NIHRDataInsights/HRCSData huggingface dataset:
Title: Mechanisms of Resistance to FGFR Inhibitors In FGFR-Dependent tumor cells
Funder: Worldwide Cancer Research

Abstract: <p>There is a growing interest in inhibiting signalling by FGFRs as a therapeutic approach to cancer. FGFRs can act as driving oncoproteins in many forms of cancer including breast cancer (amplification of FGFR1 or FGFR2), gastric cancer (amplification of FGFR2), bladder cancer (over-expression and/or mutation of FGFR3) and multiple myeloma (translocation/over- expression and mutation of FGFR3). Tumour cells with such mutations or amplifications are &lsquo;addicted&rsquo; to these de-regulated FGFRs, making them attractive drug targets. Indeed, selective FGFR tyrosine kinase inhibitors (FGFRi) have recently entered clinical trials.<br />However, we know very little about what determines the initial tumour cell response to FGFR inhibition (mechanisms of intrinsic sensitivity or resistance). Furthermore, we know nothing about how FGFR-dependent tumour cells adapt to long term FGFR inhibition (acquired resistance) and yet experience with Gefitinib, Elrotinib and Imatinib has shown that this is a real problem.<br />We have identified gastric, bladder and breast cancer cells that are addicted to FGFR signalling for proliferation or survival since they are exquisitely sensitive to the new FGFR inhibitor AZD4547. In addition, we have generated derivatives of these cells with 100-fold acquired resistance to AZD4547.</p> <p>In this project we will:-</p> <p>1. Characterise the biochemical pathways that contribute to FGFR-dependent proliferation and survival in breast and gastric cancer cell lines and their responses to FGFR inhibitors such as AZD4547.</p> <p>2. Identify factors that determine whether FGFR inhibition causes cell cycle arrest or cell death. This should lead to drug combination strategies for enhancing tumour cell death in response to FGFR inhibitors including AZD4547</p> <p>3. Identify mechanisms of acquired resistance to the clinical FGFR inhibitor AZD4547 in FGFR-dependent breast and gastric cancer cell lines and thereby identify strategies to overcome this</p> <p>4. Identify gene signatures associated with FGFR inhibition and acquired resistance to FGFR inhibitors</p>


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A novel mechanism of drug resistance in human cancer
Funder: Worldwide Cancer Research

Abstract: <p>Drug resistance is a major cause of cancer therapy failure. &nbsp;One of the main reasons for drug resistance is the expression of cell surface multidrug transporters on tumour cells, which expel chemotherapeutic drugs thereby reducing their effectiveness. &nbsp;Three main transporters that have been implicated in chemotherapy resistance: MDR1 (P-glycoprotein), MRP1 and ABCG2. &nbsp;In order to target these transporters for combination therapy it is critical to know where and why these transporters are over-expressed in tumours, but currently these issues are poorly defined. &nbsp;We report here for the first time that ABCG2 is induced by the E2F1 transcription factor in multiple cell systems &nbsp;We provide data showing that E2F1 can cause drug efflux both <em>in vitro</em> and <em>in vivo</em> and that E2F1-induced efflux can be reverted by pharmacological inhibition of ABCG2. &nbsp;Moreover, despite several reports indicating that E2F1 can promote apoptotic cell death, we importantly show that chemotherapeutic drug-induced cell death can be markedly inhibited by E2F1 in an ABCG2-dependent manner. &nbsp;Since E2F1 is believed to be deregulated in most, if not all tumours, we consider the E2F1-ABCG2 axis represents a novel and potentially widespread mechanism of drug resistance in human cancer. &nbsp;In this regard, we also have preliminary data showing a significant correlation between expression of E2F1 and ABCG2 in human lung tumours. &nbsp; Therefore, the aim of this application is to build on these initial observations as outlined below.</p> <p>&nbsp;1)&nbsp;&nbsp;&nbsp; We will elucidate the mechanism by which E2F1 induces ABCG2.</p> <p>&nbsp;2)&nbsp;&nbsp;&nbsp; We will assess E2F1&rsquo;s ability to efflux and repress cell death induced by other chemotherapeutic drugs.</p> <p>&nbsp;3)&nbsp;&nbsp;&nbsp; We will test whether other E2F family members can cause drug efflux.</p> <p>&nbsp;4)&nbsp;&nbsp;&nbsp; We will determine if knockdown of endogenous E2F1 affects chemotherapeutic responses <em>in vivo.</em></p> <p>&nbsp;5)&nbsp;&nbsp;&nbsp; We will analyse further the relationship between E2F&rsquo;s and ABCG2 in human tumour tissue.</p>


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Novel NF-kB Transcription Factor Inhibitors for the Treatment of Haematological Cancers
Funder: Worldwide Cancer Research

Abstract: <p>Oncogenic transcription factors are an increasingly important target for anticancer therapies, as inhibition could allow the&nbsp; "reprogramming&rdquo; of tumour cells, leading to apoptosis or differentiation from the malignant phenotype.&nbsp; Overactivity&nbsp;of NF-kB, and its associated proteins IKKa and IKKb,&nbsp;is strongly implicated in a variety of haematologic and solid tumour malignancies.&nbsp; In particular, NF-kB proteins are constitutively activated in multiple myeloma and many types of leukaemic cells.&nbsp; Direct inhibition of NF-kB in these cell types results in apoptosis, suggesting a possible therapeutic role for this approach in the treatment of haematological malignancies.&nbsp; Furthermore, up-regulation of NF-kB is implicated in drug resistance, so NF-kB inhibitory molecules may also re-sensitise cancer cells to the effects of standard chemotherapeutic agents.</p> <p>&nbsp;</p> <p>This application involves the design, synthesis and evaluation of small drug-like PBD-hybrid transcription factor inhibitors as potential therapeutic agents for the treatment of NF-kB-dependent haematological cancers.&nbsp; To date, evaluation of a small number of C8-linked PBD-hybrids has led to the identification of two lead molecules, KMR-04-177 and KMR-28-32, which are highly potent (<em>i.e., </em>IC<sub>50</sub> = 8.8 and 2.5 picomolar, respectively) in NF-kB-dependent primary CLL cells, with at least 3-orders of magnitude selectivity compared to normal lymphocytes or WI38 cells.&nbsp; Crucially, preliminary studies suggest that these molecules modulate NF-kB in primary CLL cells.&nbsp; The project will begin with the synthesis of focussed libraries based on these lead molecules, followed by screening against the NF-kB cognate sequence using an in-house FRET-based assay.&nbsp; This will be followed by systematic mechanistic studies to establish the precise role of the molecules in inhibiting NF-kB and downstream targets.&nbsp; The libraries will be designed to optimize characteristics including&nbsp;selective inhibition of NF-kB, water solubility and cellular penetration.&nbsp; Promising molecules will be evaluated in human tumour xenograft models&nbsp;to identify a suitable candidate for&nbsp; progression to pre-clinical development.&nbsp;&nbsp;&nbsp;</p>


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: RNA Interference Therapeutics for Neuroblastoma
Funder: Worldwide Cancer Research

Abstract: <p>&nbsp;</p> <p style="margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica;">We are developing neuroblastoma (NB) tumour-specific therapies based on RNA interference of a tumour specific oncogene, MYCN. Specificity of delivery will be achieved by a peptide-targeted nanoparticle formulation, and transcriptionally, by siRNA-mediated silencing of MYCN. NB is the most commonly occurring solid tumour in children and MYCN amplification is associated with a poor prognosis. Modification of NB cells with siRNAs to MYCN therefore offers the potential to treat neuroblastoma specifically since MYCN is amplified only in NB tumours. MYCN is a transcription factor that regulates cell division and survival and silencing leads to increased apoptosis, differentiation and lower replication rates. However, safe and effective delivery of siRNA to tumours remains technically challenging. Packaging of siRNA into nanoparticles offers the potential to improve siRNA pharmacokinetics, tumour-targeted distribution, targeted gene silencing and therapeutic efficacy. We are developing synthetic nanoparticle formulations termed Receptor-Targeted Nanocomplex (RTN), formulations of liposomes and receptor-targeted peptides which spontaneously self-assemble into nanocomplexes on mixing with plasmid DNA or &nbsp;siRNA. In this study RTN formulations will be optimised initially for NB targeting in cultured cells, comparing targeting by three different peptide sequences specific for receptors on NB cells. RTN-mediated delivery of siRNA will be assessed for silencing of hMYCN &nbsp;in NB cells at the mRNA and protein levels and by immunohistochemistry as well as assessing biological effects, such as apoptosis and replication. Efficacy of MYCN siRNA treatment will be tested in vivo &nbsp;by monitoring MYCN gene and protein silencing and tumour growth in an immunodeficient xenograft model of NB, &nbsp;which develop subcutaneous tumours. Successful proof of concept studies could lead to preclinical studies for NB with potential for siRNA delivery to a wide range of cancers.</p>


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Combinatorial targeting of MYCN and the epigenetic modifiers LSD1 and EZH2 to unlock the therapeutic potential of retinoids in neuroblastoma
Funder: SPARKS

Abstract: Tumour recurrence (regrowth of resistant cancer cells after treatment) is a major killer of children with cancer. Retinoids are among few existing drugs that eliminate resistant cells and extend survival in neuroblastoma. In neuroblastoma, abnormalities in the MYCN gene block the curative potential of retinoids. researchers have developed novel (MYCN-blocking and epigenetic) drugs that restore the potency of retinoids. They propose to further identify and study retinoid-activating drugs, and to combine them with MYCN-blocking drugs, to fully unlock the curative potential of retinoids in neuroblastoma.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Optimisation of antibody mediated killing of neuroblastoma
Funder: SPARKS

Abstract: Neuroblastoma is a cancer arising from the nervous system that primarily affects children, 50% of cases fall into a high-risk category, with 5-year survival of only 40%. Immunotherapy using anti- GD2 antibodies has recently been shown to significantly improve survival in these children, opening an exciting new avenue that needs to be further explored. Currently, different combinations of immune-stimulating treatments (IL-2 and GM-CSF) are being tested. Whilst attention has been paid to their effects on certain parts of the immune system, other areas are less well understood, in particular, other cells of the innate immune system such as gamma delta T cells. Furthermore, bisphosphonates, drugs used to treat osteoporosis, are known to stimulate gammadelta T cells and their addition may improve treatment efficacy. We will test different activators of gamma delta T cells in combination with antibodies using laboratory assays and a mouse model of neuroblastoma. These studies are designed to identify optimal combination regimes for future clinical trials aimed to augment the immune response against neuroblastoma elicited by currently available therapeutic antibodies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Enhancing immunity against neuroblastoma through the exploitation of antigen-specific T cell co-stimulation receptors
Funder: Children with Cancer UK

Abstract: The project is composed of five key elements. The first element focuses on the molecular engineering of novel neuroblastoma-specific co-stimulatory receptors (co-CARs). The second element involves functional activity screening of co-CARs in combination with NY-ESO-1 T cell receptor (TCR) targeting of neuroblastoma cell lines in vitro and seeks to identify the most promising co-CARs for further investigation. The third element of this study involves the testing of the optimal co-CARs to support engineered NY-ESO-! specific T cell activity against established neuroblastoma tumours in the NSG immunocompromised mouse model and aims to establish the level of improved function of co-CAR+ T cells. The fourth part of the study tests the optimal co-CARs/NY-ESO1 TCR in patient-derived T cells to confirm that T cells from the relevant patient group function in an optimal manner to eradicate neuroblastoma cells in vitro. Moreover, we will examine the immune status of patients undergoing standard therapy to identify whether a period of lymphodepletion occurs that could be exploited for clinical proposals to combine T cell therapy with standard treatment. The fifth element of work runs throughout the project and focuses upon the use of peptide-based technology to isolate neuroblastoma-specific T cells that can be used in adoptive transfer studies to treat patient irrespective of HLA-restriction and will serve as a source of T-cells into which the co-CAR will be tested for the receptors ability to drive enhanced immune-based killing of neuroblastoma target cells.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Oncogenic LGR5-mediated Wnt signalling as a target for neuroblastoma therapy
Funder: Children with Cancer UK

Abstract: Neuroblastoma (NB) is one of the commonest solid tumours of childhood and is thought to arise via defective differentiation of neural crest progenitor cells. More than 35% of neuroblastoma patients do not survive longer than 5 years after initial diagnosis and therapies have not improved markedly for decades. Several genetic markers and found in poor prognosis NB, most notably amplification of the MYCN proto-oncogene which occurs in about 50% of high-risk NBs (~20% of total NBs). However, despite the strong association of MYCN with poor prognosis, there has been limited success in utilising this oncoprotein for therapeutic intervention. Key limitations to developing adequate treatments for NB are our limited understanding of the molecular pathogenesis of NB and the paucity of targetable molecules. Thus there is still a high requirement for new molecular targets and therapeutic modalities. Here we show that the leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) protein is a highly promising target for therapeutic intervention in NB. LGR5 is involved in stem cell maintenance in many tissues, and is over-expressed in several cancers where it is thought to amplify the proliferative Wnt signalling pathway. Our preliminary data show that NB cells respond to the LGR5 ligand R-Spondin by activating Wnt signalling. Crucially, experimentally depletion of LGR5 in NB cells leads to dramatic cell death of NB cells. We therefore propose that LGR5 represents a crucial mediator of NB tumorigenesis and resistance to therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Phage-guided therapy against molecular targets in medulloblastoma
Funder: Children with Cancer UK

Abstract: Paediatric brain tumours are the most common solid tumours of childhood and the second most common cancer after haematological malignancies. Medulloblastoma is the most common malignant brain tumour in children. Current therapies for medulloblastoma result in an inordinately high and unacceptable rate of transient and permanent sequelae and continue to carry a high risk of significant side effects, especially for the very young. Therefore, development of novel therapeutic approaches that are non-invasive, tumour specific, safer, cost-effective and efficient is urgently needed to avoid the long-term side-effects from current treatment. Recently, a number of therapeutic targets have been identified in medulloblastoma, such as growth factor receptors, signalling pathways, matrix metalloproteinases and integrins. However, their validation and/or exploitation depend, essentially, on the development of multifunctional non-invasive delivery platforms that can simultaneously reach these multiple targets. Herein, we propose to develop bacteriophage (phage) as a multifunctional nanocarrier to guide the simultaneous delivery of therapeutic peptides and short hairpin-structured RNA (shRNA), through the intravenous non-invasive route, against their molecular targets in intracranial medulloblastoma established in mice from tumour cell lines or human primary explants. We will carry out imaging of living tumour-bearing mice to assess biodistribution and tumour specificity of the phage particles after intravenous administration. Next, therapy experiments will be designed to evaluate the effects on tumour growth, tumour size and tumour vasculature. All animals will be monitored for any signs of neurotoxicity and autopsied to confirm that the healthy brain and other normal tissues, recovered after therapy, are not affected.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Targeting the GD3 and the GD3 acetylation pathway to induce cell death in medulloblastomas
Funder: Children with Cancer UK

Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is associated with high mortality rates, and survivors frequently suffer a low quality of life resulting from devastating treatments. Advances in genomic studies have led to novel classification of molecularly and clinically distinct subgroups (1-3). This information facilitates improved patient stratification and, in turn, reduces toxic therapies for those with good prognosis. Specific pathways are emerging to be important and therefore novel targeted therapies for those with poor prognosis can be developed. The overall goal of this proposal is to pre-clinically test a therapeutic approach targeting a pathway known to function abnormally in medulloblastoma. GD3, an oncofetal ganglioside, is crucial in cell migration during normal brain development. Upon brain maturation, GD3 accumulates and is responsible for the death of supernumerary progenitor cells during embryonic brain maturation. GD3 accumulation results in cell death via a mitochondrial apoptosis pathway. GD3 as well as its acetylated form, 9-O-acetyl GD3 (GD3A) is over-expressed in brain tumours including medulloblastomas. Such acetylation prevents GD3-mediated cell death and protects tumour cells from apoptosis. The GD3A to GD3 ratio in favour of GD3A is a major player in protecting tumour cells. Sialate-O-acetylesterase (SIAE) is the enzyme responsible for removing the acetyl group. Our preliminary data reveal that SIAE gene expression is significantly lower in medulloblastoma. Based on this and established reports, we propose to genetically introduce SIAE into medulloblastoma cells to determine if cells will undergo apoptosis and to evaluate a recombinant baculovirus for gene delivery.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Identification of novel pathogenic inherited variants predisposing to childhood rhabdomyosarcoma
Funder: Children with Cancer UK

Abstract: Certain cancer predisposition syndromes, caused by germline mutations in known genes increase the risk of rhabdomyosarcoma (RMS) in children. We hypothesise that the frequency of such mutations is higher among childhood RMS cases than currently estimated and that novel causative germline mutations in other genes may also increase risk. We shall test these hypotheses in an exploratory project by analysing a sub-set of 64 blood samples from childhood RMS cases and 10 case/mother/father trios of blood samples. These samples are already held by us and ethical approval is in place. DNA will be extracted from the samples and subjected to next generation sequencing using a 2-stage approach. In stage 1 we shall screen 64 RMS case samples for mutations in genes known to predispose to RMS, including: TP53 and pathway, RAS-MAPK pathway and MMR. This unprecedented systematic screen of these genes will generate novel data. In stage 2 in a sub-set of 10 cases in whom no mutations have been found we will undertake exome sequencing of 10 child/parent trios to identify novel genes and mutations not previously linked to RMS (including de novo). The results from stage 1 and stage 2 will be mapped onto our detailed family database which includes information on congenital anomalies, birthweights, cancers and other genetic disease in the cases and their families and statistical analysis of risks will be conducted. The outcome of this project will increase understanding of the biological basis of RMS and will have implications for clinical management and treatment strategies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeting arginine transport in acute myeloid leukaemia
Funder: Children with Cancer UK

Abstract: Acute Myeloid Leukaemia (AML) is the second most common leukaemia of childhood, and despite improvements in therapy, significant numbers of patients relapse and die from their disease. We have previously demonstrated that AML blasts metabolise arginine, to create a favourable microenvironment. Arginine is a semi-essential amino-acid that plays a key role in a number of key cell processes and blast survival. A clinical grade PEG- recombinant human arginase PEG-rhArgI molecule; BCT-100, has been developed by collaborators at Bio-Cancer Treatment International (Hong Kong). BCT-100 is under clinical evaluation in phase I/II trials for adult solid tumours, with a favourable safety profile. We hypothesise that BCT-100 decreases the concentration of arginine, leading to AML cell death. The cytotoxicity of BCT-100 against AML cell lines, primary blasts from patients and murine xenografts will be determined in vitro and in vivo by flow cytometry, cell cycle analysis and immunoblotting. Synergism with standard chemotherapy drugs will be investigated in vitro and in vivo. NOG-SCID AML xenografts will be administered BCT-100 (i.v.), and AML numbers in blood, spleen and bone marrow, as well as effect on progression free survival will be measured. Where BCT-100 resistant cells are identified, the mechanisms will be investigated, including the role of alternative pathways of arginine recycling and transmembrane arginine transport. The study could provide the rationale for an early Phase clinical trial for paediatric patients with AML, and provide a new therapeutic approach for patients with other paediatric malignancies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS