Page 7 - CUA2019 Abstracts - Oncology-Prostate

2019 CUA Abstracts

proliferation (Ki-67), epithelial composition (CK 8/18), and senescence UP-4.6
(p21, p16) by immunohistochemistry (IHC) and immunofluorescence (IF) Qualitative correlations of positron-emission tomography-
techniques. MDTs were also exposed to gamma irradiation (5 or 10 Gy) detected intra-prostatic lesions with sextant transrectal
to identify homologous recombination (HR) repair efficiency by following ultrasound biopsy and post-prostatectomy histopathology results
the cells ability to form y-H2AX and RAD51 foci using IF. Khalil Hetou , Glenn Baumann , Jonathan Thiessen , Madeleine Moussa ,
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Results: Our 2D sensitivity profile characterization suggests a correlation Irina Rachinsky , Zahra Kassam , Stephen E. Pautler , Shiva Nair , Ting
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between the status of hormone dependency and sensitivity to PARPi, as Yim Lee , John F. Vallian , Aaron Ward , Joseph Chin 1,2
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well as to their efficiency in repairing double strand DNA breaks. Basing 1 Urology, University of Western Ontario, London, ON, Canada; Oncology,
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our 3D analyses on our 2D characterization, we have identified a treat- University of Western Ontario, London, ON, Canada; Medical Imaging,
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ment regimen, consisting of a 72-hour exposure to olaparib, to monitor University of Western Ontario, London, ON, Canada; Medical Physics,
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various cell fates induced by the cytostatic drug, such as cell death, cell University of Western Ontario, London, ON, Canada; Pathology,
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proliferation, and senescence. In addition, we have optimized the IF University of Western Ontario, London, ON, Canada; Chemistry and
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staining of our irradiated MDTs showing that we can reproduce the 2D Chemical Biology, McMaster University, Hamilton, ON, Canada
HR response to gamma irradiation in a 3D setting. Canadian Institutes of Health Research (CIHR), Ontario Institute for
Conclusions: This additional information will help dictate which patients Cancer Research, Smarter Imaging Program – Prostate (OICR)
would most likely benefit from this targeted treatment and would give Introduction: As part of a Prostate Cancer Image-Guided Interventions
insight on how to properly stratify patients according to molecular proper- Study, we investigated positron-emission tomography (PET) imaging with
ties in a clinical decision-making timeframe. two different tracers in the preoperative setting, for possible correlation
with clinical parameters, using transrectal ultrasound (TRUS)-guided
UP-4.5 biopsy (Bx) as the reference.
IKKε inhibition by BX795 induces cell cycle arrest and genomic Methods: A sextant template was created to compare Bx and PET findings
instability to promote the senescence in castrate-resistant with final pathological whole-mount specimens. The sum of maximum
prostate cancer cell lines standardized uptake (SUVmax) values from all positive foci was calculated
Sophie Gilbert , Benjamin Péant , Hubert Fleury , Nicolas Malaquin , Kim for each case to assess for correlation with extra-prostatic extension (EPE).
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Leclerc-Desaulniers , Anne-Marie Mes-Masson , Fred Saad 1,3 Results: F-18 Cohort: 138 prostate sites from 23 men were identified.
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1 Institut du Cancer de Montréal, Centre de Recherche du CHUM, Site-specific sensitivity and specificity of PET for any disease were 44.8%
Montréal, QC, Canada; Département de Médecine, Université de and 72.7%, respectively. For clinically significant disease (CS) (GS of 3+4
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Montréal, Montréal, QC, Canada; Département de Chirurgie, Université and higher) sensitivity increased to 55.2% but had a specificity of 62%.
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de Montréal, Montréal, QC, Canada GS-stratified analysis showed no significant difference in PET-positive
Introduction: Prostate cancer (PCa) is the third most common cause of lesions among GS subgroups (p=0.18). Bx had a sensitivity of 20% but a
cancer-related death in Canadian men. Advanced prostate cancer often specificity of 96.6% for CS disease. Mean total SUVmax in men with pT2
evolves from a hormone-sensitive (HS) to a lethal castration-resistant (CR) was similar to that in men with pT3 (9.0 vs. 8.8) (p=0.61). DCFPyL cohort:
state. Our lab has previously demonstrated that CR cells exhibit a con- 120 prostate sites were identified from 20 men. Site-specific sensitivity and
stitutive over-expression of IKKε. In this context, this kinase activates the specificity of PET for any disease were 28.4% and 74.3%, respectively.
transcription factor C/EBP-β to induce IL-6 expression. Recent studies Bx had a sensitivity of 60.3% and specificity of 66.7% for any disease.
have shown that C/EBP-β participates in the development of senescence Sensitivity and specificity of PET for CS disease increased to 32% and
in response to androgen-deprivation therapy (ADT), called androgen- 76%, respectively. Bx had a sensitivity of 32% and a specificity of 80%
deprivation induced-senescence (ADIS). We hypothesize that IKKε expres- for CS disease. GS-stratified analysis showed no significant difference in
sion has a role in PCa progression by preventing ADIS in PCa cells. PET-positive lesions among GS subgroups (p=0.73). Mean total SUVmax
Methods: BX795 is used as an inhibitor of the IKKe/TBK1 complex. We in men with pT2 (n=12) was 5.72 (standard dveiation [SD] 1.4) vs. 14.89
tested this inhibitor on CR cells (PC-3, DU-145, and C4-2b) and HS (SD 3.73) in men with pT3 (p=0.016).
cells (LNCaP and 22Rv1). DU145 cell lines are subcutaneously injected Conclusions: On qualitative, sextant-wise assessment, preoperative Bx
in our mouse model, and when the tumour reaches 400 mm , BX795 is and PET had modest correlation with RP specimens. Higher PSMA PET
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administered intra-peritoneal. SUVmax among men with EPE suggests possible utility for treatment plan-
Results: Proliferation of CR cells dramatically decreased after BX795 treat- ning. Quantitative (voxelwise) correlative studies are underway.
ment compared to HS cells. This was confirmed by the EdU incorporation
assay. The number of SA-b-Gal+ cells (senescence marker) increased in UP-4.7
CR cells with an increase of p15 and DNA damage (gH2AX foci). After Modulation of microbiota and ectopic prostate tumour growth
six days of treatment, CR cells increased G2/M phase of cell cycle. We by polyunstaturated fatty acids
also observed a pool of cells with 8N DNA content. These multinuclei Gabriel Lachance , Nikunj Gevariya , Thibaut Varin , Karine Robitaille ,
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cells were observed in DAPI staining with micronuclei. Overall, BX795 Alain Bergeron , Yves Fradet , André Marette , Vincent Fradet 1
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injection in a mouse model results in a decrease in tumour volume while 1 Oncology Axis, Centre de Recherche du CHU de Québec-Université
having no effect on mouse behaviour and body weight. Laval, Québec City, QC, Canada; Médecine, Centre de Recherche de
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Conclusions: Our study suggests that BX795 treatment promotes a cell l’IUCPQ-Université Laval, Québec City, QC, Canada
cycle disrupt in CR cells only. This cell cycle arrest is accompanied by DNA Introduction: Several studies highlighted a contributing effect of nutrient
damage and promotes a senescence phenotype. These results suggest a overload for increasing aggressiveness of several cancers, including pros-
possible involvement of IKKε in the development of a CR state and justify tate cancer (PCa). In the gut, elevated lipid ingestion promotes the replica-
further studies addressing the potential of IKKε as a therapeutic target. tion of commensal microbes and contributes to chronic inflammation.
Since omega-3 (Ω3) fatty acids (FA) have documented anti-inflammatory
properties and potential anti-cancer effects, we tested the contribution
of ingested pure polyunsaturated Ω3 and controls Ω6 and Ω9 FA for
TRAMP-C2 PCa tumour growth in immunocompetent mice.
Methods: C57BL/6 mice were fed with a low-fat diet and daily supple-
mented by oral gavage with purified monoglycerides of FAs, i.e.Ω3-
eicosapentaenoic acid (EPA), Ω3-docosahexaenoic acid (DHA),
Ω6-arachidonic acid (AA), or Ω9-rich high-oleic sunflower oil (HOSO)
until animal sacrifice (n=12 mice/group). After two weeks, TRAMP-C2
mouse PCa cells were implanted subcutaneously on each mouse flank
S110 CUAJ • June 2019 • Volume 13, Issue 6(Suppl5)