Searchable abstracts of presentations at key conferences in oncology

oa0001p036 | (1) | PacRim7

Lipid elongation in prostate cancer: an androgen regulated process and a novel therapeutic target

Nassar Zeyad D , Centenera Margaret M , Machiels Jelle , Zinonos Irene , Hanson Adrienne , Bloch Katarzyna , Mah Chui Yan , Ryan Natalie K , Williams Elizabeth D , Evdokiou Andreas , Tilley Wayne D , Selth Luke A , Butler Lisa M , Swinnen Johannes V

Objective: Although initially effective, androgen deprivation therapy fails to achieve an enduring remission in patients with advanced prostate cancer (PCa) and the cells maintain active androgen receptor (AR) signalling. Hence, a detailed understanding of the AR-driven downstream processes that are required for tumour cell growth and survival, such as lipid metabolism, is essential to reveal new therapeutic targets. In this study, we aimed to evaluate the effect of androgens ...

oa0001p016 | (1) | PacRim7

AR chromatin binding is reprogrammed in the absence of FOXA1 in ER- breast cancers

Denis Iza , Selth Luke A , Robinson Jessica LL , Mohammed Hisham , Carroll Thomas , Brown Gordon D , Neal David E , Carroll Jason S , Tilley Wayne D , Hickey Theresa E

Introduction: 75% of breast cancers (BCa) are driven by the estrogen receptor α (ER+). Tumours lacking ER (ER-) are more aggressive and have the poorest prognosis. The androgen receptor (AR) is also widely expressed in BCa (90% of primary tumours). FOXA1 is a pioneer factor required for oncogenic AR signalling in PCa but its role in AR signaling in ER-BCa is not clear. We previously showed that cell growth is increased when FOXA1 is overexpressed in AR-driven PCa and BCa ...

oa0001p010 | (1) | PacRim7

Epi-transcriptomic alterations in ER-positive breast cancer

Charmsaz Sara , Cocchiglia Sinead , Doherty Ben , Varešlija Damir , Hill Arnold D , Young Leonie S

Endocrine therapy including tamoxifen and aromatase inhibitors (AIs) are standard therapy for ER- positive breast cancer and despite its success a significant number of patients develop resistance to treatment. Transcriptional and epigenetic re-programing including DNA and RNA methylation develops with high frequency in response to therapy. Global DNA and RNA multi-omic studies have been utilized to understand the altered transcriptome of endocrine resistant breast cancer cell...

oa0001p052 | (1) | PacRim7

Novel and highly selective CDK9 inhibitors suppress proliferation of triple negative breast cancer (TNBC) cells in vitro

Winter Jean M , Mustafa Ebtihal H , Wang Shudong , Selth Luke A , Hickey Theresa E , Tilley Wayne D

This study evaluates the efficacy of two newly developed selective CDK9 inhibitors (CDK9i) across a panel of TNBC cell lines. MDA-MB-453, MFM-223, MDA-MB-468 and MDA-MB-231 TNBC cells were treated with increasing concentrations of two novel and highly selective CDK9 inhibitors and the effect on proliferation, apoptosis and expression of CDK9 targets determined. MDA-MB-453 and -468 cells showed significant growth inhibition with as little as 150 nM of CDK9i, evident 3 days afte...

oa0001p038 | (1) | PacRim7

Flicking the switch off, targeting MCL-1 in the treatment of breast and prostate cancer

Castillo L , George S , Lin H-M , Yeung N , Mawson A , Young AI , Law AM , Hastings J , Gallego-Ortega D , Deng N , Croucher D , Swarbrick A , Horvath L , Ormandy CJ , Oakes SR

The ability to survive is essential for carcinogenesis. We previously showed that in to addition promoting cancer cell survival, Myeloid Cell Leukemia 1 (MCL-1) regulates cancer cell invasion possibly via direct regulation of the cytoskeletal protein Cofilin and via modulation of the output of the SRC family kinase pathway. We also showed that dual inhibition of MCL-1 and SRC family kinases was effective in suppressing metastasis of breast cancer intraductal xenografts made fr...

oa0001p029 | (1) | PacRim7

Translation of the ERα-PR crosstalk story to the clinic (the PIONEER study), and further preclinical exploration of the diverse role of progestins in ER-positive breast cancer

Kumar Sanjeev S , Siersbaek Rasmus , Nagarajan Sankari , Provenzano Elena , Caldas Carlos , Pantziarka Pan , Baird Richard D , Carroll Jason

Background: Published preclinical findings from our lab (Cambridge Institute, CRUK) provided new insights into the functional ‘cross-talk’ between the oestrogen receptor alpha (ERα) and the progesterone receptor (PR) in breast cancer (Mohammed et al., Nature, 2015). Addition of a PR agonist to anti-oestrogens directly modifies ERα chromatin binding and the transcriptional response in breast cancer cells, and is anti-proliferative in vitro ...

oa0001p009 | (1) | PacRim7

Targeting stromal remodelling and cancer stem cell plasticity overcomes chemoresistance in metastatic triple negative breast cancer

Cazet Aurelie , Hui Mun , Elsworth Benjamin , Wu Sunny , Roden Daniel , Chan Chia-Ling , O'Toole Sandra , Watkins D Neil , Taylor Renea , Cox Thomas , Samuel Michael , Martin Miguel , Swarbrick Alexander

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblast (CAF) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production ...

oa0001p046 | (1) | PacRim7

A miR-194-regulated transcriptional network is associated with progression to androgen receptor-independent prostate cancer

Fernandes Rayzel C , Dredge Kate , Bert Andrew G , Toubia John , Pillman Katherine A , Gregory Philip A , Hickey Theresa E , Tilley Wayne D , Goodall Gregory J , Selth Luke A

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression programs and have a critical role in both normal biology and disease. We previously identified microRNA-194 (miR-194) as an important driver of prostate cancer metastasis, although the molecular mechanisms by which it mediates these effects are not well understood. This study aimed to identify target genes and pathways that are responsible for miR-194’s pro-metastatic activity. By integrating tran...

oa0001p048 | (1) | PacRim7

Exploring the clinical significance of interactions between oestrogen and progesterone receptors in breast and endometrioid adenocarcinomas by proximity ligation assay

Snell Cameron E , Smith Deborah , Gough Madeline , Liu Cheng , Middleton Kathryn , Pyke Christopher , Shannon Catherine , Woodward Natasha , Hickey Theresa E , Armes Jane E , Tilley Wayne D

Recent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-α (ER) and reprograms transcription toward better breast cancer outcomes. We investigated whether ER and PR interactions were present in breast and endometrial tumours and associated with clinical parameters including response to endocrine treatments. We developed a proximity ligation assay to detect ER and PR interactions in formalin-...

oa0001p012 | (1) | PacRim7

Targeting AR in endocrine-resistant breast cancer

Chia KeeMing , Milioli Heloisa , Portman Neil , Laven-Law Geraldine , Coulson Rhiannon , Yong Aliza , Segara Davendra , Parker Andrew , Caldon Catherine E , Deng Niantao , Swarbrick Alexander , Tilley Wayne D , Hickey Theresa E , Lim Elgene

Introduction: Resistance to endocrine therapy is a major clinical problem in estrogen receptor positive (ER+) breast cancer. The androgen receptor (AR) is expressed in ~90% of all primary ER+ breast cancers and high expression of AR is associated with a better patient outcome in this tumours. However, uncertainty surrounding the role of AR in endocrine resistance is reflected in current clinical trials in which both AR agonists and antagonists are being investigated. Here, we ...