Page 8 - CUA2019 Abstracts - Oncology-Prostate

Poster session 4: Prostate Cancer I

and tumour growth measured every day until sacrifice. Fecal samples were cated in de novo lipogenesis (FAS, ACC, and SCD1) reduced tumour growth
harvested at different time points and microbiota analyzed via 16srRNA and enhanced cell death of PCa cells. Expressions of enzymes involved in
high throughput sequencing. Blood and tumours were collected at end- de novo lipogenesis are initially decreased in patients treated with andro-
point and cytokines profiled using BioPlex Pro™ 23-plex. gen-deprivation therapy (ADT) but re-emerge at higher levels in CRPC.
Results: We observed reduced late-stage tumour growth in animals given Methods: We used two PCa cell lines: LNCaP as a hormone-sensitive
EPA. Level of cytokines for both EPA and DHA were generally similar to cell line, and C4-2B as a castrate-resistant cell line. Cells were treated
HOSO, while AA displayed a profile associated with pro-inflammatory with enzalutamide (20 uM), SCD1 inhibitor (10 uM), or a combination
cytokines. 16srRNA profiling revealed an Ω3-driven reduction of rum- of the two treatments (combo) for 72 hours. We analyzed the effect of
minococcaceae that correlated with reduced IL-17 in plasma. The Ω3 each treatment on cell proliferation and viability. We also evaluated the
treatment also correlated with altered levels of a panel of bacteria previ- effect on endoplasmic reticulum (ER) stress and reactive oxygen species
ously associated with IL-17. production (ROS). Finally, we used xenograft mice to confirm our in vitro
Conclusions: Here we report the anti-cancer effect of pure EPA molecules. observed results.
We also outline an approach that study changes in gut microbes as a Results: We showed that the combination of both treatments induces
proxy for interactions between dietary lifestyle altered immunity and a higher decrease in cell proliferation and an increase in death cells
prostate tumour growth. (apoptosis) compared to monotherapies. We also showed an increase in
ER stress and ROS production in cells treated with the combination of
UP-4.8 therapies. Finally, we showed that xenograft mice treated with the combo
had a lower tumour growth and a higher level of apoptotic cells.
Investigating a novel recombinant antibody to attenuate prostate Conclusions: Our study showed that the combination of enzalutamide
cancer progression by targeting cell surface GRP78 with an inhibitor of SCD1 could be an interesting strategy for improving
Ali Al-Hashimi , Kevin Won , Elizabeth Pham , Natalie Mariano , Julie cell response and in preventing therapy resistance.
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Bailis , Richard Austin , Bobby Shayegan 1
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1 Department of Surgery and Medicine, McMaster University, Hamilton,
ON, Canada; Department of Research, Amgen, South San Francisco, UP-4.10
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CA, United States Disease-specific costs of non-metastatic and metastatic
Introduction: Tissue factor (TF), a procoagulant protein, drives prostate castration-resistant prostate cancer in Québec
cancer (PCa) tumour progression via activation of GRP78 on the cell sur- Ivan Yanev , Armen G. Aprikian , Emma Nablsi , Zachary Vaillancourt ,
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face (cs). In PCa, GRP78 is an endoplasmic reticulum-resident chaperone Jonathan Primiani , Karen Bremner , Steven Carcone , Nicholas
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that localizes to the cell surface, where it functions as a signaling molecule Mitsakakis , Welson Rayan , Murray Krahn , Alice Dragomir 1
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with antigenic properties. PCa patients produce autoantibodies (AutoAbs) 1 Urology, McGill University, Montréal, QC, Canada; Toronto Health
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against the N-terminus of GRP78 that act as a potent driver of tumour Economics and Technology Assessment (THETA) Collaborative, Toronto
growth via upregulation of TF activity and prosurvival pathways. Here, we General Hospital Research Institute, University Health Network, Toronto,
describe a recombinant anti-GRP78 antibody (AEP8587) that competes ON, Canada
with the binding of AutoAbs to csGRP78, decreases TF activation, and Introduction: Prostate cancer (PCa) accounts for 10% of all cancers
may act as a novel therapeutic antibody with anti-tumour activity. diagnosed in Canada and 21% (21 300 new cases) of cancers among
Methods: Changes in TF activity or survival were evaluated in vitro in males. Androgen-deprivation therapy (ADT) is a very effective strategy for
the PCa cell line DU145 following treatment with anti-GRP78 AutoAbs managing PCa. However, nearly all men will develop castration-resistant
or co-treatment with either enoxaparin, a low molecular weight hepa- disease and the majority of men who die from PCa will experience a
rin (LMWH), or AEP8587. Protein expression of TF and UPR markers progression to metastatic disease.
was determined using western blotting and qRT-PCR. TF activity was Methods: We aimed to estimate the disease-specific costs of PCa patients
determined using a real-time continuous assay. AutoAbs were purified during the health states of non-metastatic castration-resistant prostate
from PCa patients (St. Joseph’s Healthcare Hamilton). cancer (nmCRPC) and metastatic castration-resistant prostate cancer
Results: Pre-prostatectomy PCa patients display high levels of anti-GRP78 (mCRPC). This cohort analysis contains 211 PCa patients from the McGill
AutoAbs (~60 μg/ml), compared to healthy controls (~5 μg/ml). Here, we University Health Centre (MUHC) that were selected retrospectively
show that anti-GRP78 AutoAb increases TF activation in vitro and leads to through the period from 2000 to the end of 2015. The patients were
increased tumour progression in a DU145 xenograft model. In contrast, followed from diagnosis of PCa until death or until the end of 2016. An
we show a co-treatment of anti-GRP78 AutoAb with either enoxaparin algorithm of detecting nmCRPC and mCRPC was based on increases
or AEP8587 completely abolishes the AutoAb-mediated increase in TF of prostate-specific antigen (PSA) levels after castration and the detec-
activity in vitro. Enoxaparin or AEP8587 co-treatment reversed the AutoAb tion of metastasis. Consecutively, the mean time per health state was
effect on increased UPR markers. identified. Resource prices were obtained from the Régie de l’assurance
Conclusions: We have identified anti-GRP78 AutoAb as a driver of PCa maladie du Québec (RAMQ) list of medications when available; when
progression. Our results indicate that a recombinant antibody, AEP8587, unavailable, prices were obtained from the MUHC internal price lists.
can bind to csGRP78 and prevent the binding of anti-GRP78 AutoAbs. This cost analysis was performed from a healthcare system perspective.
This represents a potential novel means to manage PCa progression. Results: Mean duration of nmCRPC was 26.07 months, while duration
of mCRPC was 20.79 months, with 62 and 68 patients per health state,
UP-4.9 respectively. The average disease-specific resource use per patient for 30
days was $786 for nmCRPC and $2210 for mCRPC, with the cost driver
Strategy for improving therapeutic response and delaying being chemotherapy or prescription drugs different than ADT. The total
resistance in prostate cancer through the inhibition of lipogenesis average cost for nmCRPC health state was $20 457 compared to $45
Amine Lounis , Benjamin B. Peant , Fred Saad 1 956 for mCRPC.
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1 Institut de Cancer de Montréal, CRCHUM, Montréal, QC, Canada Conclusions: The disease-specific resource utilization costs for mCRPC
Introduction: Prostate cancer (PCa) is the most common cancer in men are significantly higher than the costs for nmCRPC. The overall cost of
and the second leading cause of cancer-related deaths in men. Progression these phases of PCa should be even higher, as the present study captured
of PCa leads to a transition from androgen-dependent state to castration- only costs associated with medical health records.
resistant state (CRPC). Enzalutamide is a new-generation anti-androgen This paper has figures, which may be viewed online at:
that blocks several steps in the AR-signaling pathway. However, similar to https://2019.cua.events/webapp/lecture/136
other PCa therapies, patients eventually develop a resistance to enzaluta-
mide treatment, and the exact mechanisms responsible for this resistance
remain unclear. Many studies showed that the inhibition of enzymes impli-
CUAJ • June 2019 • Volume 13, Issue 6(Suppl5) S111