SPECIAL MEETING RECAP
Scientific Highlights from UCCCC at AACR Meeting
The University of Chicago Comprehensive Cancer Center (UCCCC) researchers interacted with over 17,000
individuals representing more than 70 countries at the
2012 American Association for Cancer Research (AACR)
Annual Meeting held March 31st - April 4th at McCormick Place. The 103rd Annual Meeting showcased every
aspect of cancer research from molecular biology to
clinical studies, and from prevention to survivorship,
exemplifying this year’s theme, “Accelerating Science:
Concept to Clinic.” UCCCC investigators shared their
progress toward advancing personalized cancer care and
forged new collaborations as they learned of their colleagues’ discoveries through participation in hundreds of
presentations, symposia, and workshops.
Meet-the-Expert Sessions
Three UCCCC members held Meet-the-Expert sessions,
providing overviews of important cancer topics in their
respective fields. UCCCC Director Michelle Le Beau,
PhD, Arthur and Marian Edelstein Professor of Medicine,
shared her expertise on genetic pathways contributing
to therapy-related myeloid leukemias, which arise in apMcCormick Place
proximately 10% of
patients who have
undergone cytotoxic chemotherapy
and radiation for a
primary cancer or
immunologic disorders. The incidence
of this disease is
increasing as a result
of improvements in
the long-term survival of patients with
cancer. In a series
of 380 patients with
therapy-related myeloid leukemias at the University of Chicago, Dr. Le Beau
observed a median survival of 8 months. Her investigations have revealed that early genetic events involving
the loss of more than one gene located on chromosome
5q, including EGR1, HSPA9, CTNNA1, APC, and RPS14, are
required for leukemogenesis. Her research is beginning
to identify specific combinations of genes that contribute to therapy-related neoplasms. Leading a team of
UCCCC researchers, Dr. Le Beau is developing a global
profile of genetic abnormalities and cooperating mutations that underlie the disease, as well as genetic factors
that increase disease susceptibility.
Mark Ratain, MD, Leon O. Jacobson Professor of Medicine, director of the Center for Personalized Therapeutics, and UCCCC associate director for clinical sciences,
described the development and implementation of pharmacogenomic diagnostics. Under the auspices of the
University of Chicago’s Center for Personalized Therapeutics, the 1200 Patients Project is building an information technology platform that provides virtual pharmacogenomic consults by integrating clinical information
with an individual’s genetic profile to help predict variability in the response to drugs, including chemotherapy
agents. The use of such a genomic prescribing system in
routine patient care has the potential to improve treatment decisions, which will improve drug efficacy and
minimize toxicity on an individualized basis.
Dorothy Sipkins, MD, PhD, assistant professor of medicine, shared her insight on the leukemia bone marrow
niche, a distinct environment within the bone marrow
that plays a key role in leukemia progression. Hematopoietic stem cells (HSCs) engraft in highly specific niches
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that regulate growth and differentiation, including
osteoblastic and vascular niches, which are defined by
their association with particular stromal cell types and
secretion of specific signaling molecules. Using a mouse
model, Dr. Sipkins has demonstrated that leukemic stem
cells, which are derived from HSCs, preferentially metastasize to vascular niches expressing stromal cell-derived
factor-1 (SDF-1). Leukemic stem cells also create malignant niches that prevent the normal functioning of HSCs.
Emerging therapeutic efforts are focused on intercepting leukemia-niche interactions.
Symposia
In a major symposium focused on next-generation therapeutics, Anthony Kossiakoff, PhD, professor of biochemistry and molecular biology, presented his work on the
delivery of synthetic antibodies to cytoplasmic targets.
Through extensive studies, he has developed synthetic
antigen binders (sABs), a new class of “designer” affinity reagents that recognize specific protein surfaces,
which are more cost effective and faster to produce
than monoclonal antibodies. Antibodies have traditionally been directed against targets on the cell surface
because they cannot penetrate the cell membrane. To
overcome this limitation, Dr. Kossiakoff developed an
efficient method using a ligand-receptor system that
facilitates delivery of sABs into the cell cytoplasm. These
reagents can be programmed to carry out a wide range
of functions once delivered to the cell interior, including
live cell imaging and inhibition of signaling pathways for
therapeutic purposes. To demonstrate the approach,
Dr. Kossiakoff generated a set of sABs tailored to induce
structural changes in the cell cytoskeleton. Introduction
of these sABs into cancer cells resulted in decreased cell
viability, demonstrating their therapeutic potential.
Brandon Pierce, PhD, assistant professor of health
studies, described his work on arsenic metabolism and
toxicity in a minisymposium covering genetic markers
of cancer risk and survival. In collaboration with Habibul
Ahsan, MBBS, MMedSc, UCCCC associate director for
population research and professor of health studies,
medicine, and human genetics, he conducted the first
genome-wide association study (GWAS) to investigate
the genetic determinants of arsenic metabolism and
gene interactions influencing the risk for arsenic-related
pre-malignant skin cancer. From an examination of over
1,300 Bangladeshi individuals exposed to arsenic in
drinking water, Dr. Pierce identified five genetic variants near the arsenite methyltransferase (AS3MT) gene
that are associated with the urinary arsenic metabolites
monomethylarsonic acid (MMA) and dimethylarsinic acid
The theme of the AACR Annual Meeting 2012, “Accelerating Science: Concept to Clinic,” reflected the synergy between basic,
clinical, and translational research that will continue to lead to
effective cancer therapies and prevention strategies.
(DMA). In a follow-up study, he demonstrated that one
of these five variants is associated with an increased risk
for arsenic-induced skin lesions, implicating the AS3MT
variant as a genetic marker in both arsenic metabolism
and toxicity.
Special Sessions
Mark Ratain, MD, Leon O. Jacobson Professor of Medicine, director of the Center for Personalized Therapeutics, and UCCCC associate director for clinical sciences,
chaired and presented at a “Regulatory Science Policy”
session addressing regulatory issues associated with the
co-development of therapeutics and their companion
diagnostic device (or test), also known as in vitro diagnostics. Companion diagnostics help distinguish patients
with biomarkers who are more likely to respond to a
given treatment. The FDA recently approved the cancer
drugs, crizotinib and vemurafenib, and their companion diagnostics (test for ALK expression in non-small
cell lung cancer and the BRAF V600E mutation in melanoma, respectively). However, regulatory uncertainties
surrounding the co-development of therapeutics and
diagnostics present challenges to develop personalized
therapies. For example, it remains unclear whether the
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cancer cells arise from the fallopian tube epithelium and
implant on the ovary as a secondary site. Contrary to
the current paradigm of the ovarian epithelial surface
serving as the primary site of origination, this model, if
confirmed, will have implications on the detection and
treatment of the disease.
The meeting brought together more than 18,000 attendees to discuss the latest advances in cancer research.
FDA will delay the approval of a drug if its companion diagnostic lacks sufficient validation, if the FDA will require
drug testing in biomarker-negative patients, or if the
FDA will require approval of existing companion diagnostics that are already considered standard-of-care. These
uncertainties present particular challenges for oncology
clinical trials that require the use of such diagnostics.
In a session on “Current Concepts and Controversies
in Organ Site Research,” Hedy Kindler, MD, associate
professor of medicine, gave an update on the progress
of clinical trials testing personalized therapies for mesothelioma. Current approaches in personalized medicine
include molecular profiling to assess disease prognosis
and developing biomarkers for the selection of patients most likely to benefit from therapy. For example,
researchers have developed a four-gene expression
ratio test that is highly predictive of overall survival in
patients undergoing surgery for mesothelioma. More
recently, studies have indicated that BRCA1 may serve
as a predictive biomarker for therapeutic response to
vinorelbine in malignant pleural mesothelioma. Similarly,
new evidence suggests that activating EGFR mutations
may predict therapeutic response; a new Phase II trial at
UChicago will examine vinorelbine response in patients
with these mutations. Key challenges toward developing personalized therapies include determining whether
the therapeutic target drives progression of the disease,
and whether the subpopulation of patients most likely to
benefit from therapy can be readily identified.
Bernard Roizman, ScD, Joseph Regenstein Distinguished
Service Professor of Molecular Genetics and Cell Biology,
and Biochemistry and Molecular Biology, presented an
overview of strategies for the clinical development of
oncolytic viruses in cancer therapeutics. Current research is focused on genetically modifying these viruses
into more potent and tumor-specific agents for direct tumor cell destruction or delivery of anticancer agents. Approaches include the development of attenuated viruses
with impaired ability to replicate in normal cells, viruses
retargeted against specific cellular proteins, and viruses
that enhance local immune response against tumors.
Fourteen clinical trials testing the use of herpes simplex
virus (HSV) as a therapeutic agent were completed
between 2000 and 2010. For example, a conditionally
replicating derivative of HSV type 1, known as G207,
showed anti-tumor activity in a Phase I trial of patients
with malignant glioma. These advances are anticipated
to establish HSV therapy as an important modality for
cancer treatment.
In addition to these talks, UCCCC members shared their
expertise in cancer biology and genetics, pharmacogenomics, and tumor immunology through dozens of
poster presentations. Altogether, these works exemplify
the UCCCC’s commitment to accelerating personalized
cancer therapeutics and interventional strategies for
cancer prevention as the standard of medical care.
Forums and Poster Presentations
UCCCC members also participated in open forums to
discuss current topics in cancer research. Ernst Lengyel,
MD, PhD, associate professor of obstetrics and gynecology, presented recent findings supporting a new model
of serous ovarian carcinogenesis, which proposes that
UChicago researchers displayed dozens of poster presentations.
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