Prof Francesco Crea

Neuroendocrine Prostate Cancer (NEPC) is an incurable disease, which originates from the trans-differentiation of prostatic adenocarcinomas exposed to prolonged hormonal therapies (1). NEPC is incurable, with a median survival shorter than 1 year. NEPC pathogenesis is largely unknown. This is due to the lack of suitable pre-clinical models for this disease. We have recently replicated a technique that allows us to transform prostate adenocarcinoma cells into NEPC cells by hypoxia conditioning (2). We propose to use this technique to develop and characterise new NEPC models, which will be then used to identify new therapeutic targets for NEPC. We would like to receive expressions of interest from a range of PhD candidates working on this project with potential industrial collaborators (part-time or full-time, depending on mutual agreement). The main aims of the project will be: 1. To generate and characterise NEPC cells by hypoxia conditioning 2. To identify genes that are differentially expressed between NEPC and non-NEPC cells 3. To test whether any of these differentially expressed genes is a promising therapeutic target for NEPC. The project will be co-created with the successful candidate. Hence, the candidate is encouraged to consider techniques that could be used to identify new therapeutic targets, referring to previous publications from our laboratory (3-5). These techniques may include innovative bioinformatic tools (e.g. analysis of RNA Seq data from patient datasets). This part of the project will be supervised by Dr Hintze, who has specific expertise in bioinformatic analyses. The final aim of this project is to generate new NEPC models, and to identify at least one new therapeutic target for this incurable disease. References 1. Wang Y, Wang Y, Ci X, Choi SYC, Crea F, Lin D, Wang Y. Molecular events in neuroendocrine prostate cancer development. Nat Rev Urol. 2021 Oct;18(10):581-596. doi: 10.1038/s41585-021-00490-0. Epub 2021 Jul 21. PMID: 34290447; PMCID: PMC10802813. 2. Danza G, Di Serio C, Rosati F, Lonetto G, Sturli N, Kacer D, Pennella A, Ventimiglia G, Barucci R, Piscazzi A, Prudovsky I, Landriscina M, Marchionni N, Tarantini F. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells. Mol Cancer Res. 2012 Feb;10(2):230-8. doi: 10.1158/1541-7786.MCR-11-0296. Epub 2011 Dec 15. PMID: 22172337; PMCID: PMC3433043. 3. Wang Y, Xue H, Zhu X, Lin D, Dong X, Chen Z, Chen J, Shi M, Ni Y, Cao J, Wu R, Kang N, Pang X, Crea F, Lin YY, Collins CC, Gleave ME, Parolia A, Chinnaiyan A, Ong CJ, Wang Y. Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation. bioRxiv [Preprint]. 2024 Apr 29:2024.04.27.591428. doi: 10.1101/2024.04.27.591428. PMID: 38746377; PMCID: PMC11092479. 4. Mather RL, Parolia A, Carson SE, Venalainen E, Roig-Carles D, Jaber M, Chu SC, Alborelli I, Wu R, Lin D, Nabavi N, Jachetti E, Colombo MP, Xue H, Pucci P, Ci X, Hawkes C, Li Y, Pandha H, Ulitsky I, Marconett C, Quagliata L, Jiang W, Romero I, Wang Y, Crea F. The evolutionarily conserved long non-coding RNA LINC00261 drives neuroendocrine prostate cancer proliferation and metastasis via distinct nuclear and cytoplasmic mechanisms. Mol Oncol. 2021 Jul;15(7):1921-1941. doi: 10.1002/1878-0261.12954. Epub 2021 Apr 26. PMID: 33793068; PMCID: PMC8253100. 5. Silvestri R, Pucci P, Venalainen E, Matheou C, Mather R, Chandler S, Aceto R, Rigas SH, Wang Y, Rietdorf K, Bootman MD, Crea F. T-type calcium channels drive the proliferation of androgen-receptor negative prostate cancer cells. Prostate. 2019 Sep;79(13):1580-1586. doi: 10.1002/pros.23879. Epub 2019 Jul 23. PMID: 31334879.

This will be a one-day symposium aimed at sarcoma (clinical specialists and researchers). Attendance will be in person (encouraged) or on-line (via Teams). We will aim to obtain CPD accreditation, as per other symposia organised by our group.

Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer. Inoperable HCC is treated with the kinase inhibitor sorafenib, an expensive drug sometimes associated with severe side effects. Currently, there is no way of predicting which HCC patients will benefit from sorafenib treatment. Histone modifications are epigenetic marks that are often deregulated in cancer cells. We have previously shown that specific histone modifications drive cancer cell resistance to therapies. Our industrial partner Volition has developed assays to measure circulating cancer-derived histones from tiny amounts of serum or plasma samples. In this project, we will use these assays to identify a circulating epigenetic signature that predicts HCC patients’ response to sorafenib.

In this proposal, I hope to understand how the cellular microenvironment, specifically NETosis, has the ability to alter 3D structure, chromatin accessibility, and gene expression. The hypothesis is that factors released through NETosis can change cell signaling pathways, and the response between mouse healthy and cancer cell lines will be different. The objective is to better understand if the epigenetic and transcriptomic response following NETs exposure differs between healthy and cancer cells.

Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer. Inoperable HCC is treated with the kinase inhibitor sorafenib, an expensive drug sometimes associated with severe side effects. Currently, there is no way of predicting which HCC patients will benefit from sorafenib treatment. Histone modifications are epigenetic marks that are often deregulated in cancer cells. We have previously shown that specific histone modifications drive cancer cell resistance to therapies. Our industrial partner Volition has developed assays to measure circulating cancer-derived histones from tiny amounts of serum or plasma samples. In this project, we will use these assays to identify a circulating epigenetic signature that predicts HCC patients’ response to sorafenib.

Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer. Inoperable HCC is treated with the kinase inhibitor sorafenib, an expensive drug sometimes associated with severe side effects. Currently, there is no way of predicting which HCC patients will benefit from sorafenib treatment. Histone modifications are epigenetic marks that are often deregulated in cancer cells. We have previously shown that specific histone modifications drive cancer cell resistance to therapies. Our industrial partner Volition has developed assays to measure circulating cancer-derived histones from tiny amounts of serum or plasma samples. In this project, we will use these assays to identify a circulating epigenetic signature that predicts HCC patients’ response to sorafenib.

Recent genomic and histopathological analyses have shown that up to 17% of castration-resistant prostate adenocarcinomas (PCas) develop neuroendocrine (NE) features [1]. This trans-differentiation induces complete androgen-independence and promotes metastatic spreading. NE-PCas are currently incurable and associated with a dismal prognosis (median survival shorter than 1 year). Therefore, there is a dire need for the identification of effective therapeutic targets for this aggressive malignancy. Calcium dynamics govern key aspects of cellular phenotypes, including tissue specification, motility and proliferation. Notably, calcium-dependent alterations are reversible and targetable by small molecule inhibitors. Increasing evidence suggests that the alteration of calcium dynamics affects the initiation and progression of some malignancies. For example, we have shown that T-type calcium channels drive the proliferation of castration-resistant PCa [2]. However, the calcium signalling toolkit is organised in a complex network of interacting molecules. This interactome has never been explored systematically in the context of a specific malignancy. In this project, we propose to study the role of calcium-dependent genes in NE-PCa pathogenesis, with the ultimate goal of identifying new therapeutic targets

Recent genomic and histopathological analyses have shown that up to 17% of castration-resistant prostate adenocarcinomas (PCas) develop neuroendocrine (NE) features [1]. This trans-differentiation induces complete androgen-independence and promotes metastatic spreading. NE-PCas are currently incurable and associated with a dismal prognosis (median survival shorter than 1 year). Therefore, there is a dire need for the identification of effective therapeutic targets for this aggressive malignancy. Calcium dynamics govern key aspects of cellular phenotypes, including tissue specification, motility and proliferation. Notably, calcium-dependent alterations are reversible and targetable by small molecule inhibitors. Increasing evidence suggests that the alteration of calcium dynamics affects the initiation and progression of some malignancies. For example, we have shown that T-type calcium channels drive the proliferation of castration-resistant PCa [2]. However, the calcium signalling toolkit is organised in a complex network of interacting molecules. This interactome has never been explored systematically in the context of a specific malignancy. In this project, we propose to study the role of calcium-dependent genes in NE-PCa pathogenesis, with the ultimate goal of identifying new therapeutic targets.

Diffuse intrinsic pontine glioma (DIPG) is the most frequent paediatric brainstem malignancy, and it is invariably associated with a dire prognosis [1]. DIPG is characterized by diffuse infiltrative growth patterns and by an invasive phenotype that underpins its inadequate response to both pharmacological and surgical treatments. DIPG response to radio- or chemo- and targeted therapies is short lived at best. Hence, it is of paramount importance to identify new targets for the development of effective therapies. The genomic landscape of DIPG has been recently described as an heterogenous collection of mutations and copy number variations in protein-coding genes. The most frequent mutation occurs at histone H3 lysine 27 (H3K27M) resulting in widespread epigenetic deregulation. Despite intensive research, no effective protein-targeting therapy has been developed for DIPG. Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200bp. For several decades, lncRNAs have been considered non-functional transcriptional noise. Recent deep sequencing data have revealed that lncRNAs represent a vast and largely uncharted region of the human transcriptome (more than 50,000 unique loci, 100nMol), broad CNS distribution and rapid cellular uptake. Antisense oligonucleotides (ASOs) are clinically approved molecules that target and silence specific RNA sequences. Our group has shown that antisense ASOs can efficiently target oncogenic lncRNAs. In this project, we will to develop lncRNA-targeting ASOs to stop DIPG proliferation, with the final goal of developing personalised therapies for this incurable disease

Neuroendocrine prostate cancer (NEPC) is the most aggressive prostate cancer type. This disease is resistant to all available therapies, highly metastatic and rapidly fatal. We believe that the elucidation of NEPC-driving pathways could pave the way for the development of effective therapies. Long non-coding RNAs (lncRNAs) are a vast and mostly uncharted region of the human transcriptome. Despite their emerging role in cancer biology, no study has assessed the relevance of lncRNAs in NEPC development. Our collaborator Dr. Wang (BC Cancer Agency) has developed a unique collection of patient-derived prostate cancer models. This collection includes the first-in-field model of transdifferentiation from prostatic adenocarcinoma to NEPC. Aims. We propose to study the role of lncRNAs in NEPC development. The objectives of this study are to determine: 1) whether transcriptomic profiles of lncRNAs in PCa pre-clinical models can elucidate the mechanisms of NEPC development. 2) if selected lncRNAs are promising therapeutic targets for NEPC. Accordingly, our specific aims will be: AIM 1: Identification, functional and clinical characterization of NEPC-driving lncRNAs. AIM 2: Development of innovative therapeutic strategies to prevent NEPC development. At the end of this project, we hope to shed new light on an incurable disease, and to identify viable therapeutic targets, which will be investigated in future translational and clinical studies.

Circulating tumour DNA (ctDNA) contains valuable information for the early detection and stratification of prostate cancer. Current methodologies are unable to capture ctDNA with sufficient efficacy. This project aims to employ cancer-specific histone post-transnational modifications to enrich ctDNA from the plasma of cancer patients. We will initially use pre-clinical models to optimize the technique. If we are successful, we intend to apply for follow-up funds to test our application in the clinics. The OU (F Crea, Joint Lead applicant) is part of a multi-disciplinary team: PI (Charlie Massie, Cambridge). Other academics involved as CoI/joint applicants: Nick Leslie (Heriot-Watt), Pedro Estrela (Bath), Tingting Zhu (Oxford), Paul Milner (Leeds).