annual AACR Team Science Award
St. Jude Children's Research Hospital Acute Lymphoblastic Leukemia (ALL) Team
Dario Campana, M.D., Ph.D.; Cheng Cheng, Ph.D.; James R. Downing, M.D.; William E. Evans, Pharm.D.; Melissa M. Hudson, M.D.; Sima Jeha, M.D.; Charles Mullighan, MBBS (Hons), MSc, M.D.; Ching-Hon Pui, M.D.; Susana C. Raimondi, Ph.D., Mary V. Relling, Pharm.D.; Raul C. Ribeiro, M.D.
The AACR Team Science Award has been established by the American Association for Cancer Research and Eli Lilly and Company to acknowledge and catalyze the growing importance of interdisciplinary teams to the understanding of cancer and/or the translation of research discoveries into clinical cancer applications. In addition, through the presentation of this Award, the AACR and Eli Lilly seek to effect change within the traditional cancer research culture by recognizing those institutions that value and foster interdisciplinary team science. These institutions will have demonstrated their support of a team science environment by creating mechanisms to enhance the required infrastructure, such as through pilot funding, technology transfer offices, shared resources, etc., and by presenting awards, honors, appointments, and promotions to those who participate in interdisciplinary teams.
The AACR Team Science Award will recognize an outstanding interdisciplinary research team for its innovative and meritorious science that has advanced or likely will advance our fundamental knowledge of cancer or a team that has applied existing knowledge to advance the detection, diagnosis, prevention, or treatment of cancer.
The St. Jude Children's Research Hospital Acute Lymphoblastic Leukemia (ALL) Team has built on the legacy of ALL research at St. Jude, capitalizing on the unparalleled commitment of institutional resources to enhance and advance NIH-funded research. Although important contributions have been made by many ALL study groups around the world, this multidisciplinary team of investigators has sustained a vast scope of integrated basic and clinical science, achieved an exemplary level of innovative translational research, and produced an extraordinary number of high-impact publications. Through the integration of biologic, genomic, and pharmacologic discoveries into comprehensive clinical protocols, the team has markedly improved cure rates of children with ALL, while making a series of seminal laboratory discoveries that unravel mechanisms of leukemogenesis and drug resistance, and identify novel therapeutic targets.
The accomplishments of this team include undertaking fundamental genomic studies of ALL blasts that have revealed new genetic pathways in leukemogenesis, particularly those regulating lymphoid maturation; making pharmacogenomic discoveries that have been translated into molecular diagnostics to individualize drug dosages to reduce toxicity and enhance efficacy (e.g., thiopurine methyltransferase polymorphism and mercaptopurine dose); the development of personalized therapy based on molecular genetics of ALL, pharmacogenetic traits of patients, pharmacodynamic principles, and early treatment response as assessed by minimal residual disease determination that has pushed the cure rate of childhood ALL toward 90%, an unprecedented result which serves a benchmark for others in the field; the demonstration that with equal access to effective treatment, the same high cure rate can be extended to diverse ethnic, racial or socioeconomic groups on a global scale; conducting comprehensive long-term follow-up and assessment of late treatment sequelae that have led to modifications in therapy to enhance the quality of life in survivors of childhood ALL; and the dissemination of ALL treatment to developing countries via education and training in its International Outreach Program and Cure4Kids website. In the past decade, the team has produced more than 1,000 research articles based on this work, routinely published in top-tier journals.
The accomplishments, dedication, and promise of continued research discoveries to further improve cure rates, to enhance the quality of life of patients, and to advance our knowledge of ALL biology, make this truly multi-disciplinary team a compelling example of the power of team science and translational research in advancing cancer cures.
Forty-Ninth Annual AACR G.H.A. Clowes Memorial Award
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
AACR G.H.A. Clowes Memorial Award was established in 1961 to honor Dr. G. H. A. Clowes, who was a founding member of the AACR and a research director of Eli Lilly. The AACR Clowes Award recognizes an individual for outstanding recent accomplishments in basic cancer research.
The AACR honors Dr. Joan Massagué for series of 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 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. He identified the TGF-b receptor components that mediate the effects of the ligand on metazoan cell differentiation, adhesion, remodeling of extracellular matrices, and inhibition of proliferation. Dr. Massagué and his group defined the biochemical mechanism of activation of the TGF-b receptor system. With Robert Weinberg, Massagué found that TGF-b receptors were absent in retinoblastomas, thereby providing the first of several mechanisms by which tumor cells escape negative growth regulation. Growth inhibition by TGF-b was linked to suppression of retinoblastoma protein (RB) phosphorylation.
The Massagué laboratory identified a family of SMAD proteins that are activated by receptor kinase-mediated phosphorylation. Subsequent studies indicated that SMADs are potent integrators of TGF-b-induced biologic responses across the genome. TGF-b signaling via the SMADs directly activates genes encoding cyclin-dependent kinase (CDK) inhibitory proteins, including p15Ink4b and p21Cip1, while antagonizing proliferation-promoting transcriptional regulators, such as Myc and E2F. Working with different colleagues Massagué identified, purified and molecularly cloned p27Kip1, and contributed to the elucidation of the crystal structure of p27Kip1 bound to cyclin A-CDK2. These studies have highlighted the many different ways by which tumor cells evade the cytostatic action of TGF-b.
Springing from observations that TGF-b can function as a pro-metastatic cytokine, Massagué undertook studies to define the basis for organ-specific metastasis in breast cancer. His laboratory used in vivo selection procedures, transcriptome analyses, functional studies and clinical associations to define gene expression programs that determine the ability of breast cancer cells to metastasize to bone or to lungs. Intriguingly, organ-specific metastatic signatures help to define the underlying nature for the preferential colonization of these different tissues. 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 the primary tumors.
Massagué and his group recently identified a set of micro-RNAs that suppress breast cancer metastasis and some of their crucial targets identified; loss of miR-335 and miR-126 are associated with increased metastatic probability and decreased survival. In turning his career full circle, 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.
Fourteenth Annual AACR Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Research
William Marston Linehan, M.D.
Chief, Urologic Oncology Branch
Center for Cancer Research
National Cancer Institute
The AACR and Bristol-Myers Squibb established this Award in 1996 to recognize outstanding achievements in clinical cancer research. It honors the late Dr. Joseph H. Burchenal, Honorary Member and Past President of the AACR, and a major figure in clinical cancer research.
Dr. W. Marston Linehan is honored for defining the genetic basis of clear cell kidney cancer, Hereditary Papillary Renal Carcinoma (HPRC), and chromophobe kidney cancer, and providing the basis for the molecular therapeutic approaches to therapy for these diseases.
In Dr. Linehan's earlier work with Dr. Berton Zbar, he discovered an abnormal region on chromosome 3 in tumors from patients with sporadic (non-inherited) renal carcinoma. This work culminated in identification of the VHL tumor suppressor gene in 1993. He then established a comprehensive hereditary kidney cancer program at NIH to study families with kidney cancer and identify the genes involved. He has continued in this leadership role for the past 25 years, carefully defining the phenotypes, clinical management, and genetic determinants of the four main inherited kidney cancers and providing clinicians and scientists with the basis for developing molecular therapies for both the hereditary and sporadic forms.
In 1995, Dr. Linehan and his colleagues described a novel inherited kidney cancer, Hereditary Papillary Renal Carcinoma (HPRC), and set up a program to recruit and study HPRC families. After spending six years identifying the gene responsible for HPRC, the c-Met proto-oncogene, they provided the initial descriptions of the pathologic phenotypes and genotype/phenotype correlations, and they defined the current approaches for HPRC clinical and surgical management. They also discovered c-Met mutation in sporadic type 1 papillary renal carcinoma) and the first non-random duplication of a mutant oncogene in human cancer. Their discovery that c-Met underlies type 1 papillary kidney cancer provided the foundation for the current therapeutic efforts targeting the HGF-Met pathway. Dr. Linehan's group recently reported the initial results of a drug trial targeting the c-Met pathway in HPRC patients.
The Linehan group's discovery of Hereditary Renal Oncocytoma led to the identification of a novel inherited chromophobe renal cell carcinoma associated with Birt Hogg Dubé (BHD) syndrome. He established a program to evaluate BHD kindreds and described the BHD phenotype and its association with kidney cancer. Through linkage analysis, he and his colleagues, Drs. Berton Zbar and Laura Schmidt, discovered the BHD gene, detailed the phenotypic and pathologic manifestations of BHD-associated kidney cancer, and reported its definitive genotype/phenotype correlation. They discovered that, in BHD-associated kidney cancer, the BHD gene resembles a tumor suppressor gene. Recently his group defined the cancer pathway for the BHD gene and provided the basis for potential therapeutic intervention in this disease. They subsequently created a BHD-knockout model, which exhibits a significantly-affected phenotype, providing the basis for clinical trials targeting the BHD pathway in patients affected with this cancer syndrome.
Dr. Linehan and his colleagues studies of Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) have greatly elucidated this novel inherited kidney cancer, characterized by germline mutation of the gene for the Krebs cycle enzyme, fumarate hydratase (FH). His group showed that HLRCC, being far more aggressive than VHL, BHD, and HPRC, cannot be managed as conservatively as these. They also described the phenotypes and germline mutations of this gene in 56 HLRCC kindreds. Along with Len Neckers, Ph.D., Dr. Linehan studied kindred kidney tumors, gaining unique insights into the FH gene pathway. He and his colleagues recently reported a detailed description of its alteration in human cancer and have described the approach to clinical management of HLRCC patients. These discoveries have led to new molecular therapeutic approaches for this lethal malignancy, now being evaluated in clinical trials.
Thirty-third Annual AACR Richard and Hinda Rosenthal Memorial Award
Todd R. Golub, M.D.
Founding Director, Cancer Program,
Broad Institute of Harvard and MIT
Charles A. Dana Investigator,
Dana-Farber Cancer Institute
Investigator, Howard Hughes Medical Institute
The AACR and the Richard and Hinda Rosenthal Foundation established this Award in 1977 to recognize research that has made, or promises to soon make, a notable contribution to improved clinical care in the field of cancer. In its desire to honor and provide incentive to clinicians relatively early in their careers, the Foundation has stipulated that recipients not be more than 50 years of age at the time the Award is received.
Dr. Todd R. Golub is recognized for his groundbreaking contributions to cancer research by applying basic biology and genomics to cancer diagnostic and therapeutic target discovery.
Following a remarkable postdoctoral training period with Dr. Gary Gilliland, during which he cloned the TEL/PDGFRß fusion in chronic myelomonocytic leukemia and identified the TEL/AML1 fusion in childhood acute lymphoblastic leukemia, Dr. Golub began his independent career by pioneering the earliest applications of genomics technologies to cancer more generally. In collaboration with Dr. Eric Lander, he first used gene expression profiling to demonstrate that global views of the cancer transcriptome could be used to establish cancer diagnoses. In that work, he laid out a generalizable analytical framework for gene expression-based cancer classification that has given birth to an entire field of cancer genomic discovery work, which is now resulting in the commercialization of genomic tests that are aiding patients in their decision-making process. In subsequent work, his laboratory demonstrated the feasibility of predicting clinical outcome in childhood brain tumors, and similarly extending this approach to lymphoma, prostate cancer, acute leukemias, lung cancer as well as a general signature of metastatic potential. Dr. Golub's laboratory has also explored the potential of microRNAs (miRNAs) for cancer classification and for regulating gene expression, and discovered that miRNA profiles have potential as cancer diagnostics, and moreover point to a strong developmental link between cancer and development.
More recently, Dr. Golub has turned his attention to ways in which the genomics might transform the process of drug discovery as well. He has recently begun using gene expression signatures as a surrogate for any biological state of interest. In this manner, a gene expression signature can serve as a read-out for any phenotype, including those that are too complex to assay in conventional cell-based assays. This concept, termed Gene Expression-Based High Throughput Screening (GE-HTS) has been applied to the discovery of small molecules capable of inducing the differentiation of acute myeloid leukemia and neuroblastoma cells, the abrogation of androgen receptor signaling in prostate cancer, and the inhibition of the action of the EWS/FLI1 protein in Ewing Sarcoma. A number of these findings have already been translated into clinical trials.
Extending the concept of gene expression signatures for drug discovery, Dr. Golub recently reported an approach, termed the Connectivity Map, for systematically connecting diseases, genes and drugs, by describing each of these entities in terms of a gene expression signature. By creating a reference compendium of gene expression profiles coupled with a series of analytical tools, he and his colleagues were able to match signatures of diseases with signatures of drugs with potential to treat those diseases. This work was taken to greatest mechanistic detail in the discovery of compounds capable of reversing drug resistance in childhood ALL and in the discovery of a new class of HSP90 pathway inhibitors. The public database and freely available analytical tools are being used by more than 7,000 registered users worldwide, and a number of clinical trials have been launched based on these results.