Download Abstracts

Abstracts ............................................................................................................................ 2
Professor Jinke Cheng: Protein SUMOylation and Tumorigenesis .................... 2
Associate Professor Graham Mann: Confronting melanoma in its homeland:
lessons for multidisciplinary cancer research ..................................................... 3
Associate Professor Christine Clarke: Endocrine signalling in normal and
malignant breast .................................................................................................. 4
Professor Zeguang Han: Functional Genomics of Liver Cancer ........................ 5
Associate Professor Qihan Dong: Lipid modifying enzymes in prostate cancer 6
Professor Yingyan Yu: IPO-38 is identified as a novel serum biomarker of
gastric cancer based on clinical proteomics technology ..................................... 7
Professor Xia Pu: The role of sphingosine kinase 1 in cancer: oncogene or nononcogene addiction?............................................................................................ 8
Associate Professor Qian Zhao: Herb-derived active compounds-based
chemical biology for leukemic cells ................................................................... 9
Professor Stephen Clarke: Inter-ethnic differences in chemotherapy............... 10
Professor Fengchun Zhang: Cancer Stem Cell and its regulation .................... 11
Associate Professor Kewen Zhao: The ubiquitination of E3 ligase EFP involves
in the degradation of transcriptional factor KLF5 ............................................ 14
Professor Des Richardson: Novel and selective anti-cancer agents that
overcome resistance to established chemotherapy: the double punch .............. 15
Associate Professor Zonghai Li: Phage display: a magic tool for cancer biology
........................................................................................................................... 16
Dr Diana Benn and Professor Bruce Robinson: Hereditary phaeochromocytoma
/ paraganglioma syndromes .............................................................................. 18
Fei Yue: Identification of Novel Biomarkers Evaluating Lymph Node
Metastasis in Colorectal Cancer........................................................................ 19
Dr Lyndee Scurr: p16INK4a-induced senescence is disabled by melanomaassociated mutations ......................................................................................... 20
Mingzhu Huang: Cancer stem cell and its microenviroment............................ 21
Biographies ...................................................................................................................... 22
Shanghai Jiao Tong University School of Medicine speakers .................................. 22
Fei Yue (Ph.D. candidate) - [email protected] ................................................. 22
Professor Fengchun Zhang - [email protected] ..................................... 23
Professor Guoqiang Chen - ............................................................................... 24
Professor Jing Yi - ............................................................................................ 24
Associate Professor Kewen Zhao - [email protected] ............................ 25
Mingzhu Huang (Ph.D. candidate) [email protected] ................ 26
Associate Professor Qian Zhao -....................................................................... 27
Professor Yingyan Yu - [email protected] ........................................ 27
Professor Zeguang Han – [email protected] ................................................... 28
Associate Professor Zonghai Li - [email protected] ................................ 30
University of Sydney speakers .................................................................................. 30
Associate Professor Christine Clarke - [email protected] ... 31
Professor Des Richardson - [email protected] ........................... 32
Dr Diana Benn - [email protected]...................................................... 33
Associate Professor Graham Mann ................................................................... 33
Dr Lyndee Scurr - [email protected] ......................................... 34
Associate Professor Xia Pu - [email protected] ..................................... 37
Abstracts
Professor
Jinke
Cheng:
Protein
SUMOylation
and
Tumorigenesis
Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine
Post-translational modifiers of the small ubiquitin-like modifier protein (SUMO)
family have emerged as key regulators of protein function and localization.
SUMO modification is a dynamic process, catalyzed by SUMO-specific E1, E2,
and E3s and reversed by a family of SUMO-specific proteases (SENPs).
Although six human SENPs have been identified, each with different cellular
locations and substrate specificities, the precise roles of SENPs in cellular
processes involved has not been well-defined. We used used functional screen
to identify HDAC1 as a target protein for SENP1 desumoylation in androgeninduced androgen receptor response. SENP1 specifically and markedly enhance
androgen-induced androgen receptor activity and androgen can also increase
SENP1 expression through androgen receptor-dependent manner. We further
determined the role of SENP1 in prostate cancer development by using
transgenic mice model. Using SENP1 knockout mice, we identified another
-induced cellular
process. Interestingly, hypoxia can induce SENP1 expression, which further
enhance hypoxia response in a positive feedback loop. These findings indicates
that SENP1 plays an important role in tumor genesis.
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Associate Professor Graham Mann: Confronting melanoma
in its homeland: lessons for multidisciplinary cancer research
Westmead Millennium Institute – University of Sydney
[to come]
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Associate Professor Christine Clarke: Endocrine signalling in
normal and malignant breast
NHMRC Research Fellow, Westmead Millennium Institute, University of Sydney
The ovarian hormones oestrogen and progesterone exert fundamental control
over the female reproductive system by multiple independent and overlapping
mechanisms. They also have non-reproductive functions in tissues such as brain
and the vasculature. While aspects of their function are known through
epidemiological studies and animal and cell line models, the mechanisms of their
action in the human breast are poorly understood. This knowledge gap exists
despite the known role of ovarian hormones in breast development and function,
and in breast cancer. The causes of breast cancer are largely unknown, but the
currently accepted view is that development of invasive breast cancer requires
multiple genetic changes, with the original mutation occurring early in
reproductive life, and additional mutations accumulating over decades until
menopause, when most breast cancers are diagnosed. Although the initiating
genetic mutations are largely unknown, the pivotal involvement of ovarian
hormones has been known for over a century. Women without ovaries have a
markedly reduced breast cancer incidence, with a risk that is analogous to the
low risk of breast cancer observed in men. The underlying mechanisms by which
ovarian hormones and the endocrine milieu contribute to development of breast
cancer are not known.
The Westmead Institute of Cancer Research, based in the Westmead Milennium
Institute at the University of Sydney Western Clinical School, focusses on
research in breast cancer from several perspectives, including basic research
and a translational research focus. It also houses the national headquarters of a
Breast Cancer Tissue Bank, which supplies biospecimens for breast cancer
research to researchers throughout Australia. The studies to be described in this
presentation have used a variety of techniques, including expression profiling,
live cell imaging and related approaches in human tissues to elucidate the
cellular targets of progesterone and the mechanisms by which the nuclear
progesterone receptor regulates transcription. The results of these studies
demonstrate
a
critical
relationship
between
nuclear
organisation
and
transcriptional activity in the progesterone signalling axis, and point to
mechanisms by which this is disrupted in cancers. Identification of such
mechanisms may lead to further understanding of critical pathways and cellular
vulnerabilities in the development of breast cancer.
------------------------------------------------------------------------------------------------------------
Professor Zeguang Han: Functional Genomics of Liver
Cancer
Department of Functional Genomics, Shanghai Jiao Tong University
Human hepatocellular carcinoma (HCC) is one of the most common cancers
worldwide. Genome-wide survey on pathological profiles of HCC will provide
insights into hepatocellular carcinogenesis. In our work, we first figured out a
comprehensive characterization of gene expression profiles of hepatitis B viruspositive HCC through the transcriptome approaches. Notably, the altered
transcriptome profiles of HCC could be correlated to a number of chromosome
regions with amplification or loss of heterozygosity (LOH)1. Subsequently, To
investigate whether the genomic DNA copy number alterations may contribute to
primary HCC, the cDNA microarray-based comparative genomic hybridization
(CGH) analysis was performed in 41 primary HCC infected by hepatitis B virus
and 12 HCC cell lines. The resulting data showed that gains involving
chromosomes 1q, 6p, 8q and 9p were frequently observed in these cases; and
whilst, losses involving 1p, 16q and 19p occurred in most patients. Interestingly,
the genomic DNA copy number alterations of most genes appeared not to be in
generally parallel with the corresponding transcriptional expression. However, the
transcriptional deregulation of a few genes, such as osteopontin (SPP1),
transgelin 2 (TAGLN2) and PEG10, could be ascribed partially to their genomic
aberrations2. In addition, the dysregulation of the genomic imprinting genes is
known to contribute to carcinogenesis. We here investigated the expression
pattern of known imprinted genes on HCC. Interestingly, a maternal expressed
gene, ARHI, was frequently down-regulated in HCC due to the DNA
hypermethylation of its promoter, where exotic ARHI could significantly inhibit the
cell growth and colony formation. However, delta-like 1 homolog (Drosophila)
(DLK1), a paternally expressed gene, was found to be significantly up-regulated
in majority of HCC specimens. The exogenous DLK1 can significantly promote
the HCC cell proliferation, whereas the suppression of endogenetic DLK1
through RNA interference can markedly inhibit cell growth, colony formation and
tumorigenicity of HCC cells3. Recently, we employed a genome-wide approach
to screen out the epigenetically silenced tumor suppressor genes associated with
HCC. Here we pay attention to these genes mapped onto chromosome 8p, the
frequent LOH region in human HCC. A putative tumor suppressor gene, SFRP1
(the secreted frizzled-related protein 1), was significantly down-regulated in many
HCC specimens, whereas the overexpression of SFRP1 can significantly inhibit
the cell growth and colony formation of HCC cells. LOH of both microsatellite
markers flanking the gene locus and DNA hypermethylation within SFRP1
promoter were found in some HCC specimens4.
------------------------------------------------------------------------------------------------------------
Associate Professor Qihan Dong: Lipid modifying enzymes
in prostate cancer
Head, Cancer Biology Group; Central Clinical School, The University of Sydney
Scientific Director, Department of Endocrinology, Royal Prince Alfred Hospital
Previous studies support a role for eicosanoid products of the cyclooxygenase
(COX) pathways in the proliferation of prostate cancer cells in culture and
regulation of tumour vascularisation and metastasis in animal models.
Pharmacological agents that block COX products effectively reduce the size of
prostate cancer xenografts. However, COX-2 selective inhibitors can have
thrombosis-related cardiovascular side effects. Since phospholipase A2 (PLA2)
enzymes regulate the provision of arachidonic acid for the production of
eicosanoids, we have investigated the role on PLA2 in prostate cancer. We have
demonstrated an increase in the PLA2 levels/activity and a loss of the natural
inhibitor of PLA2. Blocking PLA2 suppresses the growth of hormone refractory
prostate cancer cells and experimental angiogenesis. The mechanism underlying
the PLA2 effect is via PI3K/Akt pathways. As the activated Akt is associated with
poor clinical outcome, identification of a novel regulator of Akt activity in prostate
cancer cells has a potential to impact on clinical practice.
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Professor Yingyan Yu: IPO-38 is identified as a novel serum
biomarker of gastric cancer based on clinical proteomics
technology
Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University
Gastric cancer is one of the most common malignancies in China. So far, there
are few reliable serum biomarkers for early diagnosis and prognostic prediction.
The available biomarkers of CEA, CA19-9 and CA72-4 are not sufficiently
sensitive and specific for gastric cancer. In this study, a high density antibody
microarray was used for identifying new biomarkers from serum samples of
gastric cancer. Serum samples from colorectal cancer, pancreatic cancer,
hepatocellular cancer and breast cancer were also screened for comparative
study. As result, some candidate biomarkers including 45 up-regulated and 6
down-regulated in serum sample of gastric cancer were found out. IPO-38, one
of up-regulated serum proteins in gastric cancer was selected for subsequent
validation including serum IPO-38 expression by ELISA, IPO-38 protein
expressing status by immunohistochemical localization. The immunoprecipitation
by IPO-38 for gastric cancer cell line and MALDI–TOF/TOF mass spectrometer
suggested that pull-down of IPO-38 belongs to H2B histone, which was
supported by co-localization study of laser scanning confocal microscope.
Follow-up study showed that survival rate of IPO-38 negative group was better
than that in IPO-38 positive group. The study firstly clarified the property of IPO38 proliferating marker, and proposed that IPO-38 protein is a promising serum
biomarker both for diagnosis and for predicting prognosis of gastric cancer.
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Professor Xia Pu: The role of sphingosine kinase 1 in cancer:
oncogene or non-oncogene addiction?
Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney
Since we for the first time reported an oncogenic potential of sphingosine kinase1 (SphK1) (Xia, et al. Current Biology, 2000), an increasing body of evidence has
suggested a critical pathogenic role for SphK1 in a variety of human cancers.
Upon activation, SphK1 catalyses the formation of sphingosine 1-phosphate
(S1P) that serves as important signaling molecule in regulating cell survival,
proliferation, differentiation, cellular motility and evasion of apoptosis, all key
cellular processes in cancer development and progression. Over the past decade,
our group has focused on understanding the activation mechanism of SphK1 and
its role in cancer. We have demonstrated that the oncogenic activity of SphK1
entirely relies on its phosphorylation-dependent translocation to the plasma
membrane beyond the enzymatic activity (Pitson, et al. JEM, 2005), and that this
pathway can be activated by a wide variety of oncogenes or oncogenic factors.
For instance, the steroid hormone estrogen has long been recognized as a key
risk factor for the pathogenesis of breast cancer. We found that estrogen is a
strong activator of SphK1 and that SphK1 is capable of transmitting estrogen
signals to its mitogenic activity in human breast cancer cells (Sukocheva, et al.
Mol. Endocrinol, 2003). Furthermore, SphK1 plays a central role to mediate the
GPCR-EGFR transactivation in response to estrogen stimulation, revealing a
new
signaling
mechanism
whereby
SphK1
couples
three
individual
ligand/receptor systems, leading to activation of multiple mitogenic signal
pathways in a coordinative manner to promote neoplastic cell growth (Sukocheva,
et al. J. Cell Biol. 2006). More recently, our work shows that inhibition of the
SphK1 pathway by either genetic means or chemical inhibitors resulted in not
only arrest of cell growth, but also sensitizing the breast cancer cells to the
antiestrogen therapy, leading to cell death. Interestingly, blocking of the
SphK1/S1P pathway is also capable of restoring sensitivity of the resistant cells
to the drug killing effect, revealing a new way to overcoming endocrine resistance
in breast cancer. Thus, further elucidating the details of SphK1/S1P signaling,
especially in clinical relevant settings, could provide a potential interventional
target for the management of various cancers, such as breast cancer.
------------------------------------------------------------------------------------------------------------
Associate
Professor
Qian
Zhao:
Herb-derived
active
compounds-based chemical biology for leukemic cells
Department of Pathophysiology, Shanghai Jiao Tong University
Cumulative evidence indicates that traditional Chinese Medicine (TCM) is an
important resource for discoveries of drugs against cancers. In the past year, we
screened some small molecular compounds frm TCM herbs for leukemic cell
differentiation. We found that SSMU55, a small molecular compound isolated
from Isodon forrestii in Lijiang, China, can potentiate the differentiation-inducing
effect of low-dose （ 10-8M ） all- trans retinoic acid (ATRA) in acute myloid
leukemic(AML) cell lines NB4 and U937 cells. Furthermore, the differentiationinducing effect of these two reagents is not limited to ATRA-sensitive NB4 cells,
the combination of these two reagents can also induce the differentiation of NB4LR1 and NB4-MR2 cells, which are subtypes of NB4 cells resistant to ATRAinduced differentiation. More intriguingly, the treatment of NB4 and U937 cells
with SSMU55 alone or with the combination of SSMU55 and ATRA obviously
upregulate the RAR and PML-RAR protein. The up-regulation of these two
protein are also appeared in the ATRA-resistant NB4-LR1，NB4-LR2 and NB4MR2 cells after the same treatment. Moreover, SSMU55 dose not change the
mRNA level of RAR in these cells, while the half-life of RAR protein appeared
to be far longer, suggesting that the up-regulation of RAR protein is caused by
the decreased degradation of this protein. Taken together, our results suggest
that SSMU55 is a potential agent for the treatment of AML, especially in the
ATRA-resistant AML cells.
------------------------------------------------------------------------------------------------------------
Professor
Stephen
Clarke:
Inter-ethnic
differences
in
chemotherapy
Medial Oncology, Concord Hospital, University of Sydney
Even under optimal circumstances there is widespread inter-patient variability in
toxicity from chemotherapy. This means that for the same dose of treatment one
patient may experience minimal toxicity, while another may develop lifethreatening toxicity.
Many factors may contribute to differences in toxicity
including organ dysfunction, genetic variability in levels of drug metabolising
enzymes and drug interactions from concomitant medications used to treat
intercurrent illnesses. Increasingly, there has been identification of inter-ethnic
differences in drug tolerance, which in oncology have been best characterised
between Caucasians and African-Americans.
However, there are compelling
data to suggest that similar, if not greater, differences may exist between patients
of Asian and Caucasian origin.
Several studies have demonstrated major
differences in chemotherapy induced myelosuppression after treatment for both
early and advanced cancers of different tissue origins.
exploring
possible
explanations
for
these
differences,
We are currently
by
undertaking
pharmacogenetic, pharmacokinetic, nutritional and inflammatory analyses.
------------------------------------------------------------------------------------------------------------
Professor Fengchun Zhang: Cancer Stem Cell and its
regulation
Department of Oncology, Renji Hospital, Shanghai Jiao Tong University
More and more evidence suggests that breast cancer stem cells (BCSCs) play a
critical role in both initiation and relapse during tumorigenesis of breast cancer.
They display more resistant to chemotherapeutical agents which might be
account for the failure to clinical treatment. It is hypothesized that cancer stem
cells arise either from normal stem cells or from progenitor cells that have
obtained the ability to self-renew. These cells reside in side population(SP) and
belong to CD44(+)CD24(-/low) population. To explore the abnormal signalling
pathways involved in BCSCs, we isolated SP from breast cancer cell line MCF-7
to identify stem cell-like features. Furthermore, we analyzed the xenograft tumors
forming ability in NOD/SCID mice, and cultured mammospheres that expressed
several stem cell markers. We also explored the regulatory effect of cancer
stromal cells and the role of oncolytic adenoviruses E1B protein deficient virus,
which presents an anti-tumor approach for eradication of BCSCs. Methods: We
used flow cytometry(FCM) and the DNA-binding dye (Hoechst 33342) in the
presence of verapamil to isolate side population (SP) cells from human breast
cancer cell lines. MCF-7 cells were examined by fluorescence microscope after
stained with Hoechst33342 and CFSE. We detected the expression of bcrp,
cyclinD1, CXCR4, Notch1, Jagged-1, notch3, SOX2, PTEN and HIF-1α by RTPCR and cell cycle by FCM. SP or MP were injected into NOD/SCID mice for in
vivo self-renewal analysis. MCF-7 breast cancer cells were cultured in
suspension(bFGF、EGF、B27and Insulin) to generate primary and secondary
mammospheres.
CD44,
CD24
and
CD55
expression
and
β-
catenin,CXCR4,SOX2,and ALDH3A1 mRNA expression of cells derived from 11day-old secondary mammosphere cells or differentiated cells were detected.
After co-culture with stromal cell via transwell, the expression of Wnt1 ， βcatenin，Notch1 in SP and MCF-7 were detected; and the effect of migration on
MCF-7 by cancer stromal cells was detected as well. Then we infected MCF-7
cells with oncolytic adenoviruses E1B protein deficient virus, the proportions of
CD44+ ， CD24- ， CD44+CD24- cells were analysed. The infected and cocultured cells were cultured to observe the sizes and numbers and the time of
mammosphere's formation, calculate the mammosphere-forming efficiency(MFE).
Results: MCF-7 cell line contained 2~4% SP cells. The expressions of bcrp,
CXCR4, Notch1, Jagged-1, notch3, PTEN and HIF-1α were higher in SP cells.
The MP of MCF7 cells expressed higher levels of cyclinD1and SOX2 than the SP
cells. The percentage of G0/G1 in SP was the highest among SP、MP and
unsorted cells. Only 103 SP cells could give rise to tumor. Only 2 tumors were
observed in mice injected with MP cells. The proportions of CD44＋CD24－/low
and CD55highpopulation were higher in mammospheres than MCF-7 cultured on
collagen substrate, 12.05±1.00 ％ vs 4.51％±0.86 ％ and 17.41％ ±1.09 ％ vs
4.47％±0.33％, respectively。The Real-time PCR results indicated that there
was increased gene expression of β-catenin、CXCR4、SOX2、ALDH3A1 for
mammospheres than control group. Cancer stromal cells enhanced the migration
of MCF-7. The expressions of Wnt1 ， Notch1 in co-culture group were
upregulated 2.09、3.75 respectively; however down-regulation of β-catenin to
0.31. 5d Co-culture of MCF-7 mammosphere and fibroblasts via Transwell, the
sphere-formation and volume were higher in the test group than control group.
The maximum diameter of test group was 180－225um, the other one was 100－
160um.The proportions of CD44+, CD24-, CD44+CD24- in the H101 infected
gruop were 48.99%，83.82%，32.44%. They were higher than the proportions in
the control group 5.56% ， 72.71% ， 1.11%. In expriment group, the time of
mammosphere's formation was earlier than in control group; the size of
mammospheres were bigger than in control group. MFE was higher than control
group(1.26%:0.9%).
In
two
mammosphere
groups,
the
proportions
of
CD44+CD24- in experiment group was38.08%，the control group was 23.35%.
Conclusion: In this study, we isolate side population cells with stem-cell
properties from the human breast cancer cell line MCF7 successfully and
established and characterized a sphere culture model derived from SP. The
sphere culture could be maintained long term and was enriched in cells
expressing known breast cancer stem cell marker CD44(+)CD24(-).The SP and
mammosphere cells showed higher stem cell marker gene expression and higher
tumorigenicity in vivo than MCF7 cells. The microenviroment of the breast cancer
play key roles during tumorigenesis. Our data support the study of the tumor
microenviroment as a putative therapeutic target for breast cancer. oncolytic
adenoviruses E1B protein deficient virus can kill MCF-7 cells effectively in short
time. And it possibly can reduce the speed of self-renew in breast cancer
initiating cells. The research of breast cancer stem cells signals the beginning of
a new era of breast cancer research. To our knowledge, the efforts to elucidate
molecular differences between normal and cancer stem cells are expected to
produce promising approach to targeted causal therapy of malignant tumors.
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Associate Professor Kewen Zhao: The ubiquitination of E3
ligase EFP involves in the degradation of transcriptional
factor KLF5
Department of Pathophysiology, Shanghai Jiao Tong University
The transcription factor Kruppel-like factor 5 (KLF5) involves in many biological
processes, such as human carcinogenesis, angiogenesis, and smooth muscle
cell differentiation. In the previous study(1), we found that KLF5 might serves as
a tumor suppressor gene in human breast cancer, but the basal expression level
of KLF5 in these cells is nearly undetectable, while depleting estrogen from the
culture medium could stabilize KLF5. To better understand the mechanisms for
the regulation of KLF5 protein in breast cancer cells, we identified an estrogeninducible responsive RING finger protein (EFP), which is an E3 ubiquitin ligase
for 14-3-3(2), could degrade KLF5. Both exogenous and endogenous EFP
could form a protein complex with KLF5, and EFP could interact with KLF5
through more than one domain except RING finger domain. Chase assay and
proteasome inhibitor assay showed that EFP could degrade KLF5 through
proteasome pathway. Surprisingly, E3 ligase EFP could not ubiquitinate KLF5;
on the contrary, the ubiquitination of EFP itself could increase. To further
elucidate the degradation mechanism, we mutated different amino acids which
involve in the modification of EFP and found that Cysteine 50 and 53 in RING
finger domain of EFP play an important role in the degradation of KLF5 and C50,
53S mutation can abolish the interaction and degradation effect of EFP. These
findings established that E3 ligase EFP could degrade KLF5 through proteasome
pathway, and it is the ubiquitination of EFP instead of KLF5 contributes to the
degradation of KLF5, which shed new light on the proteasome degradation
mechanism.
------------------------------------------------------------------------------------------------------------
Professor Des Richardson: Novel and selective anti-cancer
agents
that
overcome
resistance
to
established
chemotherapy: the double punch
Cancer Cell Biology & NHMRC Principal Research Fellow, University of Sydney
Novel chemotherapeutics with marked and selective anti-tumour activity are
essential to develop, particularly those that can overcome resistance to
established agents. Iron (Fe) is a crucial nutrient required for cell cycle
progression and DNA synthesis and represents a novel molecular target for the
design of new anti-cancer drugs. The aim of this current study was to evaluate
the anti-tumor activity and Fe chelation efficacy of a new class of Fe chelators,
namely the d-2-pyridylketone thiosemicarbazone (DpT) series of ligands.
Our studies using these chelators (Whitnall, M. et al. (2006) PNAS USA
103(20):7670-7675) demonstrated broad anti-tumor activity in 28 different tumor
cell lines. Moreover, the compounds could overcome resistance to established
anti-tumor agents. The in-vivo efficacy of the most effective chelator identified,
Dp44mT, was assessed using a panel of human xenografts in nude mice. These
tumours included melanoma, lung carcinoma, ovarian carcinoma and brain
(neuroepithelioma). After 7 weeks, net growth of a melanoma xenograft in
Dp44mT-treated mice was only 8% of that in mice treated with vehicle. In
addition, no differences in these latter animals were found in hematological
indices between Dp44mT-treated mice and controls.
No marked systemic Fe-depletion was observed comparing Dp44mT- and
vehicle-treated mice, probably due to the very low doses (0.4-0.75 mg/kg/day)
required to induce anti-cancer activity. Interestingly, Dp44mT caused upregulation of the Fe-responsive tumor growth and metastasis suppressor, N-myc
downstream regulated gene-1, Ndrg1, in the tumor but not the liver, indicating a
potential mechanism of selective anti-cancer activity.
Further studies indicated that the potent anti-tumour activity of the DpT chelators
was due to the intracellular formation of a redox-active Fe complex (Richardson,
D.R. et al. (2006) J. Med. Chem. 49:6510-6521). Indeed, the high efficacy of
these compounds was related to the “double punch“ mechanism. That is, the
ability of the chelator to bind Fe which is essential for tumour cell growth followed
by the redox cycling of the Fe complex to generate cytotoxic free radicals.
Further studies by our group led to the design and synthesis of even more
effective agents known as the BpT series of chelators (Kalinowski, D et al. (2007)
J. Med. Chem. 50:3716-3729). Again, the efficacy of these latter compounds is
related to their ability to form a redox-active Fe complex.
In summary, these results indicate that the novel Fe chelators have potent and
broad anti-tumor activity and can overcome resistance to established
chemotherapeutics due to their unique mechanism of action.
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Associate Professor Zonghai Li: Phage display: a magic tool
for cancer biology
State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong
University
Phage display has been widely used in cancer biology now.
First, phage display has been successfully applied to identify numerous cancer
cell targeting peptide ligand. For example, we have identified a peptide ligand
named as GE11 that can bind efficiently to epidermal growth factor receptor
(EGFR). When conjugated with polyethyleneimine, GE11 peptide can deliver
reporter gene into EGFR over-expressing cancer cell line1.
Second, phage display can be used to obtain antibody fragment against cancer
associated antigen. There are some problems of conventional phage display
including low level of scFv display, need to prepare helper phage, need to rescue
by helper phage and pIII (protein III) resistance. Recently, we have developed a
new cell line named as Hpd3cells to overcome these problems2. Using this novel
phage display method, we have isolated several scFv (single chain variant
fragment) antibodies against EGFRvIII (variant III EGFR deletion mutant), a
mutant form of EGFR.
Last, phage can also be used as cancer gene delivery vectors. Wild type phages
are bacterial virus, can not infect mammalian cells. However, when polypeptide
ligand was displayed in phages, genes of interest carried by phages can be
transduced into target mammalian cells. Phage vectors have several advantages
such as low potential toxicity, easy preparation and genetic targeting. The major
limitation of current phage vectors lies in its low gene transfer efficiency. Recently,
we have developed a more efficient way to prepare cell-targeted phage vectors.
Ligand-pIII (ligand and pIII fusions) encoding helper phage genome was first
introduced into bacterial cells. The resulted cells named as Lmpcells3. Phagemid
carrying genes of interest was then transformed into the Lmpcells. The obtained
phagemid particles showed high level of ligand display and small size because
the phagemid need not encoding Ligand-pIII. In addition, we also found that
EGF-displaying phagemid particles can deliver siRNA efficiently in the presence
of hydroxycamptothecin, a chemical drug of cancer. When phagemid encoding
siRNA against Akt infected NCI-1299 NSCLC cell lines in the presence of
hydroxycamptothecin, the expression of Akt reduced by about 50%. Therefore,
phage vectors are also potential cancer gene delivery vectors4.
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Dr Diana Benn and Professor Bruce Robinson: Hereditary
phaeochromocytoma / paraganglioma syndromes
Senior Hospital Scientist & Senior Research Fellow, Kolling Institute of Medical
Research, University of Sydney
Dean, Faculty of Medicine, University of Sydney
Advances in the knowledge of the genetics of phaeochromocytoma have
broadened our understanding about the mechanisms of tumorigenesis.
Previously it was believed that 10% of phaeochromocytomas were associated
with familial cancer syndromes, but it is now recognised that a much higher
proportion of these tumours may be familial. Phaeochromocytomas are known to
be component tumors of multiple endocrine neoplasia type 2 (MEN2), von Hipple
Lindau disease (VHL) and rarely neurofibromatosis type 1 (NF1), and are
associated with mutations in RET, VHL and NF1 genes respectively. More
recently it has been found that mutations in the genes encoding for succinate
dehydrogenase subunit B (SDHB) and subunit D (SDHD) are causative in familial
phaeochromocytoma/paraganglioma. In these cases patients may present with
phaeochromocytomas
and/or
paragangliomas
including
parasympathetic
associated head and neck paragangliomas. SDHC mutations have been
associated with familial head and neck paragangliomas and rarely with
phaeochromocytoma. Importantly it has also been recognised that 12-24%1,2 of
patients with an apparently sporadic presentation may carry a germline mutation
in RET, VHL, SDHB or SDHD genes. While the genotype/phenotype correlations
are now well described for MEN2 and VHL disease, studies are only now
emerging on these correlations for SDHB and SDHD mutation associated
disease.
The International SDH Consortium3 showed significant differences in the
estimated age of first presentation (phaeochromocytoma or head and neck
paraganglioma), that is 47 years for SDHB mutation carriers and 31 years for
SDHD mutation carriers (p=0.008). In addition, the value of genetic testing in
these families was emphasised as subsequent screening of mutation positive
relatives identified related disease in 5/38 (13%) of asymptomatic mutation
carriers. Therefore, selective genetic screening of all patients with apparently
sporadic phaeochromocytoma is recommended due to differences in penetrance
and presentation.
------------------------------------------------------------------------------------------------------------
Fei Yue:
Identification of Novel Biomarkers Evaluating
Lymph Node Metastasis in Colorectal Cancer
PhD Candidate, Department of Minimally Invasive Surgery, Ruijin Hospital,
Shanghai Jiao Tong University
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the
fourth most common cause of cancer-related death across the world. In China,
the incidence and mortality rates of CRC also rank as third and fifth respectively,
both of which still keep rising. The five-year survival rate of CRC patients with
positive lymph node metastasis is less than 50% compared to around 90% for
those negative ones, indicating that lymph node metastasis is a strong negative
prognostic factor for CRC patients. In addition, around 40% of CRC patients had
already presented lymph node metastasis at their initial diagnosis. On the other
hand, evaluation of nodal metastasis is essential for the clinicians to determine
proper pre-operative neo-adjuvant therapies as well as post-operative adjuvant
therapies, which can significantly improve the survival of CRC patients with
positive lymph nodes. However, computerized tomography as well as traditional
biomarkers, such as CEA, still could not well evaluate the situation of lymph node
metastasis in CRC patients. Our proteomic research based on clinical tissue
specimens identified a batch of twelve proteins as a proteomic signature which
could correctly classify 91.6% (11/12) samples tested. Subsequently, two
proteins were selected with bioinformatic analysis as a simplified biomarker
combination, with which 83.3% (10/12) samples were still correctly classified in
cross-validation. To conclude, this biomarker combination might have promising
potentials in clinical evaluation of lymph node metastasis in CRC patients.
------------------------------------------------------------------------------------------------------------
Dr Lyndee Scurr: p16INK4a-induced senescence is disabled
by melanoma-associated mutations
Westmead Institute for Cancer Research, Westmead Millennium Institute –
University of Sydney
The p16INK4a-Rb tumour suppressor pathway is required for the initiation and
maintenance of cellular senescence, a state of permanent growth arrest that acts
as a natural barrier against cancer progression. Senescence can be overcome if
the pathway is not fully engaged, and this may occur when p16INK4a is inactivated.
p16INK4a is frequently altered in human cancer and germline mutations affecting
p16INK4a have been linked to melanoma susceptibility. To characterize the
functions of melanoma-associated p16INK4a mutations, in terms of promoting
proliferative arrest and initiating senescence, we utilized an inducible expression
system in a melanoma cell model. We show that wild-type p16INK4a promotes
rapid cell cycle arrest that leads to a senescence program characterized by the
appearance of chromatin foci, activation of acidic ß-galactosidase activity and
p53-independence. In contrast, the p16INK4a melanoma associated variants,
R24P and A36P failed to arrest cell proliferation and did not initiate senescence.
The R24P variant is specifically defective for inhibiting CDK4 activity and we
show that overexpression of CDK4, or its homologue CDK6 inhibited the ability of
wild-type p16INK4a to promote cell cycle arrest and senescence. Our data provide
the first evidence that p16INK4a can initiate a CDK4/6-dependent autonomous
senescence program that is disabled by inherited melanoma-associated
mutations.
------------------------------------------------------------------------------------------------------------
Mingzhu Huang: Cancer stem cell and its microenviroment
PhD Candidate, Department of Oncology, Renji Hospital, Shanghai Jiao Tong
University
Recently, several human cancers including leukemia and breast and brain
tumors were found to contain stem-like cells (SLC) called cancer stem cell
(CSCs). Most of these tumorigenic SLCs were identified using markers that
identify putative normal stem cells.
Stem cells have the remarkable ability to undergo both self-renewal and to give
rise to progeny that can differentiate. This capacity, in adult stem cells, has
recently been shown to be dependent on the microenvironment or niche in which
the stem cell resides.Normal stem cells depend on a niche to provide the
necessary signals for self-renewal.Likewise, cancer cells also require a special
microenvironment to maintain cancer stem cells and to support cancer cell
growth. The BMP and Wnt pathways represent a ‘Yin-Yang’ type of controlled
balance between self-renewal and differentiation.
If cancer is organized in a manner similar to normal tissue, with a minor
subpopulation of stem cells, an attendant blood supply and a unique
microenvironment, there might be a similar dependence of the stem cells on a
cancer niche. If the components of this niche could be demonstrated and
targeted, it would be of considerable interest to modify the relative support of the
stem-like cells of cancer. The idea that the niche might be a druggable target
would be extremely appealing as an adjunctive and entirely independent means
of targeting malignant cells. Perhaps the niche will be more than a biologist’s
puzzle, and will become a guide for novel therapies to enhance the regenerative
capacity of normal stem cells and limit the malignant potential of cancerous ones.
------------------------------------------------------------------------------------------------------------
Biographies
Shanghai Jiao Tong University School of Medicine
speakers
Fei Yue (Ph.D. candidate) - [email protected]
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong
University School of Medicine
Mr. Yue graduated from Tongji University School of Medicine in 2005. After his
clinical study in thoracic surgery, visceral surgery and minimally invasive surgery
of
Großharden
Hospital,
Ludwig-Maximilian-University
München
(Munich
University), Germany, he is now pursuing his doctoral education in Ruijin
Hospital, Shanghai Jiao Tong University School of Medicine. At present he is
doing his research in the Proteomics Unit, Department of Pathophysiology,
Shanghai Jiao Tong University School of Medicine, and Key Laboratory of Cell
Differentiation and Apoptosis of Chinese Ministry of Education.
Mr. Yue’s research work to date has mainly focused on the application of
proteomics in clinical cancer research, including the identification of novel
biomarkers for cancer diagnosis and prognosis. Colorectal cancer is one of the
leading cancers across the whole world. Moreover, the patients with positive
lymph node metastasis suffered a significantly shorter survival compared to
those negative ones. Unfortunately, traditional biomarkers could not well predict
the lymph node metastasis situation. Thus, he performed proteomic and
bioinformatics analysis on clinical colorectal cancer specimens for the
identification of the novel biomarkers evaluating lymph node metastasis in
patients with colorectal cancer.
------------------------------------------------------------------------------------------------------------
Professor Fengchun Zhang - [email protected]
Director of the department of Oncology, Renji Hospital, School of Medicine
, Shanghai Jiao Tong University
Professor ZHANG Feng-chun graduated with a PhD from the Jilin University in
2002 and had been sabbatical in AKITA University in Japan from 1995 to 1996
and at TOKYO University during 2002 to 2004. He is now director of the
department of Oncology, Renji Hospital, School of Medicine , Shanghai Jiaotong
University.
His research has focused on understanding the isolation and identification of
breast cancer stem cells and stromal cells, the tumor microenvironment that
might contribute to carcinogenesis and tumor progression and a potential
strategy for eradication of breast cancer by targeting cancer stem cells. The
goals of this research are to discover the mechanisms involved in the origin of
cancer stem cells, the abnormal signalling pathways of breast cancer stem cell
self-renewal. His main research contributions centre on understanding
characterization of cancer stem cells, in order to find ways to destroy them, which
might contribute significantly to the therapeutic management of malignant tumors.
Professor Zhang has published over 40 papers in journals, many of which are
highly cited, and are highly ranked within the disciplines of oncology. The
research team has been continuously funded by grants since its establishment.
Their work is supported by the grants from National Natural Science Foundation
of China (Grant “Screening susceptible genes for endocrine therapy in breast
cancer ”and Grant “Study on regulatory mechanisms of breast cancer stem
cell(BCSC) ”), Shanghai Scientific Committee (Grant “Regulatory effect of tumor
stromal cell on cancer stem cell”) and Shanghai Jiaotong University (Grant
“Study on gastrointestinal cancer stem cell”). Upon these work, they hope to
decipher the molecular mechanisms of the interaction between cancer stem cells
and stromal cells that might be crucial to explore the new clinical strategies for
the diagnosis and prevention of carcinoma.
------------------------------------------------------------------------------------------------------------
Professor Guoqiang Chen -
[to come]
------------------------------------------------------------------------------------------------------------
Professor Jing Yi -
[to come]
------------------------------------------------------------------------------------------------------------
Professor Jinke Cheng - [email protected]
Institute of Medical Sciences, Shanghai Jiao Tong University School of
Medicine
Professor Jinke Cheng graduated with a Ph.D. from the Institute of Cancer,
Peking Union Medical College in 1997 and completed post-doctoral training in M
D Anderson Cancer Center in Houston, USA. He is now a Professor, Institute of
Medical Sciences, Shanghai Jiao Tong University School of Medicine.
The research in Dr. Cheng’s laboratory focuses on the protein SUMOylation and
cell signal transduction in the development and disease. He is particularly
interested in how de-SUMOylation proteases SENPs are regulated during
cellular processes，how these SENPs control the targets activity, and what is the
role of SENPs in the development and disease. He used functional screen to
identify HDAC1 as a target protein for SENP1 desumoylation in androgeninduced androgen receptor response. SENP1 specifically and markedly enhance
androgen-induced androgen receptor activity and androgen can also increase
SENP1 expression through androgen receptor-dependent manner. He further
determined the role of SENP1 in prostate cancer development by using
transgenic mice model. He identified another SENP1 target HIF1
that SENP1 involves hypoxia-induced cellular process. Interestingly, hypoxia can
induce SENP1 expression, which further enhance hypoxia response in a positive
feedback loop. This finding may explore an important role of SENP1 in regulating
tumor angiogenesis. Dr. Cheng has published over 40 papers in peer-reviewed
journals.
------------------------------------------------------------------------------------------------------------
Associate Professor Kewen Zhao - [email protected]
Department of Pathophysiology, Shanghai Jiao Tong University School of
Medicine
Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of
Education
Associate Professor Kewen Zhao obtained her PhD degree from Shanghai
Institutes for Biological sciences, Chinese Academy of Sciences in 2005 and
completed post-doctoral training at Emory University in Georgia, USA. She is
now an Associate Professor at Shanghai Jiao Tong University School of
Medicine and Principal Research Fellow at Key laboratory of Cell Differentiation
and Apoptosis of National Ministry of Education.
Her previous work demonstrated that estrogen responsive finger protein (EFP),
which is also an E3 ligase, could degrade KLF5 in breast cancer. Although the
degradation is through proteasome pathway, but the substrate, KLF5, could not
be ubiquitinated by EFP; on the contrary, ubiquitnation of E3 ligase itself
increases and inhibiting this ubiquitination by point mutation could abolish the
degradation effect. Now, part of her present research focus on the roles of
modification of some important human proteins, the goals of this research are to
discover how these modification influence their biological functions. At the same
time, her group is trying to build a platform, which combines retrovirus
transfection, large scale cell culture, affinity purification and proteomics
identification and so on, for obtaining the native protein complex of a bait protein.
Although Dr. Zhao is very young in this field, she has published papers in peerreviewed journals, such as BLOOD, JBC, oncogene etc and her research team
has obtained grants from National Natural Science Foundation of China, Science
and Technology Commission of Shanghai and so on.
------------------------------------------------------------------------------------------------------------
Mingzhu Huang (Ph.D. candidate) [email protected]
Department of Oncology, Renji Hospital, Shanghai Jiaotong University
Mingzhu huang graduated with a master degree from Shanghai Second Medical
University in 2005, then worked at ZhongDa Hospital,Affiliated Hospital of
DongNan University for almost one year.And now he is studying in Shanghai
Jiaotong University.
His research objective was to investigate the biological characteristics of breast
cancer stem cell and its regulation.In his research,MCF-7 cells was cultured in
suspension of EGF,bFGF,B27 and Insulin,and mammoshperes was generated.It
is believed that Mammosphere cells from MCF-7 contained higher propotion of
breast cancer stem cells.And he found that four gens β-catenin,CXCR4,SOX2
and ALDH3A1,were expressed in the mammosphere cells at higher levels.
Mammosphere cells contained larger propotion of CD44＋CD24－ cells.
BMP-2 decreased the MFE(mammospheres formation efficiency ) of MCF-7 cells
and arrested cells at the G1 phase of cell cycle. Maybe One of the mechanism is
that BMP-2 inhibited DNA synthesis.
------------------------------------------------------------------------------------------------------------
Associate Professor Qian Zhao -
[to come]
------------------------------------------------------------------------------------------------------------
Professor Yingyan Yu - [email protected]
Division of Pathology, Ruijin Hospital and Shanghai Institute of Digestive
Surgery, Shanghai Jiao Tong University, School of Medicine.
Professor Yingyan Yu graduated with a Ph.D. from Okayama University ，School
of Medicine of Japan in 1993. She ever got a professional training for liver and
transplant pathology in UPMC, Pittsburgh University, USA in 2002. Now, she is a
professor, and chief pathologist of Ruijin hospital, Shanghai Institute of Digestive
Surgery, Shanghai Jiao Tong University, School of Medicine. She is engaged in
molecular pathology of gastrointestinal tumor and in charge of biological tissue
bank construction for gastrointestinal tumor.
Her research has focused on translational medicine study of gastrointestinal
cancer, including the relationship of cancer phenotype with the molecular
variation, as well as the tumor biomarkers for early diagnosis and prognostic
prediction for gastrointestinal carcinomas. The goals of this research are to
discover the mechanism of carcinogenesis or development of heterogeneous
histology phenotypes for gastrointestinal cancer. For this purpose, molecular
genetics, protein and tissue microarray methodologies have been used for
studies on human blood and tissue material. Professor Yu has published over 60
papers in English, Chinese and Japanese. Some of which are published on high
impact factor Journals. She also acts as an invited reviewer of “J Proteome Res”,
“Eur J Surg Oncol”, “J Clin Pathol” and so on. The research team has been
continuously funded by National Nature Science Fund of China as well as
National “863” High Tech Program since its establishment.
------------------------------------------------------------------------------------------------------------
Professor Zeguang Han – [email protected]
Department of Functional Genomics, Chinese National Human Genome
Center at Shanghai, Shanghai Jiao Tong University
Professor Ze-Guang Han graduated with a MD from Shanghai Second Medical
University in 1998 and worked as Principal Research Fellow Chinese National
Human Genome Center at Shanghai, Shanghai Jiao Tong University. He is now
director, Department of Functional Genomics; vice-director, Shanghai-MOST Key
Laboratory of Disease and Health Genomics, Chinese National Human Genome
Center at Shanghai, Shanghai Jiao Tong University
His research has focused on genetics and epigenetics of liver cancer, potential
oncogenes and tumor suppressor genes, secreted proteins and Schistosoma
genome. In liver cancer, the goals of his research are to establish a basis for
profound understanding of oncogenesis, and subsequent diagnosis and
therapeutics of liver cancer through integrating genomic, epigenomic and
transcriptomic data as a “systems biology” approach. Also, his research aims to
identify some oncogenes and tumor suppressor genes associated with liver
cancer and other cancers, where the genes could serve as diagnostic markers
and therapeutic targets. In addition, because schistosomiasis still remains a
serious public health problem in China, his team is now to unveil the genome of
pathogen, Schistosoma japonicum, and then employ a “systems biology”
approach, integrating genomic, transcriptomic and proteomic data, to provide
new insights into the pathophysiology of schistosomiasis and for the
development of improved interventions for disease control and will facilitate a
more fundamental understanding of schistosome biology, evolution, and the
host-parasite interplay. Professor Han has published over 50 papers in peerreviewed journals, including Nature genetics, PNAS, many of which are highly
cited. The research team has been funded by national and local grants.
------------------------------------------------------------------------------------------------------------
Associate Professor Zonghai Li - [email protected]
State Key Laboratory of Oncogenes and Related Genes, Cancer Institute of
Shanghai Jiao Tong University
Associate Professor Zonghai Li graduated with a M.D from Fudan University in
2005. He is now a Principal Investigator and Associate Professor in State Key
Laboratory of Oncogenes and Related Genes, Cancer Institute of Shanghai Jiao
Tong University.
His research has focused on Identifying antibodies or peptide ligands against
receptors over-expressed in cancer or mutant receptor expressed only in cancer,
developing receptor-targeting gene and drug delivery nanoparticle and liposome.
His team has obtained some therapeutic monoclonal antibodies against EGFR,
EGFRvIII (a mutant form of EGFR) and IGF-1R. His team also has identified
novel peptide ligands for EGFR and Tie 2 receptor. Recent, he has invented a
new phage display method for isolating antibody fragments and some scFv
antibodies against EGFR and EGFRvIII have been identified with this novel
method. He also invented some novel way to make phage gene delivery particles.
A/Professor Li has published over 20 papers in peer-reviewed journals, and
obtained 2 issued patents. He is now an invited reviewer of Nucleic Acids
Research, Biotechniques and some other academic journals.
------------------------------------------------------------------------------------------------------------
University of Sydney speakers
Associate
Professor
Christine
Clarke
-
[email protected]
Westmead Institute for Cancer Research, University of Sydney at
Westmead Millennium Institute
Associate Professor Christine Clarke graduated with a PhD from the University of
NSW in 1982 and completed post-doctoral studies at INSERM in Paris, France
and at Penn State University, in Pennsylvania, USA. She is now a NHMRC
Principal Research Fellow and Associate Professor, Faculty of Medicine,
University of Sydney, based at the Westmead Institute for Cancer Research,
Westmead Millennium Institute and Westmead Hospital.
Her research has focused on understanding the role of the ovary and the
hormones it produces (oestrogen and progesterone), in the normal breast and in
breast cancer. The goals of this research are to discover how these reproductive
hormones influence breast cancer, because it is known that without the ovaries,
breast cancer seldom develops. Her main research contributions centre on
understanding progesterone receptor action in normal and malignant tissues, and
a particular focus of the work has been to develop approaches and
methodologies that have allowed investigation of key research questions using
human material. A/Professor Clarke has published over 90 papers in peerreviewed journals, many of which are highly cited, and are highly ranked within
the disciplines of endocrinology, reproduction and oncology. The research team
has been continuously funded by peer-reviewed grants since its establishment.
Associate Professor Clarke leads the establishment of a Breast Cancer Tissue
Bank to be available to researchers throughout Australia, in conjunction with a
consortium of researchers, clinicians and health system bureaucrats. This was
established by an NHMRC Enabling Grant and additional support from the
National Breast Cancer Foundation and the Cancer Institute NSW, and is the first
publicly available comprehensively clinically annotated biospecimen resource for
breast cancer in Australia and one of a limited number internationally. The bank
started tissue collections in 2006 and is now fully operational.
Associate Professor Clarke’s major peer-review commitments have included
chairing the Research Committee of the National Breast Cancer Foundation,
membership of National Cancer Grants Specialty Committees, membership of
NHMRC program grants committee, Regional Grants Interview Panels and Grant
Review Panels, and membership of the Cure Cancer Australia Scientific
Committee.
Associate Professor Clarke has maintained a career commitment to advocacy,
policy and research translation, and was President of the Australian Society for
Medical Research, member of the NHMRC Health Advisory Committee, member
of the Commonwealth Cancer Strategies Group, member of the interim Editorial
Board of Health Insite (the Commonwealth web-based health portal) and
participated in reviews and working parties on public health-related issues.
Associate Professor Clarke is a past member of the Boards of the National
Breast Cancer Foundation and the NSW Cancer Council and is currently a
member of the Research Advisory Committee of the Cancer Institute NSW and of
the Kolling Institute Scientific Advisory Committee. She has served on the
Membership Committee of the USA Endocrine Society and on international
journal editorial boards, and currently serves as associate editor of EndocrineRelated Cancer.
------------------------------------------------------------------------------------------------------------
Professor Des Richardson - [email protected]
Cancer Cell Biology & NHMRC Principal Research Fellow, University of
Sydney
[to come]
------------------------------------------------------------------------------------------------------------
Dr Diana Benn - [email protected]
Senior Hospital Scientist & Senior Research Fellow, Kolling Institute of
Medical Research, University of Sydney
Dr Benn is a Senior Hospital Scientist and Senior Research Fellow in Cancer
Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and
University of Sydney. Since 1999 Diana has worked in Professor Bruce
Robinson’s laboratory in the field of the genetics of phaeochromocytoma. Their
early work in this field showed a 4 cM region of loss of heterozygosity and work
continues in an attempt to identifiy the putative tumour suppressor gene in this
region.
They
established
the
International
SDH
Consortium
to
study
genotype/phenotype correlations in patients with SDHB or SDHD mutations.
Clinical
data
was
collected
from
62
families
with
hereditary
phaeochromocytoma/paraganglioma and penetrance data gave valuable insights
into the differences between SDHB and SDHD associated disease. This
knowledge
will
lead
to
improved
patient
management
of
familial
phaeochromocytoma/paraganglioma.
------------------------------------------------------------------------------------------------------------
Associate Professor Graham Mann
Westmead Millennium Institute, University of Sydney
[to come]
------------------------------------------------------------------------------------------------------------
Dr Lyndee Scurr - [email protected]
Westmead Millennium Institute, University of Sydney
Dr Lyndee Scurr received her PhD in July 2001. In her first post-doctoral position
she worked on ovarian cancer with with Dr Anna deFazio to study the function of
the ankyrin repeat protein I (ANKRD1). Dr Scurr found that ANKRD1 expression
levels directly correlated to cisplatin resistance in ovarian cell lines and in ovarian
tumours. This research formed the basis of a successful commercial patent and
has led to a publication in Br J Cancer and a second manuscripted recently
submitted to Clin Cancer Res.
Dr Scurr joined the melanoma cell cycle research programme, headed by Dr
Helen Rizos, in March 2006 and has been instrumental in developing a series of
projects studying melanoma oncogenes and tumour suppressor genes. The
melanoma cell cycle research team was the first to show that melanomaassociated p14ARF mutations impair the activity of the p14ARF tumour
suppressor. Moreover, this team established that p14ARF was a pre-ribosomal
protein, and was able to post-translationally modify its binding proteins via protein
sumoylation. This group has established cutting edge technologies including
lentiviral systems to modulate gene expression in primary melanocytes and
fibroblasts, the development of 3D human skin reconstructions, and the
application of microarray analyses. These technologies will help define the
relative contribution of known melanoma tumour genes and
allow for the
identification of novel genes involved in melanoma development and progression.
------------------------------------------------------------------------------------------------------------
Associate
Professor
[email protected]
Qihan
Dong
-
Head, Cancer Biology Group, Central Clinical School, University of Sydney
and Bosch Institute
Scientific Director, Department of Endocrinology, Royal Prince Alfred
Hospital
Associate Professor Dong received a MD from the Shanghai Second Medical
University and a PhD from the Unviersity of Sydney. He spent three years as
Fogarty Fellow with the National Institutes of Health in the USA.
Dong’s group was the first to demonstrate a loss of annexin and gain of
phospholipase A2 (PLA2) in prostate cancer. He provided evidence in animals to
substantiate the therapeutic potential by targeting PLA2. Recently, he found a
feed forward loop between cPLA2 and PI3K/Akt pathways in prostate cancer
cells. As the activated Akt is associated with poor clinical outcome, identification
of a novel regulator of Akt activity has a potential to impact on clinical practice.
His finding of a characteristic loss of Annexin and gain of PLA2 in prostate
cancer has been adopted in clinical use by pathologists as a diagnostic test. The
topic has now been included in the 2nd Edition of the Encyclopaedia of Cancer
(in press, 2008).
His team has characterised a blue berry based phytochemicals for in vitro and in
vivo anti-cancer effect. A recent presentation of the work (2007) was selected by
AACR for Newswothy session. A randomised clinical trial of this phytochemicalbased therapy will begin in 2008.
In addition, his team has developed a protocol for in vitro mutagenesis. A paper
describing the protocol was awarded ‘the best methodology paper of the year’ by
Nucleic Acids Res (2004). His team has received invitation to contribute to the
third volume of In Vitro Mutagenesis Protocols (2009) from Springer.
Dong has published 40 papers (total citations of 1371) and of these he was the
first or senior author in 20. Twenty-seven papers were published after his
appointment as the Group Head. His work has led to lodgement of 3 Patents.
------------------------------------------------------------------------------------------------------------
Professor Stephen Clarke - [email protected]
Professor and Head of the Discipline of Medicine, Concord Hospital Clinical
School , University of Sydney
Senior Staff Specialist in Medical Oncology, Sydney Cancer Centre
Professor Stephen Clarke’s research interests are in cancer pharmacology and
clinical trials in colorectal and lung cancer and mesothelioma.
In 2005, Professor Clarke established the Cancer Pharmacology Laboratory at
Concord Hospital, transferring it from the previous location at Camperdown. The
laboratory expanded its focus from conventional analytical pharmacology to
assess molecular and now proteomic predictors of drug toxicity. This research
has included the impact of cancer associated inflammation on drug clearance
and toxicity. The unit has started to receive international recognition for the
inflammation research reflected by Professor Clarke having been invited to
present data at the 2008 American Society of Clinical Pharmacology and several
invited reviews on the work requested by prestigious pharmacology journals.
The other main area of achievement has been in colorectal cancer (CRC) where
Professor Clarke has been one of Australia’s leading clinical triallists and
translational researchers. He has enrolled over 250 patients on clinical studies in
CRC in the last 6 years. Much work has also gone into pharmacological,
molecular and now proteomic predictors of outcomes in CRC and he is CIA on a
$3.75 million Translational Program Grant in CRC from the NSW Cancer Institute.
Professor Clarke has also been invited to be part of management committees for
international phase III trials in CRC. In 2008 he has been invited to speak at the
National Cancer Control Network meeting in Beijing China on aspects of
colorectal cancer management.
Professor Clarke is a reviewer for numerous oncology and pharmacology
journals and is on the editorial committees for Australian Prescriber and the Asia
Pacific Journal of Clinical Oncology. He is Oncology Advisor to the Department
of Veterans’ Affairs and is a member of the Repatriation Pharmaceutical Review
Committee and the Australian Drug Evaluation Committee.
Professor Clarke has over 120 publications including 67 publications in peerreviewed journals and 3 book chapters in the last 5 years and has an H-index of
16. This is probably under representative of the significance of the publications,
with many of them being recent and the inflammatory research being novel, with
his group leading the world in the cancer inflammation and drug metabolism field.
These factors have reduced the potential for others to cite the research.
Professor Clarke has received $6 million in competitive grant funding in the past
5 years.
------------------------------------------------------------------------------------------------------------
Associate Professor Xia Pu - [email protected]
Signal Transduction Research Group, Centenary Institute, University of
Sydney
Associate Professor Xia Pu trained in Medicine with a specialization in
Endocrinology in Peking Union Medical College Hospital, after completion of his
Medical Degree in 1982 at Shanghai First Medical College. In 1996 when he
finished his 3-years post-doctoral training in Harvard Medical School and moved
to Australia, Dr Xia initiated the first Australian-based study on sphingosine
kinase (SphK) and discovered its role in the regulation of cell survival and
proliferation. He has also for the first time demonstrated an oncogenic role of
SphK. These pioneer works have helped to conceptualize SphK as a signalling
enzyme and established a new research direction in cancer area. Over the last
10 years, his research has been centred on the study of the SphK and
sphingolipid signalling pathway, which has shown a considerable international
leading profile in the area of defining the signalling mechanisms of SphK,
characterising the functional structure of the enzyme and its (patho)-physiological
in human diseases, especially in cancer.
Associate Professor Xia has consistently published in high impact-factor journals,
including Science, PNAS, Current Biol, JCI, JEM, JCB and JBC, etc. All his
research articles have received totally >2500 citations to date. Additionally, he
has published 12 patents associated with his research (9 of them are in the
national or international PCT phase). Associate Professor Xia has also
developed interests and expertise in collaboration with pharmaceutical industry
for development of new anti-cancer therapeutics.
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