NEW FRONTIERS IN CANCER RESEARCH 2018 - #VCCCpostdoc18 - VCCC Postdoctoral Symposium - Victorian Comprehensive ...
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NEW FRONTIERS IN
CANCER RESEARCH
2018
VCCC Postdoctoral Symposium
#VCCCpostdoc18
2018 ORGANISING
WELCOME COMMITTEE
Welcome to New Frontiers in Cancer Research –
the second VCCC Postdoctoral Symposium.
This conference aims to highlight the exciting research Liz Christie (Co-convener, Peter Mac)
of early- and mid- career scientists from across Victoria,
Lorey Smith (Co-convener, Peter Mac)
and to work together to find innovative ways to progress
our understanding and treatment of cancer. Richard Birkinshaw (Walter and Eliza Hall Institute)
A very warm welcome to our three plenary speakers, Rita Busuttil (Peter Mac)
who are leaders from three cutting edge fields of Bianca Capaldo (Walter and Eliza Hall Institute)
cancer research: cancer etiology and prevention, novel
therapeutic strategies, and immunology. Jessica Duarte (Olivia Newton-John Cancer Research Institute)
Our thanks to the VCCC, all of the sponsors, consumer Laura Forrest (Peter Mac)
advocates, presenters and delegates for their tremendous Dale Garsed (Peter Mac)
response to this meeting. Without their support and
Simon Keam (Peter Mac)
enthusiasm, this event would not be possible.
Adam Parslow (Olivia Newton-John Cancer Research Institute)
We wish you all a stimulating and rewarding meeting.
Emma Petrie (Walter and Eliza Hall Institute)
Regards
The 2018 Organising Committee
2 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 3
ACKNOWLEDGEMENTS PROGRAM VCCC Level 7 – Lecture Theatre B
Time Event Topic Speakers
8.30am REGISTRATION – Level 7 Foyer
8.45am Welcome Organising Committee
The Organising Committee would like to acknowledge SESSION 1 Sponsored by PerkinElmer
the generous support of the Victorian Comprehensive 8.50am Keynote 1 Translating colorectal cancer risk models for tailored Professor Jon Emery
Cancer Centre (VCCC), the Peter MacCallum Cancer prevention
Centre, and all of our sponsors.
9.20am Oral 1 Skeletal muscle loss in non-small cell lung cancer patients Dr Nicole Kiss
We would like to thank everyone who provided receiving chemo-radiation and relationship to survival
assistance along the way, including Michelle Barrett,
9.35am Oral 2 Limitrin: a therapeutic target and biomarker of breast Dr Delphine Denoyer
Erin Turner and the VCCC Communications team, the
cancer brain metastasis
Peter Mac Postdoc Society (PMPS), Caroline Owen, the
volunteer judges, and the consumer advocates. 9.50am Oral 3 IL 33 in gastro intestinal cancers: oncogene or tumour Dr Moritz Eissmann
suppressor
Finally, thank you to the keynote speakers, presenters
and all the delegates who have contributed to this 10.05am Flash Talk 1 HCK activity within the myeloid tumour stroma Dr Robert O’Donoghue
meeting. promotes lung cancer progression
10.10am Flash Talk 2 Novel KMT2A Fusion in paediatric leukaemia Dr Hansen Kosasih
10.15am Flash Talk 3 Investigating cooperative interactions between PIK3CA Dr Camilla Mitchell
mutations and APC inactivation in intestinal organoid
models
10.20am Flash Talk 4 The EHF and CDX1 transcription factors co-ordinately Dr Ian Luk
regulate the differentiation status of colorectal cancer cells
10.25am MORNING TEA – Level 7 Foyer
SESSION 2 Sponsored by BD
10.55am Oral 4 Combined CDK4/6 and PI3Kα inhibition is effective and Dr Joyce Teo
generates anti-tumour immunity in triple-negative
breast cancer
11.10am Oral 5 Rural urban variation in time to diagnosis and treatment Dr Rebecca Bergin
of colorectal or breast cancer in Victoria
11.25am Oral 6 RIPping leukaemias apart: Exploring necroptosis cell Dr Gabriella Brumatti
death in Acute Myeloid Leukaemia
11.40am Flash Talk 5 A high throughput approach to identifying Dr Kirsty Carey
pharmacological modifiers of mRNA processing and export
11.45am Flash Talk 6 RNAi & CRISPR Screens Identify Hbo1 as critical to Dr Laura MacPherson
leukaemic stem cell survival
11.50am Flash Talk 7 IL-11 as a therapeutic target to treat cancer Dr Jennifer Huynh
11.55am Flash Talk 8 Modelling chronic STAT3 pro-inflammatory signalling in Dr Fiona Tan
the initiation of head and neck cancer
12.00pm Keynote 2 Approaches to target and treat local lymphatic Dr Lisa Kaminskas
metastases
4 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 5
KEYNOTE
PROGRAM SPEAKERS
Time Event Topic Speakers Professor Jon Emery
12.30pm LUNCH – Level 7 Foyer
Herman Professor of Primary Care Cancer Research
Poster presentations sponsored by Australian Biosearch
University of Melbourne
SESSION 3 Sponsored by GeneSearch Professor Emery’s keynote address will focus on
2.15pm Oral 7 Establishment of an organoid biobank to personalise the Dr Dannel Yeo Translating colorectal cancer risk models for tailored
treatment of pancreatic cancer prevention. Professor Emery is an NHMRC Practitioner
Fellow, Director of the Cancer Australia Primary Care
2.30pm Oral 8 Low-cost sequence-based gene panel screening: a large Dr Khalid Mahmood
Collaborative Cancer Clinical Trials Group (PC4), and a
scale study of colorectal cancer
Visiting Research Fellow at the University of Cambridge.
2.45pm Oral 9 Neo adjuvant treatment resistance in aggressive Dr Marek Cmero He studied medicine at Cambridge and Oxford and
prostate cancer is driven by non genomic mechanisms obtained his DPhil at Oxford on computer decision
3.00pm Flash Talk 9 Charting the epigenetic landscape of the tumour Dr Mitchell Lawrence support to assess cancer risk in general practice. His
microenvironment research interests are in the role of primary care in
cancer prevention, diagnosis and follow-up, and primary
3.05pm Flash Talk 10 Structured interview and user manual for the selection Dr Amanda Pomery
care trials of complex interventions.
and development of cancer support group leaders
3.10pm Flash Talk 11 The smac-mimetic birinapant as a targeted therapy for Dr Najoua Laloui
triple-negative breast cancers
3.15pm Flash Talk 12 Combinatorial targeting by microRNAs coordinates post Dr Joseph Cursons
transcriptional control of breast cancer EMT
3.20pm AFTERNOON TEA – Level 7 foyer
SESSION 4 Sponsored by Promega
3.50pm Oral 10 A pilot randomised controlled trial of an online Dr Lahiru Russell
mindfulness based program for people diagnosed
with melanoma
4.05pm Oral 11 Pro Survival protein MCL 1 is a promising therapeutic Dr Michael Dengler
target in mantle cell lymphoma
4.20pm Oral 12 Mechanistic investigations into acquired resistance to Dr Rachel Thijssen
BH3 mimetics in primary CLL
4.35pm Keynote 3 Transcriptional regulation of IL-17 producing T cells and Dr Lisa Mielke
their role in gastrointestinal cancers
5.05pm Awards, Conclusion of speaker program Organising Committee
5.15pm NETWORKING EVENT – Drinks and nibbles – The Loft, Level 7
7.00pm Close
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Dr Lisa Kaminskas, NHMRC research Dr Lisa Mielke, Head of the Mucosal
fellow and senior lecturer University Immunity and Cancer Laboratory Olivia
of Queensland Newton-John Cancer Research Institute
Dr Kaminskas will present Approaches to target Dr Mielke will speak on Transcriptional regulation of
and treat lymphatic metastases. Lisa’s research IL-17 producing T cells and their role in gastrointestinal
program is primarily dedicated to using nano and cancers. In 2018 Dr Mielke was appointed Head of the
polymer-technology to optimise the delivery of Mucosal Immunity and Cancer Laboratory at the Olivia
chemotherapeutic drugs towards sites of tumour Newton-John Cancer Research Institute. Her current
growth and metastasis. In particular her focus is on work is funded by Cure Cancer Australia and focuses on
eliminating cancers that have spread to regional the role of innate lymphoid cells and T cells in regulating
(sentinel) lymph nodes and the lungs with the view intestinal inflammation and cancer progression.
to maximise the successful treatment of metastatic
cancers and improve survival rates for cancer patients.
8 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 9
SUPPORTED BY:
Corporate sponsors:
ORAL PRESENTATIONS
10 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 11
ORAL 1: SESSION 1 ORAL 2: SESSION 1
Skeletal muscle loss in non-small cell lung cancer patients receiving Limitrin: a therapeutic target and biomarker of breast cancer brain metastasis
chemo-radiation and relationship to survival
Nicole Kiss Results: Muscle area and muscle density decreased Delphine Denoyer Our data indicate that high limitrin expression is
Peter MacCallum Cancer Centre significantly by week four of CRT (-6.6 cm2, 95% Olivia Newton-John Cancer Research Institute associated with poor prognosis in HER2 and Triple
CI -9.7 - -3.1, pORAL 3: SESSION 1 FLASH TALK 1: SESSION 1
IL-33 in gastro-intestinal cancers: oncogene or tumour suppressor? HCK activity within the myeloid tumour stroma promotes lung cancer progression
Moritz Eissmann In the colon cancer setting, ST2-deficiency lead to Robert O’Donoghue findings in CRC patients. Next we used adenoviral
Olivia Newton-John Cancer Research Institute increased tumour burden in a mouse model of sporadic Austin Health, Olivia Newton-John Cancer or tamoxifen-induced Cre expression in the lung to
colorectal cancer. Reciprocal bone marrow chimera Research Institute activate oncogenic KrasG12D expression and found that
Christine Dijkstra, Frederik Masson and Matthias Ernst indicated that the radio-resistant non-hematopoietic HckCA promoted tumour progression in both models.
IL-33 is an IL-1 family cytokine, which regulates compartment contributes to the increased tumour Megan O’Brien, Rowena Lewis, Andrew Carey, Daniel Batey, To eliminate an possible contribution of Hck activity in
inflammatory responses during infections. In cancer, growth. Indeed, we found St2 expression in the Maree Faux, Gary Andreson, Tom John, Matthias Ernst. tumour cells we grafted (sc) the lewis lung carcinoma
IL-33 can act pro or anti-tumoral depending on the mesenchymal cells, in which IL-33 stimulation induced The myeloid-specific Src family kinase, HCK, promotes (LLC) cells, which are derived from a spontaneous
tumour type and stage of disease. Here we study the NF-kB pathway activation. Loss of IL-33 signalling in the proliferation and survival of myeloid leukaemia NSCLC in a C57BL/6 mouse and do not express Hck, into
role of IL-33 signalling in mouse models of gastric the non-haematopoietic radio-resistant compartment cells and the alternative activation of macrophages wildtype (Wt)or HckKO mice. We observed that all Wt
cancer and colorectal cancer. coincided with an increase in Treg infiltration and with a (AAMs) during benign inflammation. We have host mice had reached ethical endpoints for tumour
strong reduction of an IFNy gene expression signature. previously shown in that HCK activity in the tumour size or well-being within 5 weeks of engraftment, while
For gastric cancer, Kaplan-Meyer-survival analysis
Furthermore, IL-33 administration reduced colon cancer stroma predicts poor patient outcomes in colorectal only 1/3 of HckKO mice reached these endpoints in the
showed that high expression of the IL-33 receptor, ST2
allograft growth associated with tumour-infiltrating cancer (CRC) and mice with a constitutive active Hck same period of time. Next we assessed if inhibition of
in stomach cancer patients predicts poor prognosis. In
IFNy-positive T cells. (HckCA) developed more and larger tumours following Hck with the small molecule RK20449 in combination
accordance, IL-33 and St2 were highly elevated in gastric
AOM-induced CRC [Cancer Cell, 2017, 31(4):563-575]. with chemotherapy could reduce the progression
tumours in two independent mouse models. Genetic We conclude, that tumour-derived IL-33 promotes
To-date, polymorphisms and mutations in HCK have of human A549 NSCLC cells in vivo. We found the
deficiency of IL-33 signalling (ST2-/-) diminished gastric gastric cancer growth through tumour-associated mast
been observed in patients with lung cancer and chronic combination of cisplatin and RK20449 was more
tumour growth, and was associated with a decrease in cells and TAM-dependent mechanisms, while IL-33
inflammatory lung disease so we investigated the role effective in reducing tumour growth than cisplatin
mast cells, tumour-associated macrophages (TAM) and signalling within mesenchymal cells acts as a colon
of HCK in the development and progression of lung alone, while RK20449 had no impact on A549 tumour
angiogenesis. Genetic depletion or pharmacological tumour suppressor pathway.
cancer. We first examined tumour sections from lung progression as a single agent. We have found that HCK
inhibition of mast cells and TAM reduced tumour
cancer patients by IHC to detect phosphorylated HCK is active within the tumour stroma of human NSCLC
burden, again associated with decreased angiogenesis.
(pHCK) as a surrogate marker for HCK activation and and that this protein functionally promotes NSCLC
Mechanistically, we show that tumour-produced found abundant pHCK in the tumour stroma of non- growth in preclinical mouse and xenograft models,
IL-33 can activate mast cells, which in turn recruit small cell lung cancer (NSCLC) patients – consistent therefore targeting of HCK is a promising combination
pro-tumoral and pro-angiogenic macrophages to the with HCK expression in myeloid cells, the tumour therapy for the treatment of NSCLC.
tumour through release of chemokine’s. promoting properties of these cells and our previous
14 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 15FLASH TALK 2: SESSION 1 FLASH TALK 3: SESSION 1
Novel KMT2A Fusion in Paediatric Leukaemia Investigating cooperative interactions between PIK3CA mutations and
APC inactivation in intestinal organoid models
Hansen Kosasih Results: We identified a novel MLL-r: MLL-TFE3– t(11;X). Camilla Mitchell In order to understand this process in intestinal
Murdoch Children’s Research Institute This fusion causes leukaemia in syngeneic transplant Peter MacCallum Cancer Centre epithelial cells, we have successfully generated 3D
model, having a latency similar to MLL-AF9. MLL-TFE3 intestinal organoids, from our novel conditional PIK3CA
Gabriella Brumatti, Jarrod Sandow, Stefan Bjelosevic, expressing leukaemic cells have a similar drug-response Wayne Phillips mutant mouse model, where PIK3CAH1047R mutation
Ray Bartolo, Ricky Johnstone, Paul G Ekert profile to MLL-AF9 leukaemic cells. TFE3 fusions PI3K pathway activation is involved in many cancer can be activated in vitro at endogenous levels, within
Mixed Lineage Leukaemia-rearrangement (MLL-r) with other genes are known drivers of other cancer hallmarks, including metabolism, migration, intestinal stem cells (driven by LGR5-Cre). Additionally
leukaemia accounts for the majority of infant and subtypes, notably renal cell carcinoma and alveolar proliferation, and cell survival. Somatic mutations in the APC gene can be truncated and inactivated by the
paediatric acute myeloid leukaemia. It is a marker soft part sarcoma. Unlike these other fusions, this the PI3K pathway occur at a high frequency in many same Cre driver. PIK3CAH1047R mutants maintain
of poor prognosis and higher risk of relapse. MLL-r MLL fusion retains all the TFE3 functional domains. By human tumours, including 30% of colorectal cancers a budding morphology (compared to non-mutants)
juxtapose the KMT2A (Lysine Methyl Transferase 2A) making carboxy-terminal truncations of this fusion, (CRC). CRC is the most frequent malignancy of the but undergo increased proliferation, growing bigger
gene with one of at least 70 other fusion partners, we demonstrate that TFE3 domains contribute to the gastrointestinal tract, and the 3rd most common cancer and faster. APC inactivation (± PIK3CAH1047R)
producing an in-frame chimeric protein. Here, oncogenicity of this fusion protein. worldwide. PIK3CA mutations primarily occur in one of drastically changes organoid morphology into cyst-like
we describe a novel MLL-r identified in paediatric two mutation hotspots of the catalytic subunit of PI3K, spheres, in addition to increased proliferation. Using
Conclusion: In this study, we have discovered a novel
leukaemia, in which TFE3 (Transcription Factor Binding E545K and H1047R. PIK3CA mutations do not initiate western blotting and immunohistochemistry we have
and aggressive MLL fusion, MLL-TFE3. Functional
to IGHM Enhancer 3) is fused to KMT2A. cancer on their own, requiring the cooperation of other characterised the intestinal nature of these isogenic
domains of TFE3 in this fusion are important for full
oncogenes. For CRC, mutation of APC leads to benign organoids using intestinal epithelial cell markers
Methods: We used RNA-Seq to identify novel expressed leukaemogenic activity, indicating that the fusion
adenomatous polyps. Previously, our lab has shown (lysozyme, Muc2, Chromogranin A). Additionally we
fusions in paediatric leukaemia. These fusions were partners of KMT2A contribute to the oncogenicity in
that PI3K mutations cooperate with APC mutations to show that PIK3CAH1047R mutants have increases in
cloned into a tetracycline-repressible system, and MLL rearrangements.
progress CRC tumourigenesis. downstream PI3K/AKT signalling pathway markers
transduced into E14.5 murine foetal liver cells to
test oncogenicity in a syngeneic transplant model. (pAKT, pS6, stathmin, PGSK3B, pPRAS40), and APC
Harvested leukaemic cells were cultured ex vivo to inactivated organoids show increased wnt signalling
determine immunophenotype, colony-forming capacity (B-catenin). Additionally, PIK3CAH1047R mutants show
and cytokine dependency. We tested the response increased sensitivity to the PI3K inhibitor BYL719, as
of these cells to our previously published novel drug well as the establishment of resistant clone outgrowth.
combination, the SMAC-mimetic/caspase inhibitor.
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16 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 17FLASH TALK 4: SESSION 1 ORAL 4: SESSION 2
The EHF and CDX1 transcription factors co-ordinately regulate the Combined CDK4/6 and PI3Kα inhibition is effective and generates anti-tumor
differentiation status of colorectal cancer cells immunity in triple-negative breast cancer.
Ian Luk Results: Expression of EHF was significantly Joyce Teo Triple-negative breast cancer (TNBC) is an aggressive
Olivia Newton-John Cancer Research Institute downregulated in poorly differentiated CRC cell lines Peter MacCallum Cancer Centre subtype of breast cancer and new treatments are
compared to moderately differentiated lines. However, urgently needed for this disease. As single-agent
Nicholas Clemons, John Mariadason knockdown or re-expression of EHF alone failed to Stephanie Versaci1, Sathana Dushyanthen1, therapies, CDK4/6 and PI3Kα inhibitors have shown
Colorectal cancer (CRC) is a leading cause of cancer alter the differentiation status of CRC cell lines. We Franco Caramia1, Peter Savas1, Chris P. Mintoff1, little evidence of clinical activity in TNBC. Interestingly,
related deaths for which there is an urgent need therefore determined whether EHF cooperates with Magnus Zethoven1, Balaji Virassamy1, Stephen J. Luen1, we have shown that dual blockade of CDK4/6 and
to develop novel treatment paradigms. The loss of other intestinal transcription factors to regulate Grant A. McArthur1,2, Wayne A. Phillips1,2,4,5, PI3Kα is synergistically effective against multiple
differentiation is a key characteristic of colorectal cancer, differentiation. Systematic knockdown of EHF with Phillip K. Darcy1,2,3, and Sherene Loi*,1,2 TNBC models. Combined treatment was shown
and is associated with increased metastatic propensity, other transcription factors downregulated in poorly 1
Division of Research, Peter MacCallum Cancer Centre, to significantly improve disease control in human
chemo-resistance and poorer outcome. However, differentiated CRC cell lines demonstrated that the Melbourne, Victoria, Australia xenograft models compared with either monotherapy.
the molecular basis for differentiation loss is not well combinatorial knockdown of EHF and CDX1 significantly This combination treatment exerts TNBC disease
2
Sir Peter MacCallum Department of Oncology,
understood. Ets Homology Factor (EHF) is a member downregulates the expression of differentiation control by significantly increasing apoptosis, cell
University of Melbourne, Parkville, Australia
of the E26 transformation specific (ETS) family of markers and disrupted the glandular structure of cycle arrest and tumor immunogenicity as well as
transcription factors, which is highly expressed in normal moderately differentiated CRC cell lines. Conversely, the
3
Cancer Immunology Research, Peter MacCallum generating immunogenic cell death in human TNBC
colonic epithelial cells. We observed that expression re-expression of EHF and CDX1 in poorly differentiated Cancer Centre, Melbourne, Victoria, Australia cell lines. Combined CDK4/6 and PI3Kα inhibition
of EHF, along with several other transcription factors CRC cells significantly induced differentiation marker 4
Division of Cancer Surgery, Peter MacCallum significantly increased tumor-infiltrating T cell
is significantly downregulated in poorly differentiated expression and induced some features of glandular Cancer Centre, Melbourne, Victoria, Australia activation and cytotoxicity and decreased frequency
CRCs. The aim of this study was to determine the formation. Furthermore, the re-induction of EHF of immunosuppressive myeloid-derived suppressor
direct role for EHF, alone and in combination with other
5
University of Melbourne Department of Surgery,
and CDX1 significantly reduced migration of CRC cells in a syngeneic TNBC mouse model. Notably,
transcription factors, in regulating the differentiation St. Vincent’s Hospital, Melbourne, Victoria, Australia
cell lines and induced sensitivity to commonly used combined CDK4/6 and PI3Kα inhibition, along with
status of colorectal cancer cells. chemotherapeutic agents. inhibition of immune checkpoints PD-1 and CTLA-4
Methods: Affymetrix microarrays were used to induced complete and durable regressions (>1 year) of
Conclusion: The transcription factors EHF and CDX1 are
identify transcription factors, which are significantly established TNBC tumors in vivo. Overall, our results
co-ordinately downregulated in poorly differentiated
downregulated in poorly differentiated colorectal cancer illustrate convergent mechanisms of CDK4/6 and
CRCs, and work in combination to regulate the
cell lines. Differential gene expression was confirmed by PI3Kα blockade on cell cycle progression, DNA damage
differentiation status of CRCs.
q-RT-PCR and western blot. The moderately differentiated response and immune-modulation and may provide a
colorectal cancer cell line SW948 was transfected with novel therapeutic approach for TNBC.
EHF and/or CDX1 targeting siRNAs using lipofectamine.
The poorly differentiated cell line HCT116 was transfected
with EHF and CDX1 expression vectors and stable cell
lines selected by G418 resistance and GFP expression
respectively. Cell migration was analysed using the
Boyden-Chamber assay and stained for migrated cells.
18 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 19ORAL 5: SESSION 2 ORAL 6: SESSION 2
Rural-urban variation in time to diagnosis and treatment of colorectal RIPping leukaemias apart: Exploring necroptosis cell death
or breast cancer in Victoria. in Acute Myeloid Leukaemia
Rebecca Bergin Results: 433 colorectal (48% rural) and 489 breast (42% Gabriela Brumatti genes such as Ripk1, Ripk3 and Mlkl. Surprisingly,
University of Melbourne, Centre for Cancer, rural) patients, 621 GPs and 370 specialists completed Walter and Eliza Hall Institute deletion of Ripk1 induced a rapid and more aggressive
Research/Dept of General Practice; Cancer surveys. Compared to urban patients, symptomatic disease. Intravital imaging revealed increased bone
colorectal cancer patients from rural areas had Chunyan Ma, Natasha Silke, Emma Morrish, marrow infiltration of Ripk1-/- AMLs as early as 10
Council Victoria
significantly longer total interval at the median (18 days Najoua Lalaoui, Edwin Hawkins and John Silke days after transplant. The early development of these
Jon D Emery, Ruth Bollard, Alina Z Falborg, longer, 95% Confidence Interval (Cl): 9-27), 751h (53, Resistance to chemotherapy is a major problem in AMLs was independent of apoptosis resistance,
Henry Jensen, David Weller, Usha Menon, Peter Vedsted, 95% Cl: 47-59) and 901h percentiles (44, 95% Cl: 40-48). cancer treatment and is frequently associated with increased proliferation or changes on cell metabolism,
Robert J Thomas, Kathryn Whitfield, Victoria White These patients also had longer health system intervals failure of cancer cells to undergo caspase-dependent but were dependent on the kinase activity of Ripk1.
In Victoria, survival is poorer for rural compared (7--85 days longer), largely due to longer diagnostic apoptosis. Necroptosis is a form of programmed cell AML generated from a kinase-activity deficient Ripk1
to urban patients with colorectal cancer, but not intervals (6-54 days longer). In contrast, breast cancer death that occurs in the absence of caspase activity (D138N mutant) had a slight delay on the disease onset,
breast cancer. Delayed diagnosis and treatment may intervals were similar for rural and urban women, except and thus could be exploited as an anti-cancer therapy nonetheless remained more aggressive than wild-type
contribute to disparities, but research into rural-urban the patient interval, which was shorter for rural patients. to overcome apoptosis resistance. We explored the leukaemias. Our results suggest that Ripk1-mediated-
cancer pathways is lacking. We investigated time to relevance of necroptosis in the development and necroptosis may play a tumour suppression role in the
Conclusions: Consistent with variation in survival, we
diagnosis and treatment for rural and urban Victorians treatment of Acute Myeloid Leukaemias (AML). Using progression of MLL-AMLs, providing novel therapeutic
found a longer total interval for rural patients with
with colorectal or breast cancer. genetic knockout murine models of AML, we generated opportunities for the treatment of these leukaemias.
colorectal cancer, but not breast cancer. These results
primary leukaemias deficient in necroptosis-related
Methods: Population-based surveys (2013-14) were suggest that inequities can be ameliorated and may
completed by patients (aged >40, approachedFLASH TALK 5: SESSION 2 FLASH TALK 6: SESSION 2
A high throughput approach to identifying pharmacological modifiers RNAi & CRISPR Screens Identify Hbo1 as critical to leukaemic stem cell survival
of mRNA processing and export
Kirsty Carey examining their effects on cell death and RNA Laura MacPherson RNAi studies and identify the precise functional
Peter MacCallum Cancer Centre localisation within breast cancer cells. Coupled with Peter MacCallum Cancer Centre domain required to maintain LSC, we performed a
advanced image analysis, it is possible to reproducibly domain-focused CRISPR-Cas9 screen containing ~1000
Vihandha Wickramasinghe, Toby Williams detect and quantify phenotypes relating to mRNA Enid Lam, Juliana Anokye, Joy Liu, Chen-Feng Wang, sgRNAs targeting ~200 functional domains involved
Cancers with altered RNA processing are heavily reliant processing and export including nuclear retention and Christopher Vakoc, Marnie Blewitt, & Mark Dawson epigenetic regulation. All sgRNAs targeting the MYST
on gene expression to ensure production of oncogenic sub-cellular compartmentalisation of mRNA induced by Acute myeloid leukaemia (AML) is an aggressive blood acetyltransferase domain of HBO1 were significantly
protein isoforms. This creates novel vulnerabilities in compounds, and as such we have demonstrated the first cancer that remains an unmet clinical need, with over depleted in LSC and bulk leukaemic cells. Following
cancer cells that can be therapeutically exploited using ever compounds inhibiting mRNA export. This assay 70% of patients still succumbing to the disease. AML is genetic knockout of HBO1, we observed increased
compounds that affect the gene expression pathway, can also be used to monitor RNA distribution in cancer sustained by a small population of leukaemic stem cells apoptosis, cell cycle arrest and differentiation of LSC.
such as nuclear export of mRNA. Compounds inhibiting cells lines and cellular models of genetic modification. (LSC) that possess the ability to self renew indefinitely Rescue experiments demonstrated overexpressed
all other steps of the gene expression pathway are Future characterisation of compounds identified in and regenerate the cancer after therapy. Our group has wildtype but not catalytic mutant HBO1 rescued cell
promising therapeutic candidates, and many have our screen and their mode of action will facilitate our developed a novel methodology to culture an enriched growth following HBO1 knockout, indicating catalytic
reached clinical trials. Thus, development of RNA export understanding of mRNA processing and export and will population of murine LSC, allowing us for the first time activity of HBO1 to be important LSC survival and as
inhibitors offers a unique opportunity to develop hopefully lead to development of pharmacologically to study LSC biology in depth. We performed a high such small molecule inhibitors for the MYST catalytic
innovative, targeted cancer therapeutics. We have relevant compounds which can eventually advance to content shRNA screen in our LSC enriched population domain are currently being developed. Collectively,
developed and optimised a sensitive, high-throughput clinical trials as cancer therapeutics. to identify epigenetic enzymes critical to LSC. This our results support a role for HBO1 in LSC survival.
assay to screen 25,000 natural, “drug-like” compounds negative screen contained ~2000 hairpins targeting Ongoing studies include: RNA-sequencing, chromatin
~300 epigenetic regulators. Our analyses showed MYST immunoprecipitation sequencing, assay for transposase
acetyltransferase HBO1 (MYST2, KAT7) was critical to accessible chromatin sequencing, proteomics and
both our LSC and leukaemic blast populations. Hairpins acetylomics to understand the mechanistic events at
used in RNAi screen were validated by gene expression, chromatin following HBO1 depletion and inhibition.
protein and competition asssays. To complement our
22 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 23FLASH TALK 7: SESSION 2 FLASH TALK 8: SESSION 2
IL-11 as a therapeutic target to treat cancer Modelling chronic STAT3 pro-inflammatory signalling
in the initiation of head and neck cancer
Jennifer Huynh Results: MC38 growth was attenuated in il11r-/- mice Fiona Tan pro-inflammatory signalling. This pro-inflammatory
Olivia Newton-John Cancer Research Institute compared to wild type hosts. Lower tumour burden Peter MacCallum Cancer Centre signalling precedes spontaneous HNSCC development
corresponded with a modest increase in tumour- that is accelerated in the presence of chemical
Dr. Ashwini Chand, Prof. Matthias Ernst infiltrating CD8+ T cells. In addition, T cells harvested Suraya Roslan, Gabriella Farrugia, Yuchen Bai, carcinogens in mice. Loss of Grhl3 is also evident in a
Colorectal cancer is a pressing health concern and there from il11r-/- hosts expressed lower levels of GZMB, Zixuan Zhao, Charbel Darido subset of primary human HNSCC and HNSCC cell lines
is a demand to develop novel therapeutics and improve perforin and IFNγ under both basal conditions and Head and Neck Squamous Cell Carcinoma (HNSCC) in which the oncogenic miR-21 downregulates Grhl3,
current therapies to treat this disease. Immunotherapy following PMA/ionomycin stimulation. is the sixth most prevalent cancer worldwide. inducing c-MYC and promoting HNSCC growth in a
has been highly successful for the treatment of solid Tobacco smoking and frequent alcohol consumption, similar fashion to our mouse model. STAT3 was also
Conclusion: Here we report that IL-11 signalling
malignancies however the majority of colorectal betel nut chewing, genetic predisposition and shown to induce miR-21 in human HNSCC providing a
supports tumourigenesis using the MC38 colon cancer
cancers do not typically respond to immunotherapy. human papillomavirus (HPV) infection are the most link between this inflammatory node and the loss of
mouse model. For the first time, we have characterised
Accumulating evidence alludes to a role for IL-11 commonly cited risk factors for the development of Grhl3. In this project, we will evaluate the role of Stat3
a functional role for IL-11 in modulating anti-tumour
signalling in tumour development although the HNSCC. The treatment modality for HNSCC involves pro-inflammatory signalling in driving HNSCC in the
T cell function. Overall, the findings from this study
mechanisms underlying IL-11 biology in colorectal surgery, radiotherapy and/or chemotherapy that are absence of Grhl3. We will assess the interplay between
indicate IL-11 as a potential therapeutic target for the
cancer remain largely unknown. Here, we postulate administered regardless of the aetiology or molecular pro-inflammatory STAT3 and pro-oncogenic miR-21/
treatment of colorectal cancer.
that IL-11 could be a mode of immunosuppression drivers. Our laboratory has recently achieved a pivotal Grhl3/c-MYC pathways in vivo that could be targeted in
which can be targeted as a therapeutic strategy to finding in HNSCC by identifying the Grainyhead-like subsets of HNSCC. Outcomes will delineate the origin
overcome the poor responses of colorectal cancer to 3 (Grhl3) transcription factor as a critical tumour of head and neck cancer, pioneer novel therapeutic
immunotherapy. suppressor in HNSCC. Restricting deletion of Grhl3 to interventions against cancer-promoting factors, and
the oral epithelium in mice results in epithelial barrier test targeted therapies in subsets of HNSCC.
Method: To assess the utility of targeting IL-11
impairment, stimulating a chronic epithelial Stat3
signalling in colon cancer in vivo, wild type and Il11r-/-
C57BL/6 mice were injected subcutaneously in the flank
on Day 0 with 1 x 106 MC38 colon cancer cells. The mice
were then treated with an anti-PD-1 antibody i.p. dose
once every 3 days. Tumours were harvested from mice
at day 18 and were analysed by FACs. To ascertain a role
for IL-11 signalling in T cell activity, CD8+ and CD4+ T
cells were FACs-sorted from wild type and il11r-/- mice,
and activated with PMA/ionomycin for 24h. The level of
cytolytic activity was assessed by qPCR and ELISA.
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24 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 25ORAL 7: SESSION 3 ORAL 8: SESSION 3
Establishment of an oganoid biobank to personalise the treatment Low-cost sequence-based gene panel screening:
of pancreatic cancer a large-scale study of colorectal cancer
Dannel Yeo system to test the individual patient tumour’s response Khalid Mahmood We employed the Hi-Plex multiplex PCR-based
University of Melbourne to therapeutics in vitro. Our aim was to establish an University of Melbourne sequence-screening system due to its simplicity,
organoid culturing system for pancreatic tumours and throughput and low cost. We have developed software
Dannel Yeo 1,2, Ronnie Ren Jie Low 1,2,3, Belinda Lee 3,5 ,6, to test the validity of utilising organoids to predict Mark Clendenning, Marie Lorans, Harindra Jayasekara, tools for quality assessment, variant calling and
Laura M. Beyit 1,2, Leakhena Leas 2, Karey Cheong 2, therapeutic response. Thomas Green, Peter Georgeson, Neil O’Callaghan, annotation for Hi-Plex sequencing data (https://github.
Voula Dimitriadis 2, Helen Brasier 3,5, Michael Christie 5, Susan Preston, Christophe Rosty, Daniel J. Park, com/khalidm/hiplexpipe). Our tools complement and
Michelle Palmieri 3,4, Chin Wee Tan 3,4, Yumiko Hirokawa 3,4, Method: Organoid cultures were established from Polly Newcomb, Loic Le Marchand, Stephen N. Thibodeau, take advantage of the underlying Hi-Plex chemistry,
Anthony Burgess 3,4, Frederic Hollande 1, Peter Gibbs 3,5,6, patients undergoing an EUS-guided fine needle biopsy Noralane Lindor, Steven Gallinger, David Duggan, creating a streamlined and comprehensive protocol.
Tracy Putoczki 3,4, Sean M.Grimmond 1,2 or resection surgery (Whipples or pancreatectomy) Graham Casey, John L. Hopper, Finlay A. Macrae, We designed a CRC gene panel comprising the coding
for a pancreatic mass. Ethics was obtained for Ingrid M. Winship, Mark A. Jenkins, Bernard Pope,
1 Department of Clinical Pathology, University of regions of the most important candidate predisposition
collection across 8 sites in Victoria. Collected tissue and Daniel D. Buchanan for the Colon Cancer Family Registry.
Melbourne, Victoria, Australia genes from our own research and literature. Variant
established organoids were genotyped using a panel of
Only a small proportion of the heritable risk for were called using hiplexpipe and filtered on metrics
2 University of Melbourne Centre for Cancer Research, the most commonly observed PDAC mutations: KRAS,
colorectal cancer (CRC) can be attributed to mutations such as sequencing depth, allele proportions and
University of Melbourne, Victoria, Australia TP53 and Pl 6. Organoids were tested in the presence
within known CRC-associated genes, suggesting that genotype estimates. Individual variants were prioritized
3 The Walter and Eliza Hall Institute of Medical of chemotherapies using time-lapsed 3 D imaging and
additional CRC-predisposition genes are yet to be based on the criteria: (1) rare variants (ExAC MAF
Research, Victoria, Australia CellTitre-Glo.
discovered. Novel CRC predisposition genes are likely < 0.05%), (2) protein truncating variants and (3) non-
4 Department of Medical Biology, University Results and Conclusions: 57 specimens were collected to be very rare, therefore new discoveries require synonymous variants with deleterious functional
of Melbourne, Victoria, Australia fom March 2017 to March 2018 where 26 were screening large cohorts, which imposes significant cost impact based on CADD or REVEL.
obtained from fine needle biopsy and 31 from surgical constraints. Addressing this problem, we have applied a
5 The Royal Melbourne Hospital, Melbourne, Australia Analysis of our CRC-Hi-Plex screening data identified
resection. 41 (72%) were histologically confirmed to be cost-effective sequencing system to a set of candidate
predicted pathogenic variants in RNF43, NTHL1, POLE
6 Department of Medical Oncology, Western Hospital, pancreatic cancer. 7 (17%) of these samples collected genes in a large cohort of CRC cases and controls
and POLD1. We will discuss the characteristics of these
Melbourne, Australia showed no mutations demonstrating the difficulty in (~4000) from the Colon Cancer Family Registry. We then
variants and the clinicopathological features of carriers
sampling viable tumour cells. Of the remaining 34, 20 interrogated the sequencing results to determine the
in our presentation. These data suggest Hi-Plex to be
(59%) were successfully grown as organoids. Organoid spectrum of rare variants in the selected genes and the
a valuable tool for studying and diagnosing genetic
Pancreatic cancer remains one of the most lethal of mutational profile was found to mirror the matching associations of such variants with disease, including
causes of human diseases in large cohorts.
alI solid tumours and most patients do not respond tumour sample and ex vivo chemotherapy treatment clinicopathological features. The outcomes of this work
to therapies. Although there have been scientific resulted in a dose dependent response similar to will inform clinical screening practices.
advancements in our understanding of this cancer, this the drug response of the patient post-surgery. This
has not translated to any substantial improvement in illustrates the potential tool organoids could have
median survival (-4-6 months). An approach to identify in assisting and directing pancreatic cancer patient
the most effective therapy for each patient is urgently management as well as a platform to identify the
needed. Organoids, grown in a 3D environment from individual’s key targetable cancer drivers and test novel
patient tumour samples, maintain the characteristic of therapeutic combinations.
the original patient tumour, there bv providing a model
26 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 27ORAL 9: SESSION 3 FLASH TALK 9: SESSION 3
Neo-adjuvant treatment resistance in aggressive prostate cancer Charting the epigenetic landscape of the tumour microenvironment
is driven by non-genomic mechanisms
Marek Cmero prior to radical prostatectomy. Biopsies were obtained Mitchell Lawrence display remarkably distinct and enduring genome-wide
Murdoch Children’s Research Institute, from patient tumours prior to the commencement Peter MacCallum Cancer Centre changes in DNA methylation, significantly at enhancers
University of Melbourne of treatment and post-treatment from the removed (and Monash University) and promoters, compared to non-malignant prostate
prostate. We performed whole-genome and fibroblasts (NPFs). Differentially methylated regions
Despite the high incidence of prostate cancer, as many as Ruth Pidsley, Clare Stirzaker, Renea Taylor, Susan Clark
transcriptome sequencing on patient tumour samples, associated with changes in gene expression have
91% of cases remain localised and clinically indolent. In
with matched normals for the genomic analysis, and a The growth and progression of solid tumours involves cancer-related functions and accurately distinguish
cases of aggressive disease, androgen deprivation therapy
matched control cohort for the trancriptomic analysis. dynamic cross-talk between cancer epithelium CAFs from NPFs. Remarkably, a subset of changes is
(ADT) lowers the level of these circulating androgens
and the surrounding microenvironment. To date, shared with prostate cancer epithelial cells, revealing
and is currently the most effective first-line therapy. In Surprisingly, we found no consistent DNA alterations
molecular profiling has largely been restricted to the the new concept of tumour-specific epigenome
almost all patients, the effectiveness of ADT is short-lived that could explain treatment response to ADT. Low
epithelial component of tumours; therefore, features modifications in the tumour and its microenvironment.
and resistance invariably arises. The mechanisms of ADT mutation rates and the absence of changing clonal
underpinning the persistent pro-tumourigenic The distinct methylome of CAFs provides a novel
resistance are currently unknown, and knowledge of dynamics also indicated nongenomic mechanism(s)
phenotype of the tumour microenvironment are epigenetic hallmark of the cancer microenvironment
relevant biomarkers is limited. The presence of a small of resistance occurring in these patients. Furthermore,
unknown. Using whole-genome bisulphite sequencing, and promises new biomarkers to improve interpretation
number of androgen receptor splice variants has been we found no evidence of AR alterations, splice variants
we show for the first time that cancer-associated of diagnostic samples.
linked to treatment resistance, however, these are not or overexpression, nor did we observe an enrichment
fibroblasts (CAFs) from localised prostate cancer
present in all cases. We conducted a trial to investigate or depletion of ERG fusions in treatment-resistant
the underlying causes of neo-adjuvant treatment samples. Broadly similar transcriptional profiles were
resistance in high-risk prostate cancer. observed in treated vs. untreated patients, however,
we observed an enrichment of stemcell markers and
We selected high-risk, clinically localised prostate
pathways involved in epigenetic regulation. These
cancer patients who participated in an openlabel,
data indicated that further study into epigenetic
non-randomised neo-adjuvant trial. Patients were
mechanisms is necessary to elucidate ADT treatment
treated with a mix of ‘super-castration’ drugs 6 months
resistance in aggressive prostate cancer.
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28 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 29FLASH TALK 10: SESSION 3 FLASH TALK 11: SESSION 3
Structured interview and user manual for the selection and development The smac-mimetic birinapant as a targeted therapy for
of cancer support group leaders triple-negative breast cancers
Amanda Pomery anchored rating scales; produced a user manual to Najoua Lalaoui the efficacy of the clinical candidate smac-mimetic
Sir Peter MacCallum Oncology Department, facilitate standard delivery of the structured interview; Walter and Eliza Hall Institute birinapant on different subtypes of breast cancer. We
Cancer Experiences Research, piloted the structured interview to improve clinical found a differential sensitivity to birinapant amongst
utility; field tested the structured interview to develop Merino Delphine, Francois Vaillant, Goknur Giner, breast cancer subtypes. The Triple Negative Breast
The University of Melbourne
a rational scoring model. Diep Chau, Bhupinder Pal, James Whittles, Cancers (TNBC) were more sensitive to birinapant
A/Prof Miranda Xhilaga, Prof Penelope Schofield, Gordon Smyth, David L. Vaux, Jane E. Visvader, compare to ER+ breast cancers. Birinapant killing in
A/Prof Karla Gough Results: Expert consensus was reached on 52 KSA to Geoff J. Lindeman and John Silke. TNBC was dependent on TNF, TRAIL and caspases
be minimum standards for the role, and content and
Peer support groups have emerged as a community-led Breast cancer characteristics can predict treatment activation. Transcriptomic analysis using the TCGA
structure of the proposed structured interview. Pilot
approach to accessing support and connecting with responses and patient outcomes. Treatment decisions database revealed that the expression of genes
study with 3 cancer agency workers (interviewers)
others with cancer experiences. However, little was are based on the expression of three hormonal receptors: encoding positive regulators of smac-mimetic killing
and 12 cancer group leaders (interviewees) found
known about qualities required to lead a peer support ER, PR and HER2. Hormonal therapies are the mainstay were higher in TNBC in comparison to ER+ breast
the structured interview to be fit-for-purpose: 56 of
group or how to determine suitability for the role. treatment for hormone responsive breast cancer cancers. Our study demonstrated that a ‘smac-mimetic
60 ratings on suitability questions were concordant
patients, while chemotherapy is the only option for gene signature’ could be used to predict responsiveness
Aim: To produce the first pragmatic and consensus- (93%) and 139 of 156 ratings of readiness questions
patients with hormone receptor negative tumours. Key to smac-mimetic and that ER+ expression is responsible
based minimum standards to guide cancer agencies were concordant (89%). 62 current group leaders
challenges are to identify new drugs that are efficacious for smac-mimetic resistance. Importantly, we showed
with selection and development of cancer support participated in the field test. Leader characteristics and
with fewer undesirable side effects, and to match them that the combination of birinapant with chemotherapy
group leaders and a structured interview with user responses to questions were summarised, with a cut off
with the subtype of breast cancer that will respond. was superior to chemotherapy alone in the treatment
manual to enable standard delivery. score for suitability for the role determined.
Smac-mimetics block Inhibitor of Apoptosis (IAP) of TNBC PDX in vivo. Altogether our study provides the
Methods: Systematic review to identify potential Conclusion: We have developed a fit-for-purpose and rational for the clinical evaluation of smac-mimetic in
protein function, resulting in cancer cell death. Using
knowledge, skills and attributes (KSA) of support group acceptable structured interview and user guide, for the therapy for TNBC.
patient-derived xenograft (PDX) models, we evaluated
leaders described in peer-reviewed literature; online selection and development of cancer support group
reactive Delphi method with an interdisciplinary leaders. A more comprehensive pool of participants and
panel of experts to produce a relevant and appropriate result scores is recommended to determine a complete
structured interview of questions with behaviourally rational scoring model.
30 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 31FLASH TALK 12: SESSION 3 ORAL 10: SESSION 4
Combinatorial targeting by microRNAs coordinates post transcriptional A pilot randomised controlled trial of an online mindfulness-based program
control of breast cancer EMT for people diagnosed with melanoma
Joe Cursons This may in part explain why over 130 different miRNAs Lahiru Russell Results: Sixty-nine (58 %) eligible participants were
Walter and Eliza Hall Institute have a demonstrated role in directing epithelial- Peter MacCallum Cancer Centre randomized (46 in the intervention; 23 in the control
mesenchymal transition (EMT), a reversible phenotypic group); mean age was 53.4 (SD: 13.1); 54% were female.
Katherine A Pillman, Kaitlin Scheer, Philip A Gregory, switch underlying both normal and pathological Anna Ugalde, Liliana Orellana, Donna Milne, Study completion rate across both arms was 80%.
Momeneh Foroutan, Soroor Hediyeh Zadeh, processes. In a human mammary cell model of EMT, Mei Krishnasamy, Richard Chambers, David Austin The intervention was found helpful by 72% of the 32
John Toubia, Edmund J Crampin, Gregory J Goodall, we observe not only post-transcriptional responses to and Patricia M Livingston respondents. The intervention significantly reduced the
Cameron P Bracken, Melissa J Davis miRNA perturbation, but also extensive and distributed Purpose: This study assessed the feasibility and severity of FCR compared to the control group (mean
MicroRNAs (miRNAs) are important components of the transcriptional changes, suggesting miRNAs both acceptability of an online mindfulness-based difference=-2.55; 95% CI:-4.43, -0.67; p=0.008).
systems that regulate gene expression, functioning reinforce and buffer transcriptional output. Further, intervention (MBI) for people at high risk of melanoma
Conclusions: This online MBI was feasible and
in part by facilitating the degradation of target we demonstrate that miR-200 family members act in recurrence. The potential benefit of the MBI on fear of
acceptable by people at high risk of melanoma
mRNA transcripts. MiRNAs frequently target mRNAs concert with the miR-182/-183 family to coordinate cancer recurrence (FCR), worry, rumination, perceived
recurrence. It significantly reduced FCR severity in this
encoding transcription factors which themselves the reverse MET process, with combinatorial activity stress and trait mindfulness was also explored.
sample. Patients valued accessing the program at their
control miRNA expression, thus establishing feedback allowing miRNA function at dramatically reduced Methods: Participants who have completed treatment own pace and convenience. This self-guided intervention
mechanisms that can control complex phenotypic concentrations, whilst alleviating some off-target for stage 2c or 3 melanoma were recruited from an has the potential to help survivors cope with emotional
change. Many studies demonstrate miRNA function effects. Together these results show that the outpatient clinic and randomly allocated to either difficulties. An adequately powered randomised
using overexpression at levels greatly exceeding combinatorial activity of miRNAs should be addressed the online MBI (intervention) or usual care (control). controlled trial to test study findings is warranted.
physiological abundance, which can lead to effects on when studying their endogenous regulatory effects. The 6-week online MBI comprised short videos, daily
transcripts with relatively poor sequence overlap.
guided meditations and automated email reminders.
Participants were asked to complete questionnaires
at baseline and at 6-weeks post-randomisation. Study
feasibility and acceptability were assessed through
recruitment rates, retention, and participant feedback.
Clinical and psychosocial outcomes were compared
between groups using linear mixed models.
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32 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 33ORAL 11: SESSION 4 ORAL 12: SESSION 4
Pro-survival protein Mcl-1 is a promising therapeutic target Mechanistic investigations into acquired resistance to BH3 mimetics
in mantle cell lymphoma in primary CLL
Michael Dengler To explore the potential of directly inhibiting Mcl-1 for Rachel Thijssen idea, we compared the development of resistance in
Walter and Eliza Hall Institute treating MCL, we exposed a panel of MCL cell lines to Walter and Eliza Hall Institute isogenic TP53-null lines to their wild-type counterparts
the new specific Mcl-1 inhibitor S63845. Four of five in long-term cultures. Also, it seems likely that the
Marco J. Herold, Andrew W. Roberts and cell lines tested were very sensitive to the inhibitor. M.A. Anderson, C.E. The, D.H. Gray, A.W. Roberts, microenvironment for the CLL cells (lymphoid tissues)
Jerry M. Adams Furthermore, Mcl-1 inhibition showed synergy when D.C.S. Huang could influence response to venetoclax. To explore this
Aberrant expression of apoptosis-regulating combined with targeted therapies, such as the Bruton’s The impairment of apoptosis is a crucial attribute further, we set up a model system culturing primary CLL
Bcl-2 family members can promote malignant tyrosine kinase inhibitor ibrutinib or ABT-199. of many cancers. In chronic lymphocytic leukemia cells with feeder cells expressing hCD40L and cytokine
transformation and resistance to therapy. Direct (CLL), this is driven by overexpression of the survival IL-21 to mimic the CLL-T cell interaction, as well as
To confirm these results in a more clinically relevant
inhibition of Bcl-2 itself using the Bcl-2-specific protein BCL2. Targeting BCL2 with the BH3 mimetic IgM to stimulate the B-cell receptor. We analyzed CLL
setting, we are testing the efficacy of the Mcl-1 inhibitor
antagonist ABT-199 (venetoclax) has already shown compound venetoclax has proven to be highly effective samples before, during and after 6 weeks of culture
in primary samples from MCL patients, using CD40L-
great promise for hematologic malignancies in the for patients with relapsed or refractory (R/R) CLL; the with a panel of 42 antibodies that detect expression of
expressing feeder cells to mimic the microenvironment.
clinic. The Bcl-2-relative Mcl-1 is also deregulated in overall response rate (ORR) was ~80% in the early key markers by CyTOF (mass spectrometry by Cytometry
Initial tests show sensitivity of primary MCL cells to
many blood cancers and hence may also be a promising phase clinical trial. However, the disease progresses by Time of Flight). Our preliminary results suggest that
S63845. Although CD40L-stimulation can modulate
therapeutic target. within two years of commencing venetoclax in ~50%, the microenvironment selects for CLL cells with altered
S63845 action, we find that cell death can be restored
notably in those with complex karyotypic abnormalities. expression of BCL2 proteins, possibly accounting for
Mantle cell lymphoma (MCL) is an aggressive form of by combination treatment strategies.
Using validated laboratory models, we are attempting their resistance.
non-Hodgkin lymphoma that typically responds only
Together, our findings strongly suggest that Mcl-1 to address whether such karyotypic abnormalities
transiently to chemotherapy. Hence, new therapeutic Taken together, our ongoing studies will help us
is crucial for maintenance of MCL. It represents a promote the acquisition of resistance and if so, how.
approaches are urgently needed. To establish whether understand why resistance emerges and have
promising therapeutic target for this and related The tumor suppressor TP53 is often lost in CLL: even
Mcl-1 is critical for maintaining MCL cell survival, we significant implications for how venetoclax is best used,
malignancies and might well circumvent their though its deletion or mutation does not impact upon
first tested the impact of acute Mcl-1 knockout using for preventing the development of therapy resistance or
frequently observed resistance to current therapies. venetoclax sensitivity, we hypothesized that its loss
an inducible CRISPR/Cas9 system. Intriguingly, its to develop strategies to tackle resistance.
might promote the acquisition of resistance. To test this
knockout triggered spontaneous apoptosis in most MCL
cell lines tested.
34 | New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 New Frontiers in Cancer Research – VCCC Postdoctoral Symposium 2018 | 35You can also read
