Oncology Abstracts

Endocrine resistant estrogen receptor positive (ER+) breast cancers are dependent upon cyclin-dependent kinases (CDK) 4/6 for proliferation, making them highly suitable for CDK4/6 inhibitor treatment. Despite initial efficacy, acquired resistance to CDK4/6 inhibitors is emerging and is now a major consideration in pre-clinical and clinical drug development. Current models of CDK4/6 inhibitor resistance do not mimic the clinical scenario where CDK4/6 inhibition will occur in th...

Metastasis is the major cause of death in breast cancer patients, largely due to the poor efficacy of existing therapies. Here we report that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, we demonstrate that BMP4 acts as an autocrine mediator to modulate a range of known metastasis regulating genes, including SMAD7, via activation of c...

We have recently discovered that metals which coordinate with selected compounds can be prepared inside liposomes. This technology, which we refer to as Metaplex™ technology, is enabling development of a brand new class of therapeutics. Previously the development of metal drug complexes (CDCs) has been hindered because of their very poor aqueous solubility. As an example, diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for the treatm...

Objective: Prostate cancer susceptibility is influenced by common variants at multiple loci, however, the mechanisms by which these germline variants influence prostate cancer risk remain largely unknown. A single nucleotide polymorphism (SNP) rs17632542 in the PSA gene has been identified to be associated with prostate cancer risk using large scale genome-wide associate studies. This SNP was previously questioned for its association with prostate cancer due to its association...

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Uncontrolled genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but relatively few drivers have been identified for this process. Cyclin E1 and cyclin E2 are cell cycle regulators whose dysregulation in oncogenesis promotes both increased proliferation and genomic instability. Due to their roles in normal physiological endoreduplication of the genome for specialised cell types, we hypothesised that cyclin E1 and cyclin E2 may be drivers o...

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 ...

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...

There is bidirectional interplay between PR and ER in human breast cancers. There is evidence for a reprogramming of ER chromatin binding sites with 470 genes differentially regulated by dual treatment with estrogen plus progestogen compared to estrogen alone in breast cancer cell lines. Functionally, there was an additive anti-cancer effect with the addition of natural progesterone to endocrine therapy in preclinical breast cancer models. This is a phase II multi-site, random...

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 ...

A current challenge in cancer therapeutics is incomplete response to treatment and emergence of therapy-resistant disease. Androgen deprivation therapy (ADT), the standard treatment for advanced prostate cancer, and effectively reduces the tumour burden in most patients. Yet, residual tumour cells that withstand ADT eventually develop lethal castration-resistance. Eliminating these castrate-tolerant cells, by combining ADT with other treatments, might delay or even prevent cas...

Overexpression of ErbB-2, a member of ErbB family of receptor tyrosine kinases, occurs in 15–20% of breast cancers (BC) and is considered a major oncogenic driver. Despite clinical efficiency of ErbB-2-targeted therapies (e.g. trastuzumab), resistance to said drugs is a major issue. While ErbB-2 is mainly a cell membrane-bound receptor, it can migrate to the nucleus (NErbB-2) where it acts as a transcription factor or coactivator. We revealed that NErbB-2 is a major proli...

Epithelial-mesenchymal transition (EMT) and the reverse mesenchymal-epithelial transition (MET) are normal biological processes, however they are also thought to play a critical role in the progression and metastasis of cancers, including breast cancer. Cancer cells reactivate the gene expression programs of EMT and MET through a wide range of mechanisms, and better understanding of these regulatory processes will lead to the identification of therapeutically actionable target...

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 ...

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Aggressive prostate cancer is characterized by altered lipid metabolism and metabolic stress. At a subcellular level these changes are localized to the endoplasmic reticulum (ER) and mitochondria. Traditionally the function of these organelles has been studied separately. A growing body of evidence shows that the interaction between mitochondria and ER at specialized membrane contact sites play a key role in regulating fundamental cellular processes such as lipid synthesis, mi...

In a bid to discover genomic features associated with prostate cancer (PrCa) development and progression, copy number variations (CNVs) have been studied in tumour samples. Early comparative genomic hybridisation (CGH) studies led to the identification of many chromosomal regions of loss and gain, with a small number of these shown to be consistent across studies and, significantly, some suggested to be associated with PrCa progression. More recently a small number of studies ...

Circular RNAs (circRNAs) are a newly appreciated class of regulatory RNA species that play vital roles in various cell signaling and metabolic processes. Deregulated expression of circRNAs has been found to be associated with various human diseases including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, initi...

Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as ‘translational of...

Tumour cell heterogeneity constitutes a challenge for cancer treatment and deeply impact the outcome of patients. A simultaneous overview of cancer cells and associated stromal cells is critical for the design of improved therapeutic regimes. Single-cell RNA-seq has emerged as a powerful method to unravel heterogeneity of complex biological systems; this has enabled in vivo characterization of cell type compositions through unsupervised sampling and modelling of trans...

The establishment of mammographic screening programs has resulted in a striking increase in the incidence of ductal carcinoma in situ (DCIS), with DCIS accounting for approximately 20% of all new screen-detected breast cancers. An estimated 40% to 70% of DCIS lesions may progress to invasive disease if left untreated. This number is considerably reduced by treatment: surgical excision followed by radiation therapy is curative in over 95% of cases. However, of the DCIS...

The standard of care for early postmenopausal ERα+ breast cancer patients is adjuvant endocrine therapy, with or without a CDK 4/6 inhibitor in the metastatic setting. However, many patients are resistant or experience recurrence 10 to 15 years after treatment. A subset (10–40%) of ERα+ therapy-resistant breast cancers express somatic ESR1 mutations. The two most common ERα mutations are Y537S and D538G, which confer ERα constitutive activity. Lasofoxi...

Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of female cancer related death. Despite significant advances in early detection, surgery and therapy, treatment remains a challenge if metastatic disease develops. Metastasis occurs with high frequency in triple negative (ER/PR/HER2 negative, TNBC) breast cancers, which are a heterogeneous group of cancers with poor clinical outcome. We used an integrated approach to identify miRNAs tha...

The propensity of cancer cells to transition between epithelial and mesenchymal phenotypic states via the epithelial-mesenchymal transition (EMT) program can regulate metastatic processes, cancer progression, and treatment resistance. Transcriptional investigations using reversible models of EMT, revealed the mesenchymal-to-epithelial reverting transition (MErT) to be enriched in clinical samples of metastatic castrate resistant prostate cancer (mCRPC). From this enrichment, a...

Mammographic density (MD) is an independent risk factor for breast cancer, however what molecule or pathway within MD tissue contributes to this risk? High MD is characterized by an abundance of connective tissue stroma which is rich in heparan sulfate proteoglycans (HSPGs). Of these, SDC1 and SDC4 are upregulated in breast cancer, and we have observed a significantly higher abundance of these proteins in high vs low MD pair-wise comparisons from breast tissue from 8 individua...

High breast density is an independent risk factor for breast cancer. There is exciting potential for breast density to become a widespread health assessment tool, used to identify the women most at risk of breast cancer in order to intervene early and reduce that risk. However, a better understanding of causal biological mechanisms that lead to high breast density is required in order to develop therapeutic approaches. This project aimed to identify and investigate biological ...

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 ...

Androgen receptor (AR) signalling is essential to nearly all prostate cancer cells. Any alterations to AR-mediated transcription can have a profound effect on prostate carcinogenesis and tumour growth. While the AR protein has been extensively studied, little is know about mutations to the non-coding regions where AR binds to DNA. Using clinical whole genome sequencing, we demonstrate that AR binding sites have a dramatically increased rate of mutations that is greater than an...

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Background: Elevated circulating macrophage inhibitory cytokine -1/growth differentiation factor 15 (MIC-1/GDF15), interleukins 4 (IL4) and 6 (IL6) levels were associated with poor prognosis and resistance to docetaxel chemotherapy in an exploratory cohort of men with metastatic castration resistant prostate cancer (mCRPC). To establish level 2 evidence of biomarker utility, these cytokines were tested in internal and external validation cohorts.Methods:...

Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC. We have undertaken an integrative analysis of gene expression and DNA copy number to identify nov...

Steroid hormone receptors (SHR) play a major role in the normal breast development and breast cancer progression. Estrogen receptor (ER) is expressed in approximately 75% of breast cancers, and the majority of these tumours also express the androgen receptor (AR). While ER-directed therapies have been effective in the majority of patients, a significant subset develops resistance and requires alternative treatment approaches. In the endocrine-resistant setting, emerging insigh...

Prostate cancers are considered immunologically ‘cold’ tumors as they demonstrate poor response to check-point inhibitor therapy (CPI). Enrichment of interferon gamma (IFNγ) response genes, critical for innate and adaptive immune response to viral infections, have been demonstrated to indicate a positive response to CPI. Tumor IFNγ signaling acts as both an activator and inhibitor of effector T-cell response/trafficking via regulation of Th-1 chemokines (CX...

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 ...

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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...

The exquisite dependency of PCa on androgens for growth and survival was first recognized in the 1940’s when Huggins and Hodges demonstrated the antitumour activity of hormonal manipulation in the treatment of PCa. Since then, androgen deprivation therapy has been the standard of care in the treatment of metastatic and locally advanced PCa. Drugs targeting the androgen/androgen receptor (AR) axis have been well-validated clinically and remain without a doubt the most effe...

The plastic cancer cell model establishes that genetically identical cancer cells undergo bi-directional conversions between the highly aggressive tumour-initiating (TIC) state and the non-TIC cell state. We have identified subpopulations of breast cancer cells that readily switch from the non-TIC to TIC state, through activation of the EMT transcription factor ZEB-1. We have shown that non-TICs of basal BrCa are uniquely endowed with this plastic phenotype due to the cell&#14...

This study was conducted to define the role of Dachshund in prostate cancer, through assessing human prostate cancer samples and through genetic deletion in the mouse. Prostate cancer (PCa), the second leading cause of death in American men. A better molecular understanding of the disease is necessary in order to develop novel targeted therapies of metastatic PCa. Known genetic drivers to tumor initiation include PTEN and NKX3.1 deletions, rearrangements of the TMPRSS2</em...

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Estrogen Receptor (ER) signalling, upregulation of the cyclin/CDK pathway, and suppression of p53 form a critical axis controlling proliferation of ER positive breast cancer. In this setting, mutation of p53 is relatively rare and suppression of p53 function can be achieved via regulators MDM2 and MDMX. Activation of p53 by inhibition of MDM2 is a promising therapeutic target in p53 wildtype tumours and several drugs are currently in clinical trials. We hypothesised that the M...

Introduction: The process of Epithelial Mesenchymal Transition (EMT) involves the transition of cells from a differentiated epithelial phenotype to a less differentiated mesenchymal phenotype. Mammographic breast density (MBD) refers to the proportion of high opacity area on a mammogram. EMT may be triggered in cancer cells by a range of therapies including cytotoxic chemotherapy, with cell line and animal suggesting chemoresistance may result. High MBD in patients being treat...

Breast cancer is a heterogeneous disease that can be classified into a number of molecular subtypes that predict prognosis and influence clinical treatment. Cellular heterogeneity is also evident within breast cancers and plays a key role in their development, evolution and metastatic progression. How clinical heterogeneity relates to cellular heterogeneity is poorly understood. We have approached this question using single-cell RNA-Seq on 1000s of individual cells from well-e...

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...

Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. By integrating pre-clinical models and cli...

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-...

Seventy percent of breast cancers are classified as estrogen-receptor positive (ER+) and ER is the key proliferative driver in these tumours. Clinically, ER+ patients receive ER-targeted (endocrine) therapies to inhibit ER activity and whilst these agents reduce the risk of recurrence, up to 43% patients develop drug resistance within 15 years. Hence, identification of mechanisms underlying these resistant mechanisms could extend the use of endocrine-therapies. Profound altera...

Deregulation of the CDK4/6-cyclin D-Rb-E2F pathway is common in subtypes (e.g. ER+/HER2−) of breast cancer, and activation/amplification of cyclin D1 (CCND1) and CDK4/6, or deletion/mutation of CDKN2A gene that encodes p16INK4a are the major mechanisms. Aberration in the upstream pathways such as PI3K/Akt/mTOR can also lead to the deregulation of the CDK4/6 axis, which drives carcinogenesis and development of resistance to therapies. Therefore, inhibition of CDK4/6 is a ...

NEPC is a lethal subtype of PCa frequently arising from adenocarcinoma via NE transdifferentiation following ADT. In AACR-PCF West Dream Team series of sequential biopsies of over 300 CRPC biopsies, NEPC was discovered in 17% of cases, making neuroendocrine transdifferentiation one of the most common mechanisms underlying ADT resistance. However, a mechanistic understanding of both NEPC development and its aggressiveness remain elusive. Research in this field has been hampered...

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...