Cancer - BWH Research Day

3RD ANNUAL
RESEARCH DAY
ABSTRACT BOOKLET
CANCER
MILLER ATRIUM
112 PERIODONTAL BONE LOSS AND RISK OF EPITHELIAL OVARIAN CANCER
Ana Babic, PhD
Ana Babic, Elizabeth M. Poole, Kathryn L. Terry, Daniel W. Cramer, Ricardo P. Teles, Shelley S. Tworoger
Ovarian cancer is the 5th cause of cancer deaths in the United
States. Due to its late diagnosis and poor availability of treatment
options, the ovarian cancer survival is relatively low – about 44 %
in 5 years. In order to be able to design appropriate prevention
and screening strategies, it is crucial to identify factors that lead to
ovarian cancer. One of the proposed hypotheses is that high levels
of inflammation could increase risk of ovarian cancer. Periodontal
disease is a chronic disease that affects more than 40% of adult
US population. It affects the structures supporting teeth, such as
gums and bones, and can lead to tooth loss. It was shown that
periodontal disease sufferers have increased levels of inflammation.
We therefore hypothesized that due to underlying inflammation
periodontal disease could be associated with higher risk of ovarian
cancer. We tested this hypothesis among 60,560 participants of the
large US-based study (Nurses Health Study). Contrary to our original
hypothesis, we observed that women with periodontal bone loss,
in particular women younger than 69 years, have decreased risk of
ovarian cancer, even though this association has not reached statistical significance.
Periodontitis, a chronic inflammatory reaction to changes in the oral microbiome, is common in the adult population in the United States. It is associated
with increased risk of several medical conditions, including cardiovascular
diseases, and potentially with lung, oral and pancreatic cancer. One of the proposed mechanisms behind these associations is systemic inflammation, which
has also been implied in ovarian cancer etiology. In this study we investigated
association between periodontal bone loss, a marker of severe periodontitis,
and risk of epithelial ovarian cancer among 60,560 participants of the Nurses’
Health Study. Contrary to our hypothesis, we observed a non-significant, 14%
(95% CI: 0.64-1.15) decrease of overall ovarian cancer, and a 24% (95% CI:
0.53-1.09) decrease in risk for serous/poorly differentiated tumors. The association was suggestively different among women younger than 69 years (HR:
0.61, 95% CI: 0.36-1.00), compared to those older than 69 years (HR: 1.11,
95% CI: 0.76-1.62, p-heterogeneity=0.06). The number of natural teeth and
number of root canals, which are other markers of oral health, were not associated with ovarian cancer risk. The unexpected observation of periodontal bone
loss being inversely associated with ovarian cancer risk needs to be confirmed
in independent populations.
113 FIBULIN-3 REGULATES CANONICAL NFKB SIGNALING IN GLIOMA CELLS AND SURROUNDING STROMAL CELLS TO
PROMOTE TUMOR INVASION
Nandhu Mohan-Sobhana, PhD
Nandhu Mohan-Sobhana, Aneta Kwiatkowska, Mariano S. Viapiano
Fibulin-3 is a protein produced in malignant brain tumors (glioblastomas) that is absent in normal brain. We have previously demonstrated that fibulin-3 increases tumor invasion and resistance to
therapy, and have focused in studying the molecular mechanisms of
this protein in order to target it. Here, we demonstrate that fibulin-3 activates a major mechanism known as NFkB pathway, which
regulates tumor growth, invasion, and inflammation in the tissue
surrounding the tumor. Our results suggest that this mechanism underlies the effects of fibulin-3 and may be disrupted when fibulin-3
is targeted in brain tumors. Therefore, targeting fibulin-3 could have
important applications for long-term glioblastoma therapy.
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Fibulin-3 is an extracellular matrix protein secreted by glioma cells but absent
from normal brain, which increases tumor invasion and resistance to apoptosis.
Here we show that fibulin-3 activates canonical NFkB by TNF-alpha-dependent
and Notch-dependent mechanisms, both in glioma and surrounding normal
cells in the brain. In vitro gain- and loss-of-function experiments demonstrated
that fibulin-3 activates the classical NFkB cascade and regulates expression of
NFkB-downstream genes (MMP9, MMP13, TNC, MLCK, VEGF). Further analysis
demonstrated that fibulin-3 activates the TNF-alpha convertase ADAM17 that
releases soluble TNF-alpha to activate NFkB. At the same time, fibulin-3 downregulated the expression of the deubiquitinase CYLD, which is regulated by
Notch and inhibits canonical NFkB signaling. Fibulin-3-overexpressing tumors
were larger and more invasive than controls, and showed increased expression
of NFkB/p65 in the tumor stroma and tumor-associated astrocytes. In agreement, knockdown of NFkB/p65 reduced the pro-invasive effects of fibulin-3,
suggesting that this pathway mediates the effects of fibulin-3 in glioma. Taken
together, our results suggest that NFkB is a novel major mechanism triggered
by fibulin-3 in glioma cells and their microenvironment, and underlies the proinvasive role of this ECM protein.
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114 IMPACT OF PHYSICAL FORCES ON 3D OVARIAN CANCER BIOLOGY: TARGETING FLOW-INDUCED EMT, CELLULAR
HETEROGENEITY AND BIOMARKER MODULATION
Imran Rizvi, PhD
Imran Rizvi, PhD; Umut Gurkan, PhD; Savas Tasoglu, PhD; Nermina Alagic, MD; Lawrence B. Mensah, PhD; Zhiming Mai, PhD; Jonathan P. Celli, PhD; Michael Glidden, BS; Sriram Anbil, BS;
Utkan Demirci, PhD and Tayyaba Hasan, PhD
The biological characteristics and treatment response of cancers
is influenced by an array of factors including flow-induced shear
stress, communication with stromal partners, and composition of the
matrix. These physical and biological cues in the cancer microenvironment play deterministic roles in the fate of metastatic tumors
and contribute to resistance and recurrence. Research platforms
that integrate these signals are critically needed to identify targeted
treatments, design mechanism-based combinations, and ultimately
to help improve the management of the most lethal cancers. Current
findings will be presented on the impact of flow and stromal communication on the biological characteristics of 3D ovarian cancer
cultures, and their susceptibility to conventional and emerging
therapies.
Many physical and biological factors influence the growth of tumor metastases
including flow-induced shear stress, stromal partner signaling, and matrix composition. Here the impact of hydrodynamic stress and stromal communication
on the biology of metastatic ovarian cancer (OvCa) is evaluated. The motivation
for this study stems from clinical observations that the most stubborn tumors
are often found in the peritoneal gutter, a region that is subjected to fluidic
stress from ascites and a common site of recurrence. A microfluidic model for
3D tumor growth is introduced to establish the role of flow on OvCa heterogeneity. Flow caused a significant increase epithelial-mesenchymal transition
(EMT) compared to non-flow controls. A transcriptionally-regulated significant
decrease in E-cadherin, with a concomitant significant increase in vimentin and
spindle-like morphology, along with a significant post-translational upregulation of epidermal growth factor receptor (EGFR) activity is observed. These
findings inform a new treatment-planning framework for cancer targeting flowinduced molecular changes. Photodynamic therapy, a light-based biophysical modality, synergizes with conventional agents including EGFR inhibitors
and could locoregionally prime resistant disease. Targeted co-delivery of the
treatments on a single construct (photoimmunotherapy) enhances selectivity
and reduces chemotherapy cycles. Future studies will validate these findings in
patient samples and will integrate heterotypic partners.
115 EFFECT OF PEG PAIRING ON CANCER-TARGETING LIPOSOMES
Phei Er Saw, PhD
Phei Er Saw, Mikyung Yu, Sangyong Jon, Omid C. Farokhzad
Nanoparticles for cancer therapy has been the hot issue since
decades ago. While some are trying to synthesize new drugs to
circumvent cancer, we are trying to optimize nanoparticles encapsulating anti-cancer drug to obtain the best therapeutic efficacy while
reducing drug side-effects. our aim is to make personalized benchto-bedside medicine that is not only effective, but improves patients
compliance as well. Among many nanoparticles, liposome is the
first FDA approved nanoparticle now being used in various cancer
therapy. Here, we try to enhance the cancer cell speicific targeting of our liposome with aptide (a potent targeting ligand specific
to tumor associated fibronectin) and to find out the best pairing
combination of poly(ethylene) glycol linker length that will result in
the most uptake of liposome in human glioblastoma cells and tumor
model. We observed that even in the same nanoparticle system, by
simply optimizing the pairing of PEG, significant improvement can
be made.
Standardized poly(ethylene glycol)-modified (PEGylated) liposomes are typically constructed using PEG with 2000 Da (PEG2000). Targeting ligands are
also generally conjugated using variously functionalized PEG2000. However,
standardized protocols used PEG2000 not because it has been optimized to
enhance tumor uptake of nanoparticles. Here, we investigated the effect of various PEG pairings—that is, PEGs for targeting-ligand conjugation and PEGs for
achieving ‘stealth’ function—on cancer cell- and tumor-targeting efficacy. A class
of high-affinity peptides (aptides) specific to extra domain-B of fibronectin
(APTEDB) was used as a model cancer-targeting ligand. We synthesized a set
of aptide-conjugated PEGylated phospholipids (APTEDB PEG2000 DSPE and
APTEDB PEG1000 DSPE) and then paired them with background PEGylated
phospholipids with diverse molecular weights (PEG2000, PEG1000, PEG550,
and PEG350) to construct various aptide-conjugated PEGylated liposomes.
Liposomes with APTEDB PEG2000/PEG1000 and APTEDB PEG1000/PEG550
pairings showed the highest uptake in EDB-positive cancer cells. Furthermore,
in a U87MG xenograft model, APTEDB PEG2000/PEG1000 liposomes retarded
tumor growth to the greatest extent, followed closely by APTEDB PEG1000/
PEG550 liposomes. Among the PEGylated liposomes tested, pairs in which
background PEG length was about half that of the targeting ligand-displaying
PEG exhibited the best performance, suggesting that PEG pairing is a key
considerations in the design of drug-delivery vehicles.
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116 BKM-120: AN ANTI-INVASIVE CANDIDATE FOR THE TREATMENT OF GLIOBLASTOMA
Maria Carmela Speranza, PhD
Maria Carmela Speranza, M.O. Nowicki, E. Antonio Chiocca and Sean E. Lawler
Glioblastoma (GBM) is the most common primary malignant
brain tumor and is one of the most lethal human cancers. GBM is
characterized by hallmarks of proliferation, angiogenesis, stemness
and invasion, and is impossible to fully resect surgically leading to
inevitable recurrence. It is widely recognized that an anti-invasive
strategy is needed, however, there is nothing available clinically. The
phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently deregulate pathways in cancer and in recent years several
PI3K inhibitors have been examined in clinical trials. BKM-120 (Buparlisib), is an oral pan-class-I PI3K inhibitor that can penetrate the
blood-brain-barrier (BBB) and is currently in phase I and II studies.
Although the PI3K pathway is known to play a role in cell migration,
surprisingly this has been overlooked in all the studies published
on PI3K-inhibitors in GBM. Because of the need for anti-invasive
approaches and the fact that BKM-120 selectively targets PI3K and
penetrates the BBB, we investigated its effects on GBM invasion
and we show that BKM-120 inhibits GBM cell migration in vitro and
in vivo. Thus, BKM-120 is a candidate BBB drug, that may be useful
as an anti-invasive therapeutic for the treatment of highly invasive
tumors such as glioblastoma.
BKM-120 is a selective pan-class I phosphatidyl-inositol-3 kinase (PI3K) inhibitor. BKM-120 can penetrate the blood-brain barrier and it is currently in clinical
trials for a several types of solid tumor. The PI3K pathway is one of the most
commonly deregulated in glioblastoma and therefore represents an important
therapeutic target. Several studies have examined the cytotoxic effects of BKM120, however, surprisingly little attention has been paid to the potential role of
PI3K in cell migration; this is a key feature of glioblastoma, and no drugs are
currently available that have been shown to prevent migration in patients. We
found that BKM-120 is a potent anti-invasive molecule in different glioblastoma cell lines analyzed in a range of in vitro cell migration assays. This effect
is clearly distinguishable from cytostatic and cytotoxic effects which occur
at higher drug concentrations and longer incubation times. The blockade of
migration was reversible, accompanied by morphological changes and pronounced alterations in both cell/cell and cell/substrate adhesion. In vivo, BKM120 led to marked alterations in tumor spread in an orthotopic xenograft. Thus,
BKM-120 is a candidate blood-brain barrier penetrant drug, that may be useful
as an anti-invasive therapeutic for the treatment of highly invasive tumors such
as glioblastoma.
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