Director

Ralph R.
Weichselbaum
Clinical trials, Tumor biology
University of Chicago Center
Bio

I have devoted my career to translational research in cancer. While a faculty member at Harvard, I defined the role of potentially lethal radiation damage in human tumor cells and the role of this type of DNA repair in radiotherapy.

I have devoted my career to translational research in cancer. While a faculty member at Harvard, I defined the role of potentially lethal radiation damage in human tumor cells and the role of this type of DNA repair in radiotherapy.

As the head of radiotherapy at the Dana Farber/Brigham and Woman’s Hospital, my team was the first group of investigators to use induction chemotherapy in the treatment of head and neck cancer. I then moved to the University of Chicago, where my team made seminal discoveries in basic signal transduction mechanisms after ionizing radiation exposure, and in separate studies discovered that mechanisms of radiation resistance/sensitivity are mediated by cytokine activation in tumors. Combining these concepts we conceived "genetic radiotherapy.”  In this bench-to-bedside application of a transcriptional targeting gene therapy paradigm, radiation activates DNA sequences from a radio (or chemo) inducible promoter, in this case the CArG elements from the EGR-1 gene that are cloned upstream of a cDNA for a toxin, (TNFα). Commercialized as TNFerade (GenVec) this genetic construct has been studied in phase 1, 2, and 3 clinical trials.

We also discovered that genes in the Stat 1 interferon pathway mediate resistance to ionizing radiation and some chemotherapeutic agents and contribute to tumor metastasis. A subset of these genes forms the basis for a predictive gene signature for women with breast cancer who receive adjuvant radiotherapy and/or chemotherapy radiotherapy. Together with colleagues at the University of Chicago, I have recently been investigating the relationship between radiotherapy and immunotherapy and how to optimize both. We are also investigating the clinical and molecular basis of oligometastases of subset metastases curable with localized therapy. We have conducted several clinical trials using stereotactic body radiotherapy for oligometastatic disease and have developed the basis of a microRNA classifier to identify patients with oligometastasis.

Education
• BS, University of Wisconsin, Madison, 1967
• MD, University of Illinois, Chicago, 1971
• Medical intern, Highland-Alameda County Hospital, Oakland, California, 1971-72
• Resident in radiation therapy, Joint Center for Radiation Therapy, Harvard Medical School, Boston, 1972-75
• Harold H. Hines Jr. Professor and Chairman, University of Chicago, 1990-2000
• Daniel K. Ludwig Professorship and Chairman, University of Chicago, 2001-present

Achievements
• Lee Lecture, University of Minnesota, 1987
• Clifford Allen Lecture, University of Oregon, 1989
• MacLaren Lecture, Hamilton Regional Cancer Centre, Ontario, 1991
• Evan and Marion Helfaer Lectureship, Medical College of Wisconsin, 1994
• Ruvelson Lecturer, University of Minnesota, 1996
• Member, Institute of Medicine, National Academy of Sciences, 1997
• John B. Little Award, Harvard University, 1998
• Glenn Sheline Lecturer, University of California, San Francisco, 1998
• Lecturer, Herman D. Suit Science Festivity Days, Boston, 2002
• Copeland Lecturer, The University of Texas M.D. Anderson Cancer Center, Houston, 2004
• Simon Kramer Lectureship, Thomas Jefferson University, Philadelphia, 2004
• Tolmach Lecturer, Annual Tolmach Symposium, Washington University, St. Louis, Missouri, 2010
• Keynote Speaker, Thermal Society, Portland, Oregon, 2011
• Keynote Speaker, Oligometastases Workshop, International Symposium on Lung Cancer, University of Leuven, Belgium, 2013
• Samuel Hellman Teaching Award, Department of Radiation Oncology, University of Chicago, 2013
• Member, National Cancer Policy Forum, Institute of Medicine, 2011-14

 


Achievements
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Director

Geoffrey L.
Greene
Signaling, Stem cells
University of Chicago Center
Bio

 

My lab studies the molecular mechanisms by which female steroid hormones regulate development, differentiation and/or cellular proliferation and survival in hormone responsive tissues and cancers.

This research has direct relevance to breast cancer genesis, progression, treatment and prevention, as well as to the development of compounds that can be used for hormone replacement therapy in postmenopausal women. The overall objective of my research is to determine the molecular distinctions between estrogen agonism and antagonism in hormone-dependent tissues and cancers and to use this information to identify, develop and characterize novel compounds that can be used for hormone replacement therapy and as breast cancer chemoprevention and chemotherapeutic agents.

Natural and synthetic ligands regulate diverse signaling and transcriptional networks via one or both of two estrogen receptor subtypes, ERα and ERβ. The structural and functional events underlying ligand-specific co-regulator recruitment and resultant transcriptional activation or repression are complex and still not well defined for both ERs. However, the development of diverse ER subtype-selective ligands has provided powerful molecular tools to study the linkage between ligand and transcription. Detailed structure-function information for the two ERs, a major focus of my lab, has proved useful both for understanding as well as designing ligands with tissue- and pathway-selective behaviors. Structural information for ERα and ERβ ligand-binding domains (LBDs) occupied by some of these ligands has helped define the relationship between receptor ligand positioning and the formation of different cofactor-binding surfaces. Combined with knowledge gained from extensive genomic and proteomic mapping studies of ER target genes and interacting proteins for both ER subtypes, it should be possible to improve breast cancer treatment and prevention strategies.

More recently, we have begun to study the role of cancer stem cells and tumor heterogeneity, focusing especially on the roles and targeting of nuclear receptors in triple negative breast cancer progression and treatment.

Education
• BA, The College of Wooster, Wooster, Ohio, 1969
• PhD, Northwestern University, Chicago, Illinois, 1974
• Postdoctoral Trainee, University of Chicago, Chicago, Illinois, 1974-77

Current appointments
• Professor and Chair, Ben May Department for Cancer Research
• Chair, Committee on Cancer Biology
• Co-Director, Ludwig Center for Metastasis Research

Achievements
• Exchange Scientist, US/France Cooperative Science Program (NCI/INSERM), 1978
• Exchange Scientist, US/France Cooperative Science Program (NCI/INSERM), 1982
• Exchange Scientist, US/France Cooperative Science Program (NSF/CNRS), 1984
• Ernst Oppenheimer Award; The Endocrine Society, 1988
• Visiting Professor, University of Modena, Modena, Italy, 1991
• John Brewer Distinguished Alumni Lectureship, Northwestern University Medical School, 1992
• Tartikoff-Semel Award, Revlon/UCLA Women’s Cancer Research Program, 1997
• Distinguished Visiting Scientist, UCLA Brain Research Institute, Los Angeles, 1998
• Inaugural Lecturer, Olof Pearson Lectureship, Case Western Reserve University, 1998
• Virginia and D. K. Ludwig Professor for Cancer Research, 2003
• Visiting Professor, University of Parma, Parma, Italy, 2004
• NAMS/Wyeth Pharmaceutical SERMs award from the North American Menopausal Society, 2006
• Jacob Hollenberg Lectureship in Biomedical Science, The Manitoba Institute of Cell Biology, Winnipeg, Manitoba, 2009
• Susan G. Komen for the Cure Brinker Award for Scientific Distinction, 2009
• Keynote Lecturer, Great Lakes Nuclear Receptor Conference, Northwestern University, 2012


Achievements
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Host: 

The Ludwig Center is housed within the University of Chicago Medical Center.

University of Chicago Center

Director

Ralph R.
Weichselbaum
Clinical trials, Tumor biology
University of Chicago Center
Bio

I have devoted my career to translational research in cancer. While a faculty member at Harvard, I defined the role of potentially lethal radiation damage in human tumor cells and the role of this type of DNA repair in radiotherapy.

I have devoted my career to translational research in cancer. While a faculty member at Harvard, I defined the role of potentially lethal radiation damage in human tumor cells and the role of this type of DNA repair in radiotherapy.

As the head of radiotherapy at the Dana Farber/Brigham and Woman’s Hospital, my team was the first group of investigators to use induction chemotherapy in the treatment of head and neck cancer. I then moved to the University of Chicago, where my team made seminal discoveries in basic signal transduction mechanisms after ionizing radiation exposure, and in separate studies discovered that mechanisms of radiation resistance/sensitivity are mediated by cytokine activation in tumors. Combining these concepts we conceived "genetic radiotherapy.”  In this bench-to-bedside application of a transcriptional targeting gene therapy paradigm, radiation activates DNA sequences from a radio (or chemo) inducible promoter, in this case the CArG elements from the EGR-1 gene that are cloned upstream of a cDNA for a toxin, (TNFα). Commercialized as TNFerade (GenVec) this genetic construct has been studied in phase 1, 2, and 3 clinical trials.

We also discovered that genes in the Stat 1 interferon pathway mediate resistance to ionizing radiation and some chemotherapeutic agents and contribute to tumor metastasis. A subset of these genes forms the basis for a predictive gene signature for women with breast cancer who receive adjuvant radiotherapy and/or chemotherapy radiotherapy. Together with colleagues at the University of Chicago, I have recently been investigating the relationship between radiotherapy and immunotherapy and how to optimize both. We are also investigating the clinical and molecular basis of oligometastases of subset metastases curable with localized therapy. We have conducted several clinical trials using stereotactic body radiotherapy for oligometastatic disease and have developed the basis of a microRNA classifier to identify patients with oligometastasis.

Education
• BS, University of Wisconsin, Madison, 1967
• MD, University of Illinois, Chicago, 1971
• Medical intern, Highland-Alameda County Hospital, Oakland, California, 1971-72
• Resident in radiation therapy, Joint Center for Radiation Therapy, Harvard Medical School, Boston, 1972-75
• Harold H. Hines Jr. Professor and Chairman, University of Chicago, 1990-2000
• Daniel K. Ludwig Professorship and Chairman, University of Chicago, 2001-present

Achievements
• Lee Lecture, University of Minnesota, 1987
• Clifford Allen Lecture, University of Oregon, 1989
• MacLaren Lecture, Hamilton Regional Cancer Centre, Ontario, 1991
• Evan and Marion Helfaer Lectureship, Medical College of Wisconsin, 1994
• Ruvelson Lecturer, University of Minnesota, 1996
• Member, Institute of Medicine, National Academy of Sciences, 1997
• John B. Little Award, Harvard University, 1998
• Glenn Sheline Lecturer, University of California, San Francisco, 1998
• Lecturer, Herman D. Suit Science Festivity Days, Boston, 2002
• Copeland Lecturer, The University of Texas M.D. Anderson Cancer Center, Houston, 2004
• Simon Kramer Lectureship, Thomas Jefferson University, Philadelphia, 2004
• Tolmach Lecturer, Annual Tolmach Symposium, Washington University, St. Louis, Missouri, 2010
• Keynote Speaker, Thermal Society, Portland, Oregon, 2011
• Keynote Speaker, Oligometastases Workshop, International Symposium on Lung Cancer, University of Leuven, Belgium, 2013
• Samuel Hellman Teaching Award, Department of Radiation Oncology, University of Chicago, 2013
• Member, National Cancer Policy Forum, Institute of Medicine, 2011-14

 


Achievements
Read More

Director

Geoffrey L.
Greene
Signaling, Stem cells
University of Chicago Center
Bio

 

My lab studies the molecular mechanisms by which female steroid hormones regulate development, differentiation and/or cellular proliferation and survival in hormone responsive tissues and cancers.

This research has direct relevance to breast cancer genesis, progression, treatment and prevention, as well as to the development of compounds that can be used for hormone replacement therapy in postmenopausal women. The overall objective of my research is to determine the molecular distinctions between estrogen agonism and antagonism in hormone-dependent tissues and cancers and to use this information to identify, develop and characterize novel compounds that can be used for hormone replacement therapy and as breast cancer chemoprevention and chemotherapeutic agents.

Natural and synthetic ligands regulate diverse signaling and transcriptional networks via one or both of two estrogen receptor subtypes, ERα and ERβ. The structural and functional events underlying ligand-specific co-regulator recruitment and resultant transcriptional activation or repression are complex and still not well defined for both ERs. However, the development of diverse ER subtype-selective ligands has provided powerful molecular tools to study the linkage between ligand and transcription. Detailed structure-function information for the two ERs, a major focus of my lab, has proved useful both for understanding as well as designing ligands with tissue- and pathway-selective behaviors. Structural information for ERα and ERβ ligand-binding domains (LBDs) occupied by some of these ligands has helped define the relationship between receptor ligand positioning and the formation of different cofactor-binding surfaces. Combined with knowledge gained from extensive genomic and proteomic mapping studies of ER target genes and interacting proteins for both ER subtypes, it should be possible to improve breast cancer treatment and prevention strategies.

More recently, we have begun to study the role of cancer stem cells and tumor heterogeneity, focusing especially on the roles and targeting of nuclear receptors in triple negative breast cancer progression and treatment.

Education
• BA, The College of Wooster, Wooster, Ohio, 1969
• PhD, Northwestern University, Chicago, Illinois, 1974
• Postdoctoral Trainee, University of Chicago, Chicago, Illinois, 1974-77

Current appointments
• Professor and Chair, Ben May Department for Cancer Research
• Chair, Committee on Cancer Biology
• Co-Director, Ludwig Center for Metastasis Research

Achievements
• Exchange Scientist, US/France Cooperative Science Program (NCI/INSERM), 1978
• Exchange Scientist, US/France Cooperative Science Program (NCI/INSERM), 1982
• Exchange Scientist, US/France Cooperative Science Program (NSF/CNRS), 1984
• Ernst Oppenheimer Award; The Endocrine Society, 1988
• Visiting Professor, University of Modena, Modena, Italy, 1991
• John Brewer Distinguished Alumni Lectureship, Northwestern University Medical School, 1992
• Tartikoff-Semel Award, Revlon/UCLA Women’s Cancer Research Program, 1997
• Distinguished Visiting Scientist, UCLA Brain Research Institute, Los Angeles, 1998
• Inaugural Lecturer, Olof Pearson Lectureship, Case Western Reserve University, 1998
• Virginia and D. K. Ludwig Professor for Cancer Research, 2003
• Visiting Professor, University of Parma, Parma, Italy, 2004
• NAMS/Wyeth Pharmaceutical SERMs award from the North American Menopausal Society, 2006
• Jacob Hollenberg Lectureship in Biomedical Science, The Manitoba Institute of Cell Biology, Winnipeg, Manitoba, 2009
• Susan G. Komen for the Cure Brinker Award for Scientific Distinction, 2009
• Keynote Lecturer, Great Lakes Nuclear Receptor Conference, Northwestern University, 2012


Achievements
Read More

Host: 

The Ludwig Center is housed within the University of Chicago Medical Center.

Ludwig Center at the University of Chicago
5758 South Maryland Avenue MC 9006
Chicago, IL, us, 60637
T 773 702 0817
F 773 834 7233

Metastasis, the deadliest aspect of cancer, is notoriously resistant to treatment. At the Ludwig Center, we are searching for new ways to take advantage of cutting-edge technologies to identify, characterize and target disseminated tumor cells, with the goal of eventually developing successful treatment or prevention strategies for metastasis.

Ludwig Center at the University of Chicago
5758 South Maryland Avenue MC 9006
Chicago, IL, us, 60637
T 773 702 0817
F 773 834 7233

Directors

Ralph R. Weichselbaum

I have devoted my career to translational research in cancer. While a faculty member at Harvard, I defined the role of potentially lethal radiation damage in human tumor cells and the role of this type of DNA repair in radiotherapy.

As the head of radiotherapy at the Dana Farber/Brigham and Woman’s Hospital, my team was the first group of investigators to use induction chemotherapy in the treatment of head and neck cancer. I then moved to the University of Chicago, where my team made seminal discoveries in basic signal transduction mechanisms after ionizing radiation exposure, and in separate studies discovered that mechanisms of radiation resistance/sensitivity are mediated by cytokine activation in tumors. Combining these concepts we conceived "genetic radiotherapy.”  In this bench-to-bedside application of a transcriptional targeting gene therapy paradigm, radiation activates DNA sequences from a radio (or chemo) inducible promoter, in this case the CArG elements from the EGR-1 gene that are cloned upstream of a cDNA for a toxin, (TNFα). Commercialized as TNFerade (GenVec) this genetic construct has been studied in phase 1, 2, and 3 clinical trials.

We also discovered that genes in the Stat 1 interferon pathway mediate resistance to ionizing radiation and some chemotherapeutic agents and contribute to tumor metastasis. A subset of these genes forms the basis for a predictive gene signature for women with breast cancer who receive adjuvant radiotherapy and/or chemotherapy radiotherapy. Together with colleagues at the University of Chicago, I have recently been investigating the relationship between radiotherapy and immunotherapy and how to optimize both. We are also investigating the clinical and molecular basis of oligometastases of subset metastases curable with localized therapy. We have conducted several clinical trials using stereotactic body radiotherapy for oligometastatic disease and have developed the basis of a microRNA classifier to identify patients with oligometastasis.

Education
• BS, University of Wisconsin, Madison, 1967
• MD, University of Illinois, Chicago, 1971
• Medical intern, Highland-Alameda County Hospital, Oakland, California, 1971-72
• Resident in radiation therapy, Joint Center for Radiation Therapy, Harvard Medical School, Boston, 1972-75
• Harold H. Hines Jr. Professor and Chairman, University of Chicago, 1990-2000
• Daniel K. Ludwig Professorship and Chairman, University of Chicago, 2001-present

Achievements
• Lee Lecture, University of Minnesota, 1987
• Clifford Allen Lecture, University of Oregon, 1989
• MacLaren Lecture, Hamilton Regional Cancer Centre, Ontario, 1991
• Evan and Marion Helfaer Lectureship, Medical College of Wisconsin, 1994
• Ruvelson Lecturer, University of Minnesota, 1996
• Member, Institute of Medicine, National Academy of Sciences, 1997
• John B. Little Award, Harvard University, 1998
• Glenn Sheline Lecturer, University of California, San Francisco, 1998
• Lecturer, Herman D. Suit Science Festivity Days, Boston, 2002
• Copeland Lecturer, The University of Texas M.D. Anderson Cancer Center, Houston, 2004
• Simon Kramer Lectureship, Thomas Jefferson University, Philadelphia, 2004
• Tolmach Lecturer, Annual Tolmach Symposium, Washington University, St. Louis, Missouri, 2010
• Keynote Speaker, Thermal Society, Portland, Oregon, 2011
• Keynote Speaker, Oligometastases Workshop, International Symposium on Lung Cancer, University of Leuven, Belgium, 2013
• Samuel Hellman Teaching Award, Department of Radiation Oncology, University of Chicago, 2013
• Member, National Cancer Policy Forum, Institute of Medicine, 2011-14

 

Geoffrey L. Greene

My lab studies the molecular mechanisms by which female steroid hormones regulate development, differentiation and/or cellular proliferation and survival in hormone responsive tissues and cancers.

This research has direct relevance to breast cancer genesis, progression, treatment and prevention, as well as to the development of compounds that can be used for hormone replacement therapy in postmenopausal women. The overall objective of my research is to determine the molecular distinctions between estrogen agonism and antagonism in hormone-dependent tissues and cancers and to use this information to identify, develop and characterize novel compounds that can be used for hormone replacement therapy and as breast cancer chemoprevention and chemotherapeutic agents.

Natural and synthetic ligands regulate diverse signaling and transcriptional networks via one or both of two estrogen receptor subtypes, ERα and ERβ. The structural and functional events underlying ligand-specific co-regulator recruitment and resultant transcriptional activation or repression are complex and still not well defined for both ERs. However, the development of diverse ER subtype-selective ligands has provided powerful molecular tools to study the linkage between ligand and transcription. Detailed structure-function information for the two ERs, a major focus of my lab, has proved useful both for understanding as well as designing ligands with tissue- and pathway-selective behaviors. Structural information for ERα and ERβ ligand-binding domains (LBDs) occupied by some of these ligands has helped define the relationship between receptor ligand positioning and the formation of different cofactor-binding surfaces. Combined with knowledge gained from extensive genomic and proteomic mapping studies of ER target genes and interacting proteins for both ER subtypes, it should be possible to improve breast cancer treatment and prevention strategies.

More recently, we have begun to study the role of cancer stem cells and tumor heterogeneity, focusing especially on the roles and targeting of nuclear receptors in triple negative breast cancer progression and treatment.

Education
• BA, The College of Wooster, Wooster, Ohio, 1969
• PhD, Northwestern University, Chicago, Illinois, 1974
• Postdoctoral Trainee, University of Chicago, Chicago, Illinois, 1974-77

Current appointments
• Professor and Chair, Ben May Department for Cancer Research
• Chair, Committee on Cancer Biology
• Co-Director, Ludwig Center for Metastasis Research

Achievements
• Exchange Scientist, US/France Cooperative Science Program (NCI/INSERM), 1978
• Exchange Scientist, US/France Cooperative Science Program (NCI/INSERM), 1982
• Exchange Scientist, US/France Cooperative Science Program (NSF/CNRS), 1984
• Ernst Oppenheimer Award; The Endocrine Society, 1988
• Visiting Professor, University of Modena, Modena, Italy, 1991
• John Brewer Distinguished Alumni Lectureship, Northwestern University Medical School, 1992
• Tartikoff-Semel Award, Revlon/UCLA Women’s Cancer Research Program, 1997
• Distinguished Visiting Scientist, UCLA Brain Research Institute, Los Angeles, 1998
• Inaugural Lecturer, Olof Pearson Lectureship, Case Western Reserve University, 1998
• Virginia and D. K. Ludwig Professor for Cancer Research, 2003
• Visiting Professor, University of Parma, Parma, Italy, 2004
• NAMS/Wyeth Pharmaceutical SERMs award from the North American Menopausal Society, 2006
• Jacob Hollenberg Lectureship in Biomedical Science, The Manitoba Institute of Cell Biology, Winnipeg, Manitoba, 2009
• Susan G. Komen for the Cure Brinker Award for Scientific Distinction, 2009
• Keynote Lecturer, Great Lakes Nuclear Receptor Conference, Northwestern University, 2012

TEAM

Steven J.
Chmura
University of Chicago Center
Bio

The traditional concept of cancer staging is typically M0 or M1, defining those patients deemed potentially curable or those where intervention is designed to extend time until cancer death. Recent research suggests a population of patients exists where limited metastatic disease (lung, breast, colon, renal and many others) deemed oligometastatic. Potentially oligometastatic patients might obtain long-term cure by aggressive local ablative therapy (surgery, radiation and other treatments).

My Research has been on both the clinical-trial development side of oligometastatic cancer and the translational aspects  locally and on the national level. From the latter perspective, I wish to  identify tumor cell markers, circulating DNA, microRNA or others that will better identify those patients likely to benefit from aggressive and expensive local therapy.

Education
PhD, pathology, University of Chicago College of Medicine, 1997

MD, University of Chicago College of Medicine, 1999

Awards
Summa cum laude, University of Illinois, 1988

American Society for Radiation Oncology young investigator award, 2004

PI for RTOG University of Chicago, 2006-present

Director of clinical and translational research, University of Chicago, 2006-present

Nikolai N.
Khodarev
University of Chicago Center
Bio

Interactions of primary tumors and metastatic clones with the host microenvironment create the major selection forces that drive an evolution of heterogeneous tumor clones. One of the major components of these forces is Jak/Stat-signaling, which may be activated in tumor cells by multiple cytokines and growth factors. Like any signaling system, Jak/Stat signaling has pro-survival and pro-death components; that balance determines outcome of this signaling in tumor cells. Our research is aimed at detecting specific downstream Jak/Stat-dependent genes and proteins that can be used as targets for the increased killing of various tumor clones by genotoxic therapy, and at the same time can be used for the restriction of metastatic dissemination. We are also interested in the role of microRNAs in metastases, especially in the differences between microRNAs expressed in the limited metastases (oligometastases) compared to widely disseminated metastases (polymetastases). We believe that detection of such differentially expressed microRNAs in the clinical cohorts of an oligo- and polymetastatic patients will provide new knowledge about mechanisms of metastatic dissemination and will lead us to the new therapeutical approaches to restrict metastatic dissemination and to make metastatic disease potentially curable.

Education
MD (internal medicine), I.M. Sechenov 1st Moscow Medical School, 1976

PhD (biochemistry), I.M. Sechenov 1st Moscow Medical School, 1981

DSc (biochemistry), Center of Medical Biotechnology, Department of Health, Moscow, USSR, and Academy of Medical Science, USSR, 1989

Mitchell C.
Posner
University of Chicago Center
Bio

My primary clinical and research interests are focused on the management of upper gastrointestinal cancer, the molecular and genetic basis of gastrointestinal malignancy, viral gene therapy of solid tumors and the molecular basis of the oligo/poly metastatic state. I have written more than 200 original articles, published abstracts and book chapters and received numerous awards for investigative efforts and teaching, including the Basic Science and Clinical Research Award from the Society of Surgical Oncology. I have served as chairman of the Gastrointestinal Committee of the American College of Surgeons Oncology Group, the only national surgically focused cooperative group dedicated to clinical trials research.

Education
BS, University of Michigan, Ann Arbor, Michigan, 1977

MD, State University of New York, Buffalo, New York, 1981

Surgery, University of Colorado, Denver, Colorado, 1981-86

Surg Oncol, Memorial Sloan-Kettering Cancer Center, New York, New York, 1986-88

Awards
Ben Eiseman Surgical Resident Research Award; University of Colorado School of Medicine, Denver, Colorado, 1986

Winner, Best Paper in Clinical Research; Annual Fellow/Residents Competition; Society of Surgical Oncology, New Orleans, Louisiana, 1988

Resident/Fellow Award; Best Clinical Research Paper; Fellow, Ulysses Ribeiro, MD; senior suthor, Mitchell C. Posner, MD; 49th Cancer Symposium of the Society of Surgical Oncology, Atlanta, Georgia, 1996

American Society of Clinical Oncology Merit Award; resident, R. Erlich, MD; senior author, Mitchell C. Posner, MD; American Society of Clinical Oncology Annual Meeting, Philadelphia, Pennsylvania, 1996

Resident Essay Award; Best Basic Science Research Paper; resident, James O Park; senior author, Mitchell C. Posner, MD; 55th Cancer Symposium of the Society of Surgical Oncology, Denver, Colorado, 2003    

Honorary Faculty Member; Pontificia Universidad Catolica de Chile, Santiago, Chile, 2011

Everett E.
Vokes
University of Chicago Center
Bio

I am the John E. Ultmann Professor and chairman of Department of Medicine who brings together multi-modality teams to address complex solid tumors leading to improved treatment outcomes. My work on the treatment of lung and head and neck cancer and the interaction of chemotherapy and radiation and novel treatment approaches has contributed to increased cure rates and spared many patients from radical surgery. I was one of the first recipients of ASCO’s Translational Research Professorship and have written more than 500 papers and book chapters.

Education
Pre-medical education, University of Bonn Medical School, West Germany, 1973-75

 University of Bonn Medical School, West Germany, 1975-1980

Clerkship, St. Luke's Hospital, Sydney, Australia, 1978

Flexible internship (internal medicine, surgery, OB/Gyn), Malteser Hospital, Bonn, West Germany, 1979-1980

Awards
John E. Ultmann Professor

Member, American Society for Clinical Investigation, 1998

Yang-Xin
Fu
University of Chicago Center
Bio

I completed my medical residency at Peking Union Medical College Hospital in 1986 and received my PhD in tumor immunology from the University of Miami. After completing my pathology residency at Washington University in 1998, I became an assistant professor and attending physician in the Department of Pathology and was promoted to tenured professor in 2005. I was associate editor of the Journal of Immunology and am associate editor of Cancer Immunology Research, as well as a section editor for Cellular and Molecular Immunology. I work on translational medicine, especially immunotherapy and immunopathology in cancer and infectious diseases. I have published more than 130 papers in those fields, many in high-impact journals such as Science, Nature Immunology, Nature Medicine, Cancer Cell, and Immunity.

Education
MD, Shangai Medical University, Shangai, China, 1983

PhD, immunology, University of Miami, Miami Florida, 1990

Stephen J.
Kron
University of Chicago Center
Bio

Cancer can be considered a disease of perpetual cellular youth. In normal cells, proliferation and exposure to environmental stress promote persistent DNA damage at eroded telomeres or within chromosomes, leading to senescence, a cellular proxy for aging. Cancer cells maintain the capacity to proliferate even in the face of genomic instability or genotoxic stress. In studying how to restore the senescence response to cancer cells, our studies revealed a role for metabolic reprogramming in maintaining immortality. Inducing DNA damage while blocking cancer metabolism can induce cellular senescence, suggesting a new approach to cancer treatment.

Education
PhD, cell biology, Stanford University, 1990

MD, Stanford University, 1990

MSE, bioengineering, University of Pennsylvania, 1983

BA, biochemistry, University of Pennsylvania, 1982

Awards
Arnold and Mabel Beckman Foundation Young Investigator, 1996

James S. McDonnell Foundation Scholar Award, 1998

NSF Career Award, 1999

Leukemia & Lymphoma Society Scholar, 2002

Stohlman Scholar of the Leukemia & Lymphoma Society, 2007

Michael T.
Spiotto
University of Chicago Center
Bio

Genes that promote viral propagation also remove the common checkpoints that guard against malignant transformation. But these events are not sufficient to cause cancer, and it remains unclear what subsequent genetic changes must occur to eliminate the final barriers to malignancy. We have developed a novel inducible HPV-positive and applied forward- and reverse-genetic approaches to identify genes that cooperate with HPV to cause cancer. These models will advance our understanding of the cellular changes that enable virally infected cells to become cancer, and help to identify novel biomarkers and therapeutic targets for this disease.

Education
Resident/postdoctoral clinical fellow, Stanford University Medical Center, Stanford, California, 2010

Internship, Memorial Sloan Kettering Cancer Center, New York, New York, 2006

MD, University of Chicago, Chicago, Illinois, 2005

PhD, pathology, University of Chicago, Chicago, Illinois, 2003

BS, biological chemistry, University of Chicago, Chicago, Illinois, 1998

Awards
Burroughs Wellcome Career Award for Medical Scientists, 2012

Martin J. Brown Award for Radiation Oncology Research, Stanford University, 2009

Roentgen Resident/Fellow Research Award, Stanford University, 2009

Malcolm Bagshaw Award, Stanford University, 2008

Holman Pathway Recipient, 2007-09

Leon O. Jacobson Basic Science Prize, University of Chicago, 2005

John Van Prohaska Award for outstanding potential in teaching, research and clinical medicine, University of Chicago, 2005

Alpha Omega Alpha, University of  Chicago, 2004

Selected for Clinical Pathophysiology and Therapy Teaching Assistant, 2004

Award for best dissertation in the Department of Pathology, 2003

Award for best dissertation in the Division of the Biological Sciences, 2003

Robert Priest Award in Pathology, University of Chicago, 2003

Keystone Symposia Travel Scholarship, 2003

University of Chicago Cancer Research Center Travel Award. 2002

Growth and Development Training Program (NIH funded MD-PhD training program), 2000-05

RESEARCH AREAS

Goals of the Ludwig Center (click to expand)

One of our current research areas focuses targeting steroid hormone receptors to detect metastases and deliver treatment directly to tumor cells through the use of radiolabeled hormones. This highly specific targeting holds great promise for the treatment of metastatic cancers of the breast, prostate, ovary and lung. We also investigate the mechanism of oligometastasis, an intermediate stage between localized and widespread disease. By understanding the origins and possible treatments of this stage of disease, we hope to further our knowledge of metastasis. These investigations also include studies of how microRNAs influence metastatic behavior and the immune activating effects of radiotherapy.

Receptor targeted radiotherapy
We aim to develop and characterize novel steroid receptor modulators (SRMs) that can be used at any stage of tumor progression to image and kill tumor cells that express one or more members of the steroid receptor family, including the estrogen Receptor (ER), androgen Receptor (AR), and progesterone receptor (PR). Many human tumors, especially those of the male and female reproductive tract, express significant levels of two or more of these receptors, which makes them suitable for targeting, in contrast to existing therapies that rely on the use of single receptor antagonists or hormone deprivation to inhibit tumor cell proliferation and promote apoptosis. Because breast and prostate cancers express high levels of ER and AR, respectively, our focus is on these receptors and cancers as therapeutic targets. The Center is investigating the feasibility of labeling receptor ligands with a short-lived radioisotope to identify tumors that have sufficient levels of these receptors to be a target for intracellular radiotherapy with the same isotope. Initially, breast and prostate cancers will be studied, but this technique could be applied to cancers of the ovary and lung.

Tumor targeted nanoparticles
Additionally, we aim to develop novel nanoparticle reagents for cancer imaging and therapy. This multidisciplinary initiative would create nanoscale materials with the ability to selectively and precisely image tumor cells, as well as deliver therapy to a wide array of cancers. Initially, researchers are targeting CD47-expressing breast cancer cells with microRNA-containing, self-assembling nanoparticles, to determine the feasibility of using this approach to deliver chemotherapy only to tumor cells.

Understanding and treating oligometastasis
We propose to discover the mechanism of and potential treatments for oligometastasis as a step toward understanding metastatic spread and identifying a substantial proportion of patients with this subset of metastasis. By understanding this stage of cancer spread, we hope to find effective and safe treatments for different stages of metastasis.

One of the most promising treatments for oligometastasis is stereotactic body radiotherapy (SBRT), which allows for higher precision and higher doses of radiation than other externally delivered radiation technologies. The Ludwig Center has conducted several clinical trials of SBRT treatment on patients with metastases in multiple sites, with data suggesting that oligometastasis does in fact exist and that some patients might experience a survival benefit from SBRT or surgery. We hope to better identify the patients that might benefit from this type of treatment. To this end we are studying a microRNA signature to identify these patients and gain further insights into the behavior of metastasis.  We are also investigating the basis of resistance to radiotherapy and chemotherapy through a newly identified pathway that involves genes that mediate the effects of interferons. These investigations are important because patients with oligometastasis are likely to receive both radiotherapy and chemotherapy.

Combinatorial therapies and tumor heterogeneity
Frequently, tumors that initially respond to single agent steroid receptor-based therapies, such as tamoxifen or bicalutamide, will become resistant to therapy. Tumor heterogeneity and evolution play important roles in this behavior. Consequently, investigators at the Ludwig Center are investigating how tumors develop therapy resistance and what can be done to prevent or circumvent this behavior. One approach we are pursuing is to identify and develop novel small molecules that will target two or more nuclear receptors that are expressed in a heterogeneous cell population and act synergistically to cause tumor regression and/or sensitize tumors to ionizing radiation and/or other chemotherapies. Breast, head and neck, lung, ovary and prostate cancers are being studied, with a particular focus on triple negative breast cancer.

 

The role of immunology in radiotherapy (click to expand)

Radiotherapy has long been considered a successful treatment option for localized tumors, but recent data suggest that radiotherapy might activate the immune system and that the combination of radiotherapy and immune therapies could have the potential to improve both local and distant control of tumors.

Patients generally receive prolonged treatment with chemotherapy or fractionated radiotherapy. Despite initial responses, treatment resistance frequently develops.  Because of technological advances in radiotherapy, patients with clinically advanced disease can now be treated with high-dose, or ablative, radiotherapy with limited damage to the normal surrounding tissues. Surprisingly, we found that some of the anti-tumor effects of radiotherapy are dependent on T cell responses. Ablative radiotherapy improves antigen presentation both in the tumor microenvironment and in the draining lymph nodes, and increases dendritic cell and T cell chemokines leading to the reduction or eradication of the tumor or microscopic metastasis. Furthermore, we discovered that the immune-mediated effects of ablative radiotherapy are blunted by the use of conventional fractionated radiotherapy or chemotherapy, but amplified by local immunotherapy. These studies challenge the current methods of treatment for advanced localized tumors and emphasize the importance of the immune system in preventing tumor relapse. We have conducted several investigations to more fully understand the mechanisms underlying combined radio- and immunotherapies. Targeting cancer cells and the adjacent stromal cells can lead to complete destruction of tumors after adoptive transfer of tumor antigen-specific cytotoxic T lymphocytes. However, if cancer cells express low levels of the tumor antigen, surrounding stromal cells have limited access to tumor antigen for cross-presentation and will not be destroyed and the tumor escapes destruction. We discovered that by treating these tumors expressing low levels of tumor antigen with irradiation or chemotherapy, a sufficient amount of tumor antigen is released to sensitize stromal cells for destruction by cytotoxic T lymphocytes. This work was performed in collaboration with the Spiotto, Schreiber and Fu laboratories in the Departments of Immunology and Pathology.

We recently described the role of type I interferons in local radiotherapy-mediated tumor control. We observed that ablative radiotherapy increased intratumoral production of type I interferon by infiltrating bone marrow derived cells and that the anti-tumor effects of radiotherapy are substantially diminished in type I interferon nonresponsive hosts (animals with germline deletion of the type I interferon receptor). As noted above, radiotherapy dramatically increases the cross-priming capacity of tumor-infiltrating dendritic cells from wild-type mice, but not type I interferon receptor-deficient mice. By using adenoviral-mediated expression of type I interferon, we demonstrated that delivery of externally produced type I interferon into the tumor tissue in the absence of radiotherapy is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose radiotherapy can trigger the production of type I interferon that initiates a cascading innate and adaptive immune response. The cell autonomous effects of interferon on tumor cells are described in a separate section. This work was performed in collaboration with the Fu lab.

CURRENT WORK
We are a collaborating with the Fu lab on studies of the tumor microenvironment to investigate how radiation alleviates tumor immunosuppression and how radiotherapy can best be integrated with blocking antibodies to PD-1 (programmed cell death protein 1) and its ligand PD-L1. The PD-1/PD-L1 axis inhibits T cell function and blockade of this signaling system is reported to enhance the effector phase of T cell function. We recently reported an essential role of the immune system in inducing tumor equilibrium (analogous to clinically stable disease). A stable state was induced in experimental tumors after radiation, and the equilibrium state could be broken after depletion of CD8+T cells or gamma interferon leading to rapid tumor relapse. Remarkably, the immune microenvironment was a greater determinant of tumor regression/equilibrium than intrinsic tumor radiosensitivity. Treatment of tumors in radiation-induced equilibrium with blocking antibodies to PD-L1 augmented T cell responses and mediated tumor rejection indicating that T cell negative regulatory networks are an important barrier to T cell functional activity in the irradiate tumor microenvironment. We are working with the Fu lab to produce a vaccine against papilloma virus and with the Kron lab to produce an effective senescent cell vaccine. We are also collaborating with the Wolchok laboratory at the Ludwig Center at Memorial Sloan-Kettering to study the effect of an agonistic antibody to OX40, in combination with radiotherapy. OX40 is expressed on activated T cells and enhances the priming and effector phases of T cell function. In addition, we are working with the Yamini laboratory in the Department of Surgery at the University of Chicago to define the role of the p50 subunit of NFkB, an important transcription factor that functions both in immunity and DNA repair.

 

References
Liang H, Deng L, Chmura S, Burnette B, Liadis N, Darga T, Beckett MA, Lingen MW, Witt M, Weichselbaum RR, Fu YX. Radiation-induced equilibrium is a balance between tumor cell proliferation and T Cell-mediated killing. J Immunol. 2013 Jun 1;190(11):5874-81. doi:10.4049/jimmunol.1202612.Epub 2013 Apr 29.

Burnette B, Fu YX, Weichselbaum RR. The confluence of radiotherapy and immunotherapy. Front Oncol. 2012; 2:143.

Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 2011 Apr 1; 71 (7) : 2488-96.

Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009 Jul 16; 114 (3) : 589-95.

Meng Y, Efimova EV, Hamzeh KW, Darga TE, Mauceri HJ, Fu YX, Kron SJ, Weichselbaum RR. Radiation-inducible immunotherapy for cancer: senescent tumor cells as a cancer vaccine. Mol Ther. 2012 May; 20 (5) :1046-55.

Meng Y, Mauceri HJ, Khodarev NN, Darga TE, Pitroda SP, Beckett MA, Kufe DW, Weichselbaum RR. AdEgr-TNF and local ionizing radiation suppress metastases by interferon-beta-dependent activation of antigen-specific CD8+ T cells. Mol Ther. 2010 May; 18 (5) :912-20.

Schmitt AM, Crawley CD, Kang S, Raleigh DR, Yu X, Wahlstrom JS, Voce DJ, Darga TE, Weichselbaum RR, Yamini B. p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage. Mol Cell. 2011 Dec 9; 44 (5) :785-96.

Schreiber K, Arina A, Engels B, Spiotto MT, Sidney J, Sette A, Karrison TG, Weichselbaum RR, Rowley DA, Schreiber H. Spleen cells from young but not old immunized mice eradicate large established cancers. Clin Cancer Res. 2012 May 1; 18 (9) :2526-33.

Wu TH, Schreiber K, Arina A, Khodarev NN, Efimova EV, Rowley DA, Weichselbaum RR, Schreiber H. Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes. Cancer Immun. 2011 Jun 30; 11:2.

Zhang B, Bowerman NA, Salama JK, Schmidt H, Spiotto MT, Schietinger A, Yu P, Fu YX, Weichselbaum RR, Rowley DA, Kranz DM, Schreiber H. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med. 2007 Jan 22; 204 (1) :49-55.

 

Identification and use of novel chemo/radiotherapy targets and reagents in metastatic cancers (click to expand)

Steroid Receptors as targets for receptor-directed radiotherapy

Co-Investigators:
Robert Hanson
John Katzenellenbogen
Ralph Weichselbaum

Steroid receptor proteins are widely used as targets for hormone- or hormone ablation-based management of breast and prostate cancers, either alone or in combination with radiotherapy and chemotherapy.  Tamoxifen, a partial estrogen antagonist, is the signature adjuvant therapy for breast cancers that express estrogen receptor alpha (ERα). It has also proved to be effective in a prevention setting for women at increased risk for breast cancer.  Casodex, an androgen antagonist that targets androgen receptor (AR), when combined with LHRH agonists, is an established treatment for primary as well as metastatic prostate cancers, in combination with radiation therapy.  For both cancers, metastatic tumors that respond initially to these therapies almost always progress to an antagonist-resistant state, frequently being stimulated by the antagonist.  Many recurrent, hormone-resistant tumors continue to express ER and/or AR, and these receptors are still potential targets for alternative therapies.  In some cases, more potent antagonists (e.g., Fulvestrant for BC or Enzalutamide for PC), or hormone ablation (e.g. aromatase inhibitors for BC, or Aberaterone for PC) are effective in treating these resistant tumors.  Recent data also suggest that estrogens (BC) and androgens (PC) may be paradoxically effective in patients whose tumors become resistant to antagonists.  Thus, BC/PC progression from hormone dependence to apparent independence is complex, and our understanding of the underlying mechanisms is incomplete, due in part to tumor heterogeneity and evolution to resistant states.

The primary focus of our research is to exploit ERα/β, AR and progesterone receptor (PR) in progressive BCa and PCa in novel ways that take advantage of their continued presence. We are actively developing and characterizing radiolabeled SRMs (steroid receptor modulators) and steroid analogs that can be used to image and kill tumor cells that express, or are proximal to tumor cells that express, ERα/β, AR or PR. Receptor-specific ligands labeled with I123, Br76 or I131 are being explored and tested in cell and animal tumor models for their ability to inhibit cell/tumor growth or induce cell death. These same agents are also being exploited for tumor imaging. It is likely that primary and metastatic cancers of the lung and ovary, which express ERa/b, AR and/or PR, will also benefit from ligand-mediated radiotherapy, possibly using a combinatorial approach. These studies involve collaborations with Ralph Weichselbaum, Robert Hanson, at Northeastern University, and John Katzenellenbogen at the University of Illinois.

Receptor-directed cancer therapy is attractive because steroid receptors (SRs) have high affinity and specificity for small molecule ligands that are easily delivered to tumors throughout the body.  Multiple human tumors, especially those of the reproductive tract, express steroid receptors. In addition, receptor density within tumor cells is high enough to allow targeting.  Furthermore, it is possible to label receptor ligands with an radioisotope that allows imaging, thereby providing a means to assess whether the primary tumor, or more importantly metastases, contain sufficient concentrations of steroid receptors to be candidates for therapy with the same ligand or an analogous ligand.

With the recent recognition that prostate and breast cancers also express ERβ, and that receptor-selective ligands have been developed for both ERα and ERβ, it may be possible to selectively target ERβ without the potential therapeutic complications resulting from the presence of ERα in reproductive tract tissues where ERα is dominant, especially the uterus.  Conversely, it should also be possible to selectively target ERα, thereby avoiding tissues that predominantly express ERβ (e.g. bladder, intestine, lung, ovary, prostate). If this approach proves feasible, it could be extended to other steroid receptor-containing cancers such as those in the ovary (ERβ, AR, PR), colon (ERβ) and lung (ERα, ERβ, PR). Our approach is to test both Auger electron-emitting and beta-emitting isotopes of iodine, with the goal of delivering high linear energy transfer, LET, (123I  - Auger electrons), resulting in short range damage that is effective in micrometastases, as well as longer range radiation (131I – beta decay) that will irradiate adjacent tumor cells that may not contain these receptors. 123I also emits a 159 keV gamma that can be used for imaging (SPECT) to determine the location of metastases in animal models and humans.  In addition, 76Br can be used as a short-lived (t1/2 = 16 hr) isotope for PET imaging and 77Br (t1/2 = 57 hr) as a potential therapeutic radioisotope (Auger emitter). We will also explore the possible use of 211At, an alpha particle emitter, for therapeutic purposes. All of these isotopes can be introduced into receptor-selective steroid analogs at the 17α-position of the D ring, using the same chemistry.

The basis for this therapy approach is that radiolabeled ligand-SR complexes localize to DNA response elements associated with target genes.  Because SRs are intimately associated with cellular DNA, Auger electron cascades involved in nuclides that decay by electron capture give rise to high radiation density within a very small range, typically limited to the cell nucleus.  For decay with a 13 hr half-life [123I], on average about 12 electrons are deposited in this volume.  The major advantage of this approach is that, unlike the use of antiestrogens or aromatase inhibitors, which are currently the standard treatment for breast cancers, receptor-expressing tumor cells can be unresponsive to traditional therapies, which is common for metastatic disease.  This approach only requires that tumor cells express the appropriate SRs that are able to bind and deliver radiolabeled steroid to chromatin/DNA binding sites in the nucleus.

 

Identification and targeting of micro-RNAs involved in breast cancer metastasis (click to expand)

Co-investigators:

Huiping Liu
Michael Clarke
Ralph Weichselbaum

Patient tumor-derived orthotopic breast cancer models in mice with spontaneous metastases
To explore effective strategies that target metastasis, including poly-metastasis versus oligometastasis, a reliable, more representative and predictive model of human metastatic disease is needed. The commonly used models to study metastases, including those involving established human cancer cell line explants in mouse tumor models, metastatic tumor models via bloodstream injections, or murine tumor models, do not fully recapitulate human disease.  To overcome these limitations, we have generated more representative human-in-mouse tumor models by implanting dissected patient tumors, or tumor cells derived from pleural effusions, directly into NOD/SCID mouse mammary fat pads. We established 8 orthotopic breast tumor xenograft models, two derived from ER+ breast cancer specimens, two from Her2+ specimens and four (M1-M4) from ER-PR-Her2- triple negative breast cancer specimens. M1-M4 developed spontaneous lung metastases.  In addition, we used lentiviral vectors to transduce breast cancer stem cells (BCSCs) with firefly luciferase-eGFP or –tdTomato (luc-GFP or luc-Tom), thereby establishing a noninvasive bioluminescence imaging approach to monitor the metastatic progression of BCSC-initiated tumors. These tagged, patient-derived tumors will be extremely useful for monitoring treatment response in these mouse models. Also, we are using these models for functional validation studies of candidate genes, microRNAs, and/or signaling pathways to determine their roles in polymetastasis versus oligometastasis.

 

Identification of miRNAs that regulate lung metastases
Using miRNA real-time PCR primers (Taqman assay probes from AB), we have begun to examine miRNA expression profiles in human breast cancer xenografts and their derivative models from lung metastases, which grow in the orthotopic mammary fat pads at a slower rate and in a less aggressive manner than the parental tumors. A short list of miRNAs that are significantly down regulated in parental tumor models has been identified and includes miR-30c.  We hypothesize that differentially expressed miRNAs play a regulatory role in lung metastases of human breast cancer models. Future plans include functional validation of these miRNAs in breast cancer cells line in vitro, primary tumor cells in vitro and human breast cancers in vivo. Experimental parameter readouts will include tumor growth and invasion as well as bioluminescent imaging of tumor growth and metastasis in vivo.  In addition, we use 3D cultures of primary breast cancer cells for validation studies.  These models will help define the importance and roles of miRNAs in breast cancer polymetastasis versus oligometastasis in the lung and other metastatic sites. In addition, the information gained can be linked directly back to the patient from which each tumor line was derived.

 

Development of cancer cell targeted nanoparticles for imaging and therapy

Co-investigators:
Huiping Liu
Matthew Tirrell
Seungpyo Hong

In conjunction with our microRNA work, we are developing two different types of nanoparticle formulations for microRNA delivery. One involves dendron-based polymers. A second approach uses self-assembling micelles, formed electrostatically between negatively charged mi-RNA mimetics and peptide amphiphiles or positively charged peptides, Our preliminary work shows that both nanoparticle formulations can assemble with DNA nucleotide mimetics of microRNAs.

To specifically target tumor cells or cancer stem cells, we are using anti-CD47 mAb to generate an F(ab’)2 that can be coupled to different nanoparticle formulations. We are currently optimizing the coupling of anti-CD47 to Dendron polymer nanoparticles and electrostatically driven micelles. These particles will be then be tested for efficacy in cell-based studies.

 

Combinatorial therapies and tumor heterogeneity

Co-investigators:
Ya-Fang Chang
Marianne Greene
Muriel Lainé

Tumors that initially respond to single agent steroid receptor-based therapies, like tamoxifen or bicalutamide, almost invariably become resistant to therapy. Tumor heterogeneity and evolution play important roles in this behavior. To overcome these limitations, we are investigating how tumors develop therapy resistance and what can be done to prevent or circumvent this behavior. One approach is to identify and develop novel small molecules that will target two or more nuclear receptors that are expressed in a heterogeneous cell population and act synergistically to cause tumor regression and/or sensitize tumors to ionizing radiation and/or other chemotherapies. Breast, head and neck, lung, ovary, and prostate cancers are being studied, with a particular focus on triple negative breast cancer (TNBC). We are profiling a series of TNBCs, including patient-derived tumors, for the expression of all 48 nuclear receptors, including mRNA and protein, as well as a number of known, associated transcriptional coregulators, to determine potential therapy targets. Both approved and investigational NR agonists and antagonists will be used to target expressed NRs. This project also involves identifying and profiling CSCs and/or therapy-resistant cells that are present in the bulk tumor population. Our human tumor-in-mouse model will be used to determine in vivo efficacy of drugs that target NRs of interest.

 

Oligometastasis, a curative subset of metastatic disease (click to expand)

It is increasingly recognized that distant metastasis may not always be numerous and widespread.  A clinically-limited number of metastases have been designated as “oligometastasis” (Hellman and Weichselbaum 2011), a concept that certain metastases may originate from cells with limited potential for dissemination or/and represent intermediate state in the widespread metastases dissemination. Clinical evidence supports the idea that some oligometastases are curable.

Currently, clinical criteria have been used to select patients with limited metastases for the local therapies of curative intent. Despite the selection criteria, survival rates of only 25% demonstrate that the majority of patients selected for therapy are not cured.  A method for accurate classification of oligo- and poly- metastatic patients could have important clinical implications in both assignment of therapy prognosis as well as therapeutic targets for metastasis.  To establish a molecular classification and mechanistic explanation of oligo- and polymetastatic progression, we are studying microRNAs, - small non-coding RNA molecules regulating gene expression through binding with messenger RNAs. Using microRNAs profiling researchers in LCMR found patterns of these regulatory molecules which are expressed differently in patients with oligometastases as compared with polymetastatic patients.  Based on these differentially expressed microRNAs currently two projects are under development: The design of molecular markers for prediction of oligo- vs polymetastatic dissemination of cancer and the identification of down-stream genes and pathways which may be used for targeted suppression of metastases development.  As part of this project we propose to use an annotated data set of colon cancer oligo and poly liver metastasis from the University of Chicago. We propose to extract microRNAs and perform RNA seq to establish the molecular basis of oligometastasis in an organ disease specific situation.

This work was/is being done in collaboration with Mitchell Posner (Surgical Oncology); Mark Ferguson (Thoracic Surgery); Nikolai Khodarev, Steve Chmura, and Joe Salama (Radiation Oncology);  and Yves Lussier (Bioinformatics at the University of Illinois, Chicago). We are expanding our investigation to a broader definition of the role of microRNA within the metastatic cascade with Center co-director Geoffrey Greene. 

Treatment of oligometastasis with stereotactic body radiotherapy (SBRT)
One of the most promising treatments for oligometastasis is SBRT, which offers greater precision and allows much higher doses to limited target volumes than previous radiation delivery technologies. In an initial study of the safety and effectiveness of metastasis-directed SBRT for multisite extracranial oligometastasis, we reported progression-free survival rates of 33.3% and 22.0% at the one and two year follow  up time The overall survival rates  were 81.5% and 56.7%. Of the patients whose tumors did progress, 72% did so in limited (1-3) metastatic sites. Remarkably with treatment the 5 year survival rate of these 61 patients is 25%. This study considered with the previous biological studies suggest that the oligometastatic state exists and that some patients may experience a survival benefit from SBRT or surgery.

We have also investigated the use of SBRT for the treatment of oligometastatic renal cell carcinoma. Although renal cell carcinoma (RCC) is widely considered to be radioresistant, SBRT can control intracranial metastases associated with RCC. In this study, patients with RCC and limited metastases were treated on a 3-fraction dose-escalation protocol or an off protocol with 10 fractions of 5Gy. The treatment was well tolerated by most patients, with the most common acute toxicity being fatigue. After two years, local tumor (irradiated metastasis) control was 91.4% and the overall survival rate was 85%. Those patients who underwent treatment for all metastatic sites had a 2 year lesion control rate of 100% and distant control rate of 35.7%.

In another clinical investigation of SBRT for patients with limited volume metastatic non-small cell lung cancer (NSCLC), we reported that SBRT provides durable lesion control and may provide some patients with long-term progression-free survival. The 18-month local control, distant control, overall survival and progression-free survival rates were 66.1%, 31.7%, 52.9% and 28.0%.  In the previous section on radiotherapy and immunity we noted that large fraction sizes may induce anti-tumor immunity. We are planning clinical studies in oligometastasis with immune modifiers.

 

References
Rudra S, Malik R, Ranck MC, Farrey K, Golden DW, Hasselle MD, Weichselbaum RR, Salama JK. Stereotactic body radiation therapy for curative treatment of adrenal metastases. Technol Cancer Res Treat. 2013 Jun;12(3): 217-24. doi:10.7785/tcrt.2012.500320. Epub 2013 Jan 25.

Liauw SL, Connell PP, Weichselbaum RR. New paradigms and future challenges in radiation oncology: an update of biological targets and technology. Sci Transl Med. 2013 Feb 20; 5(173): 173sr2. doi:10.

Corbin KS, Hellman S, Weichselbaum RR. Extracranial oligometastases: a subset of metastases curable with stereotactic radiotherapy. J Clin Oncol. 2013 Apr10;31(11):1384-90. doi:10.1200/JCO.2012.45.9651. Epub 2013 Mar 4.

Hasselle MD, Haraf DJ, Rusthoven KE, Golden DW, Salgia R, Villaflor VM, Shah N, Hoffman PC, Chmura SJ, Connell PP, Vokes EE, Weichselbaum RR, Salama JK. Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer. J Thorac Oncol. 2012 Feb; 7 (2) :376-81.

Salama JK, Hasselle MD, Chmura SJ, Malik R, Mehta N, Yenice KM, Villaflor VM, Stadler WM, Hoffman PC, Cohen EE, Connell PP, Haraf DJ, Vokes EE, Hellman S, Weichselbaum RR. Stereotactic body radiotherapy for multisite extracranial oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer. 2012 Jun 1; 118 (11) :2962-70.

Khodarev NN, Roizman B, Weichselbaum RR. Molecular pathways: interferon/stat1 pathway: role in the tumor resistance to genotoxic stress and aggressive growth. Clin Cancer Res. 2012 Jun 1; 18 (11) :3015-21.

Ranck MC, Golden DW, Corbin KS, Hasselle MD, Liauw SL, Stadler WM, Hahn OM, Weichselbaum RR, Salama JK. Stereotactic Body Radiotherapy for the Treatment of Oligometastatic Renal Cell Carcinoma. Am J Clin Oncol. 2012 Aug 2.

Lussier, YA, Khodarev NN, Regan K, Corbin K, Li H, Khan SA, Gnerlich, J, Darga TE, Fan H, Karpenko O, Paty PB, Posner MC, Chmura SJ, Hellman S, Ferguson MK, Weichselbaum RR. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS One 2012; 7 (12): e50141. Doi:10.1371/journal.pone.0050141. Epub 2012 Dec 10.

Solanki AA, Weichselbaum RR, Appelbaum D, Farrey K, Yenice KM, Chmura SJ, Salama JK. The utility of FDG-PET for assessing outcomes in oligometastatic cancer patients treated with stereotactic body radiotherapy: a cohort study. Radiat Oncol. 2012 Dec 18;7:216.doi 10.1186/1748-717X-7-216.

Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011 Jun; 8 (6) :378-82.

Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y, Zhang Q, Khan SA, Yang X, Hasselle MD, Darga TE, Malik R, Fan H, Perakis S, Filippo M, Corbin K, Lee Y, Posner MC, Chmura SJ, Hellman S, Weichselbaum RR. MicroRNA expression characterizes oligometastasis(es). PLoS One. 2011; 6 (12) :e28650.

Khodarev NN, Roach P, Pitroda SP, Golden DW, Bhayani M, Shao MY, Darga TE, Beveridge MG, Sood RF, Sutton HG, Beckett MA, Mauceri HJ, Posner MC, Weichselbaum RR. STAT1 pathway mediates amplification of metastatic potential and resistance to therapy. PLoS One. 2009 Jun 8; 4 (6) :e5821.

Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE, Haraf DJ, Hellman S, Weichselbaum RR. An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease. Clin Cancer Res. 2008 Aug 15; 14 (16):5255-9. doi:10.1158/1078-0432.CCR-08-0358.

Macdermed DM, Weichselbaum RR, Salama JK. A rationale for the targeted treatment of oligometastases with radiotherapy. J Surg Oncol. 2008 Sep 1; 98(3):202-6. Doi:10.1002/jso.21102.

 

The Jak STAT1 axis, interferon signaling, resistance to cytotoxic therapy and metastasis (click to expand)

STAT1 is activated by interferon and other ligands such as epidermal growth factor and interleukin-6 (IL-6). Following activation, STAT1 is translocated to the nucleus and activates transcription of interferon stimulated genes (ISGs). Although activation of STAT1 by interferon is associated with anti-viral defense and tumor suppression, data emerging from our laboratory indicates that expression of the STAT1 pathway and downstream interferon stimulated genes (ISG’s) confers cellular resistance to DNA damaging agents and mediates aggressive tumor growth. Recent advances in the development of Janus-activated kinase/STAT inhibitors and peptide inhibitors specific for the individual STAT proteins provide new insights into the various effects of this pathway on tumor behavior, as well as new and potentially novel targets for cancer therapy.

The term radio-resistance is usually applied to the restoration of wild-type sensitivity to radiation in model organisms that have DNA repair defects. Clinically, the term refers to tumors that are not cured by local radiotherapy. To identify genes that mediate tumor radio resistance, we subject xenografts of a radiosensitive tumor line to repeated cycles of radiation and serial passage in animals which resulted in a selection of radio-resistant tumors. Expressional profiling of the resistant and the radiosensitive tumors identified a set of genes that were differentially overexpressed in the radio-resistant cells. Of these 49 initially identified genes, we identified 31 as interferon stimulated genes including STAT1, the apical transcription factor of this group of genes. This set of genes was designated as the interferon DNA damage signature (IRDS). Further experiments revealed that members of the IRDS are up regulated by fractionated radiation in vitro and in xenografted tumor models and expressed in human tumors. Enforced expression of STAT1 in radiosensitive lines rendered the lines radio-resistant and knock-down of STAT1 rendered the cells radiosensitive. This work has been confirmed by other investigators.  Over expression of STAT 1 also mediated resistance to doxorubicin. This work was performed in collaboration with Nikolai Khodarev (Radiation and Cellular Oncology and Ludwig Center) and Bernard Roizman (Molecular Genetics and Cell Biology)

 

Clinical translation studies of STAT and interferon stimulated genes
To evaluate the clinical significance of these experimental observations, we investigated expressional databases from a variety of different cancers. 37% of head and neck, 48% of lung, 29% of prostate, 48% of breast, and 50% of high-grade gliomas constitutively expressed interferon stimulated genes. Other investigators have similar results showing the expression of interferon stimulated genes in breast, lung, ovarian, and cervical cancer. We developed an IRDS 7-gene classifier applied to a data set of 295 patients with early stage breast cancer. The 243 patients who received adjuvant radiotherapy were analyzed for local-regional failure using Kaplan-Maier survival statistics. Results showed that the IRDS-positive patients suffered a 30% to 40% increase in local failure rate compared with IRDS-negative patients. Further analyses with independent databases are necessary to validate these results.  Chemo-resistance was also associated with overexpression of the STAT1 pathway by us and others. Analysis of the breast cancer databases with the IRDS demonstrated that patients who received adjuvant chemotherapy were significantly more likely to fail with distant metastasis and not respond to adjuvant chemotherapy when they expressed the IRDS. Thus the 7-gene IRDS has potential to be a clinical meaningful classifier in the context of a predictive (as contrasted with prognostic assay). That is, expression of these genes is likely to determine which patients will respond to cytotoxic anti-tumor therapies. This work was performed in collaboration with Nikolai Khodarev and Andrew Minn  Formerly supported by the Ludwig Center in the Radiation and Cellular Oncology University of Chicago and currently in the Dept. of Radiotherapy University of Pennsylvania)  We are evaluating the IRDS as an applied clinical test for woman undergoing treatment for breast cancer.

 

STAT1 and interferon stimulated genes and the tumor microenvironment
Colleagues have reported that chronic expression of interferons alpha and beta rendered cells radio resistant and similar data were obtained by our laboratory. Interferon can select tumor clones resistant to a toxic tumor microenvironment and concurrently to genotoxic therapy. We demonstrated this by showing that melanoma lines cultivated by serial passage or by prolonged exposure to interferon were resistant to both chemotherapeutic agents as well as radiation. These data suggest that tumor clones with STAT1 dependence resistant to a cytotoxic environment may have selective advantage to promote aggressive tumor growth. We extended our observation of this by demonstrating that melanoma cells selected for high expression of STAT1 were more highly metastatic than melanoma cells with low expression of STAT1 and that these phenotypes could be reversed by suppression of STAT1 (NN Khodarev).

 

Current research
We are performing a siRNA screen to determine which of the interferon resistant downstream genes are important and in which tumors specific ISGs mediate resistance to radiotherapy and chemotherapy. Hopefully, these studies will lead to new investigations of mechanisms of tumor resistance and eventually metastasis. We have identified surprising targets in the endogenous viral “sensing “pathway mediated in part by STING. We are intensively investigating these new targets.  These studies on tumor cell autonomous interferon signaling will be integrated with our investigations on the host response to DNA damage and the role of interferons.

 

References
Duarte CW, Willey CD, Zhi D, Cui X, Harris JJ, Vaughan LK, Mehta T, McCubrey RO, Khodarev NN, Weichselbaum RR, Gillespie GY. Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiform in a subtype-specific manner. PLoS One. 2012;7(1):e29653. Epub 2012 Jan 5.

Khodarev NN, Roizman B, Weichselbaum RR. Molecular pathways: interferon/stat1 pathway: role in the tumor resistance to genotoxic stress and aggressive growth. Clin Cancer Res. 2012 Jun 1;18(11):3015-21. Epub 2012 May 21.

Pitroda SP, Zhou T, Sweis RF, Filippo M, Labay E, Beckett MA, Mauceri HJ, Liang H, Darga TE, Perakis S, Khan SA, Sutton HG, Zhang W, Khodarev NN, Garcia JG, Weichselbaum RR. Tumor endothelial inflammation predicts clinical outcome in diverse human cancers. PLoS One. 2012;7(10):e46104. doi: 10.1371/journal.pone.0046104. Epub 2012 Oct 4.

Khodarev NN, Roach P, Pitroda SP, Golden DW, Bhayani M, Shao MY, Darga TE, Beveridge MG, Sood RF, Sutton HG, Beckett MA, Mauceri HJ, Posner MC, Weichselbaum RR. STAT1 pathway mediates amplification of metastatic potential and resistance to therapy. PLoS One. 2009 Jun 8;4(6):e5821.

Khodarev N, Ahmad R, Rajabi H, Pitroda S, Kufe T, McClary C, Joshi MD, MacDermed D, Weichselbaum R, Kufe D. Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer. Oncogene. 2010 Feb 11;29(6):920-9. Epub 2009 Nov 16.

Pitroda SP, Wakim BT, Sood RF, Beveridge MG, Beckett MA, MacDermed DM, Weichselbaum RR, Khodarev NN. STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect. BMC Med. 2009 Nov 5;7:68.

Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev N, Su AW, Shaikh AY, Roach P, Kreike B, Roizman B, Bergh J, Pawitan Y, van de Vijver MJ, Minn AJ. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci USA. 2008 Nov 25;105(47):18490-5. Epub 2008 Nov 10.

 

PUBLICATIONS

Leong H, Mathur PS, Greene GL 2008, Inhibition of mammary tumorigenesis in the C3(1)/SV40 mouse model by green tea. Breast cancer research and treatment 107:359-369.

Nettles KW, Bruning JB, Gil G, Nowak J, Sharma SK, Hahm JB, Kulp K, Hochberg RB, Zhou H, Katzenellenbogen JA, Katzenellenbogen BS, Kim Y, Joachmiak A, Greene GL 2008. NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nature chemical biology 4:241-247.

Nettles KW, Gil G, Nowak J, Metivier R, Sharma VB, Greene GL 2008. CBP Is a dosage-dependent regulator of nuclear factor-kappaB suppression by the estrogen receptor. Molecular endocrinology 22:263-272.

Leong, H., Mathur, P.S., and Greene, G.L. 2009. Green tea catechins inhibit angiogenesis through suppression of STAT3 activation. Breast cancer research and treatment 117, 505-515.

Walker, M.P., Zhang, M., Le, T.P., Wu, P., Laine, M., and Greene, G.L. 2011. RAC3 is a pro-migratory co-activator of ERalpha. Oncogene.

Romero, I.L., Lee, W., Mitra, A.K., Gordon, I.O., Zhao, Y., Leonhardt, P., Penicka, C.V., Mui, K.L., Krausz, T.N., Greene, G.L., et al. 2011. The effects of 17beta-estradiol and a selective estrogen receptor modulator, bazedoxifene, on ovarian carcinogenesis. Gynecol Oncol.

Bockhorn, J., Dalton, R., Nwachukwu, C., Huang, S., Prat, A., Yee, K., Chang, Y.F., Huo, D., Wen, Y., Swanson, K.E., et al. 2013. MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nature communications 4, 1393.

Balbas, M.D., Evans, M.J., Hosfield, D.J., Wongvipat, J., Arora, V.K., Watson, P.A., Chen, Y., Greene, G.L., Shen, Y., and Sawyers, C.L. (2013). Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2, e00499.

Schmitt AM, Crawley CD, Kang S, Raleigh DR, Yu X, Wahlstrom JS, Voce DJ, Darga TE, Weichselbaum RR, Yamini B. p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage. Mol Cell. 2011 Dec 9; 44 (5) :785-96.

Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009 Jul 16; 114 (3) : 589-95.

Corbin KS, Hellman S, Weichselbaum RR. Extracranial oligometastases: a subset of metastases curable with stereotactic radiotherapy. J Clin Oncol. 2013 Apr10;31(11):1384-90. doi:10.1200/JCO.2012.45.9651. Epub 2013 Mar 4.

Lussier, YA, Khodarev NN, Regan K, Corbin K, Li H, Khan SA, Gnerlich, J, Darga TE, Fan H, Karpenko O, Paty PB, Posner MC, Chmura SJ, Hellman S, Ferguson MK, Weichselbaum RR. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLoS One 2012; 7 (12): e50141. Doi:10.1371/journal.pone.0050141. Epub 2012 Dec 10.

Liauw SL, Connell PP, Weichselbaum RR. New paradigms and future challenges in radiation oncology: an update of biological targets and technology. Sci Transl Med. 2013 Feb 20; 5(173): 173sr2. doi:10.

Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev N, Su AW, Shaikh AY, Roach P, Kreike B, Roizman B, Bergh J, Pawitan Y, van de Vijver MJ, Minn AJ. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci USA. 2008 Nov 25;105(47):18490-5. Epub 2008 Nov 10.