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News and events from the Institute of Cancer Therapeutics

You can find notable news articles relating to the Institute of Cancer Therapeutics below.

June 2022

Targeted delivery of a colchicine analogue provides synergy with ATR inhibition in cancer cells

Despite significant preclinical promise as anticancer agents, vascular-disrupting agents have yet to fulfil their clinical potential due to systemic toxicities. ICT2588 is a tumour-selective MT1-MMP-targeted prodrug of azademethylcolchicine, ICT2552. We investigate activation of ICT2588 and subsequent release of ICT2552 in tumour cells, and examine its ability to induce G2/M cell cycle arrest. We also explore synergism between ICT2588 and ATR inhibition, since colchicine, in addition to its vascular-disrupting properties, is known to induce G2/M arrest, DNA damage, and trigger apoptosis. Several ATR inhibitors are currently undergoing clinical evaluation. The cellular activation of ICT2588 was observed to correlate with MT1-MMP expression, with selective release of ICT2552 not compromised by cellular uptake and prodrug activation mechanisms. ICT2588 induced G2/M arrest, and triggered apoptosis in MT1-MMP-expressing cells, but not in cells lacking MT1-MMP expression, while ICT2552 itself induced G2/M arrest and triggered apoptosis in both cell lines. Interestingly, we uncovered that the intracellular release and accumulation dynamics of ICT2552 subsequent to prodrug activation provided synergism with an ATR inhibitor in a way not observed with direct administration of ICT2552. These findings have important potential implications for clinical combinations of ICT2588 and DNA repair inhibitors.

Image of a Research Fellow at the ICTBiochemical Pharmacology Journal logo

Lead author Dr. Francis Barnieh (UoB STARTER Fellow) commented “…our paper uncovers new insights into ICT2588 (developed here at the ICT), and how it behaves when administered with a DNA damage repair targeted agent in clinical trial, which is currently a very hot topic in cancer research…”

To read the full article 

May 2022

ICT PhD students scoop best Oral and Poster presentation awards at DMDG Early Career Meeting

ICT PhD students winning award at scientific conferecneDMDG logo (scientific group)

The DMDG Early Career Meeting; “Hot Topics in the Lab” was held at Nottingham Trent University in May, for scientists in industry and academia in the early stages of their careers in DMPK (drug metabolism and pharmacokinetics). The DMDG (Drug Metabolism Discussion Group) is a network of drug metabolism (DMPK) experts from predominantly big and small pharma and biotech companies across the globe. The year’s meeting, co-organised and co-chaired by ICT Starter Fellow Dr. Francis Mprah Barnieh, brought together early career scientists from AstraZeneca, Novartis, Vertex, Signature, Merk KGaA, GSK, University of Dundee, UCB and many others. Reinforcing the ICT’s strong links with industry, the ICT and University of Bradford also had a strong presence, with oral and poster presentations by PhD students Alexandra Serre and Athina Polykandritou along with research intern Herbie Garland (each supervised by Prof Robert Falconer and Prof Paul Loadman). 

In addition, the meeting was graced with Industrial insight talks by Jamie Henshall – Associate Director, UCB; Mike Briggs - DMPK Director Charles River Laboratories; and Rachel Rose - Principal Scientist PBPK Certara UK, and Dr Muhammad Wahajuddin from the ICT.

ICT academics and PhD students at DMDG conference

Dr Muhammad Wahajuddin, Alexandra Serre, Dr. Francis Mprah Barnieh, Athina Polykandritou and Herbie Garland

 

To learn more about DMDG please visit their website 

Semi-Synthetic Analogues of Cryptolepine as a Potential Treatment of Malaria, Human African Trypanosomiasis, and Cancer

The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that affordable and available novel are urgently needed and should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization. Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer.

Steve Shnyder Scientific Journal logo

 

Co-author and Senior Lecturer in Cancer Biology at the ICT Dr Steve Shnyder commented “Given the often prohibitive costs of effective medicines for treating diseases such as malaria, trypanosomiasis and cancer in the developing world, the approach taken in this paper of a relatively cheap semi-synthesis of more effective analogues of cryptolepine from source plant material isolated in traditional eco-friendly ways shows much promise for this strategy.“

 

To read the full article

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for the treatment of B cell malignancies. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by an expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

 

To read the full article 

 

Paul Loadman Scientific Journal logo

Co-author Prof. Paul Loadman from the ICT commented "ICT in Bradford were involved in this exciting project in the early days of the Phase II clinical trial. Amanda Race in particular was central to generating the pharmacokinetic data for AMG319 and for the analysis of that data in partnership with Cancer Research UK Center for Drug Development OfficeThis was when ICT was part of the Leeds/Bradford Experimental Cancer Medicine Centre (ECMC). This manuscript represents a huge amount of work from a large, multidisciplinary group over many years and ICT are very proud to be part of that. The work within the GCP laboratory in ICT has enabled a better understanding of the drug concentrations of AMG319 achieved during the Phase II trial described in this Nature publication"

 

April 2022

Spring Seminar Series

The Institute of Cancer Therapeutics warmly invites you to a global edition of our seminar series on the 28th April 2022 at 12pm (GMT).

‘Identification of novel synthesised flavone derivatives for development as anti-proliferative and anti-angiogenic agents’

In this presentation, Professor Osborn will discuss some of the challenges and opportunities in the development of flavones as lead compounds for anti-cancer therapies. Emphasis will be placed on the design and synthesis of the novel flavones, the biological methods implemented to determine their anti-proliferative and anti-angiogenic properties, and the deduction of structure-activity relationships. She will also exemplify the benefits of multi-disciplinary approaches when tackling problems of biological and therapeutic importance.

We look forward to seeing you there.

To access the seminar please utilise the following

MS Teams link:

https://teams.microsoft.com/l/meetup-join/19%3ameeting_OGEzZmE4OTUtNDI1OC00NGUwLWFmOTktMjZjYzJiOTBmZGJl%40thread.v2/0?context=%7b%22Tid%22%3a%22245ea2d1-4365-4726-805a-631eb93d93aa%22%2c%22Oid%22%3a%22c879e8fe-608d-4452-bd99-111c8792ac46%22%7d

Photo of an academic from the University of Reading

Professor Helen Osborn, University of Reading will be presenting ‘Identification of novel synthesised flavone derivatives for development as anti-proliferative and anti-angiogenic agents’

Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Activity in Prostate Cancer

Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumour types including prostate cancer and are considered a potential target for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB) has been extensively reported as a pan-inhibitor of ALDH isoforms, and here, we report on the synthesis, ALDH isoform selectivity, and cellular potencies in prostate cancer cells of 40 DEAB analogues; three analogues (1415, and 16) showed potent inhibitory activity against ALDH1A3, and two analogues (18 and 19) showed potent inhibitory activity against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity (IC50 = 10–200 μM) compared with DEAB (>200 μM) against three different prostate cancer cell lines. Analogues 14 and 18 were more potent than DEAB against patient-derived primary prostate tumour epithelial cells, as single agents or in combination treatment with docetaxel. In conclusion, our study supports the use of DEAB as an ALDH inhibitor but also reveals closely related analogues with increased selectivity and potency.

To read the full article

 

 ICT staff  Klaus PorsScientific journal logo

Lead author Professor Klaus Pors Professor of Chemical Biology at the Institute of Cancer Therapeutics commented “This study is part of a wider programme of activity focused on discovering chemical tools to probe a class of enzymes known as aldehyde dehydrogenases (ALDHs). Members of the ALDH family are thought to be implicated in the onset of diseases while also protecting cells against e.g. chemo- and radiotherapy used to treat cancer. Importantly, however, we believe ALDH expression can be exploited for therapeutic intervention as an adjuvant therapy to improve standard of care treatment options.”

 

 

March 2022

ICT Researcher wins Royal Society Award

Dr. Amalia Ruiz a lecturer at the Institute of Cancer Therapeutics has recently been awarded a Research Grant from The Royal Society (£20 000). This is a scheme for scientists in the UK who are at an early stage in their career and want to purchase specialised equipment and consumables to pursue their research. 

The aim of Dr Ruiz’s project is to design a smart delivery nanosystem to solve the issues associated with a non-specific delivery of drugs. This nanocarrier intends to be selective, safe by design and displays a stimulus-responsive behaviour controlled by external means. 

This project is aimed at developing a multifunctional nanoparticle that will release the chemotherapeutic drug in response to a local temperature increase and simultaneously generate toxic oxygen molecules that kill prostate cancer cells. For this purpose, Dr Ruiz will use a combination of lasers that will activate the nanoparticle to provide full spatial and temporal control of the release process. Moreover, this nanosystem will allow imaging of the tumour to assess its response to therapy saving prostate cancer’s patients’ lives and reducing NHS costs. 

Research scientist looking through a microscope

 

Dr. Amalia Ruiz, Lecturer in Biochemistry and Pharmacology at the ICT

3 Fully-Funded PhD Studentships at the ICT Announced

The Institute of Cancer Therapeutics (ICT) is excited to announce 3 fully-funded PhD studentships. Two PhD studentships will be the latest recruits to our Doctoral Training Centre (DTC), while a third PhD studentship is an exciting opportunity for a medic with a passion for cutting-edge cancer research.

We are now looking for applications from outstanding potential PhD candidates to embark on PhD projects commencing in October 2022.

PhD project titles:

Project #1: Targeting integrin degradation in the lysosome for anti-metastatic drug discovery

 

Project #2: Development of tumour targeted theranostic for breast cancer with enhance therapeutic index

 

Project #3: Investigation of prostate cancer stem cell targeting therapeutics with clinical potential

Front of ICT Building

For more information on:

  • Why study at the Institute of Cancer Therapeutics?
  • What we can offer and who should apply?
  • Information on funding and how to apply
  • A detailed description of the projects 

Please download the pdf file below

3 Fully-Funded PhD Studentships at the ICT

If you require this information in an alternative format, please contact our team.

Optimal Drug Delivery to Tumours Using Ultrasound-Triggered Therapeutic Microbubbles

Advanced drug delivery systems, such as ultrasound-mediated drug delivery, show great promise for increasing the therapeutic index. Improvements in delivery by altering the ultrasound parameters have been studied heavily in vitro but relatively little in vivo. In this publication, the same therapeutic microbubble and tumour type are used to determine whether altering ultrasound parameters can improve drug delivery. Liposomes were loaded with SN38 and attached via avidin: biotin linkages to microbubbles. The whole structure was targeted to the tumour vasculature by the addition of anti-vascular endothelial growth factor receptor 2 antibodies. Tumour drug delivery and metabolism were quantified in SW480 xenografts after application of an ultrasound trigger to the tumour region. Increasing the trigger duration from 5 s to 2 min or increasing the number of 5 s triggers did not improve drug delivery, nor did changing to a chirp trigger designed to stimulate a greater proportion of the microbubble population, although this did show that the short tone trigger resulted in greater release of free SN38. Examination of ultrasound triggers in vivo to improve drug delivery is justified as there are multiple mechanisms at play that may not allow direct translation from in vitro findings. In this setting, a short tone burst gives the best ultrasound parameters for tumoural drug delivery.

To read the full article

Logo of a scientific journal about drug delivery

Paul Loadman

Co-author Prof. Paul Loadman from the ICT commented "This is the latest paper from the long-standing relationship ICT has with the Leeds Microbubble Consortium (https://microbubbles.leeds.ac.uk). The group have experimented with different “bursts” of ultrasound to release the drug from the liposomes targeted to the tumour. With the in vivo work undertaken in Leeds and analysis of tumoral drug release  carried out in Bradford it was found that the short tone burst resulted in the greatest release of free SN38 in the tumours."

 

February 2022

ICT Global Seminar Series

The Institute of Cancer Therapeutics, University of Bradford warmly invites you to a global edition of our seminar series

Dr Giacomo Reina, Kyoto University will be presenting:

Carbon nanomaterials for photodynamic therapy

on the 17th February 2022 at 12pm (GMT).

Summary:

  • Recently developed applications of carbon nanomaterials for photodynamic (PDT) therapy
  • Use of carbon nanodots for active targeting and PDT
  • Use of graphene oxide for activatable PDT and GSH depletion

We look forward to seeing you there.

Join the seminar through MS teams here

 

Speaker at the ICT global seminar

Dr Giacomo Reina, Kyoto University

A graphene oxide-BODIPY conjugate for glutathione depletion and photodynamic therapy

Boron dipyrromethene derivates (BODIPYs) are promising photosensitisers (PSs) for cancer treatment using photodynamic therapy (PDT). This study investigates the functionalisation of graphene oxide (GO) with a BODIPY derivate for glutathione (GSH) depletion and PDT. We demonstrated the efficacy of a GO adduct containing an α-chlorine-substituted BODIPY for the simultaneous depletion of intracellular GSH and the photogeneration of reactive oxygen species using a halogen white light source (5.4 mW cm−2) with a maximum in the range of 500–800 nm, which significantly reduced cell viability (<50%) after irradiation. Our study provides a new vision on how to apply BODIPY derivates and potentiate the toxicity of PDT in prostate and other types of cancer.

 

To read the full article

 

ICT staff member Amalia Estrada

Co-Leadauthor Dr Amalia Ruiz Lecturer at the Institute of Cancer Therapeutics commented "this study is part of a research line focussed on developing novel nanomaterials for combinatory therapies tackling cancer from different angles. The long-term aim is to develop a theranostic nanomaterial that acts locally, with improved therapeutic index than traditional chemotherapy, and with the ability to simultaneously image the tumour.”

January 2022

ICT academic joins the Editorial Board of the international journal “Cells”

Dr Steve Shnyder, Senior Lecturer in Tumour Biology at the Institute of Cancer Therapeutics has been selected to join the Editorial Board of the journal “Cells” (ISSN 2073-4409).

Cells is an international, peer-reviewed, open access, journal of cell biology, molecular biology, and biophysics, published semi-monthly online by MDPI. Cells has an impact factor of 6.600 (2020) and a 5-Year Impact Factor of 6.663 (2020).

Scientific publication logo

Steve Shnyder

November 2021

Is tumour-expressed aminopeptidase N (APN/CD13) structurally and functionally unique?

Aminopeptidase N (APN/CD13) is a multifunctional glycoprotein that acts as a peptidase, receptor, and signalling molecule in a tissue-dependent manner. The activities of APN have been implicated in the progression of many cancers, pointing toward significant therapeutic potential for cancer treatment. However, despite the tumour-specific functions of this protein that have been uncovered, the ubiquitous nature of its expression in normal tissues as generally reported remains a limitation to the potential utility of APN as a target for cancer therapeutics and drug discovery. With this in mind, we have extensively explored the literature, and present a comprehensive review that for the first-time provides evidence to support the suggestion that tumour-expressed APN may in fact be unique in structure, function, substrate specificity and activity, contrary to its nature in normal tissues. The review also focuses on the biology of APN, and its “moonlighting” functional roles in both normal physiology and cancer development. Several APN-targeting approaches that have been explored over recent decades as therapeutic strategies in cancer treatment, including APN-targeting agents reported both in preclinical and clinical studies, are also extensively discussed. This review concludes by posing critical questions about APN that remain unanswered and unexplored, hence providing opportunities for further research.

 

a person in a white lab coat standing facing the camera with arms folded.a black and white logo for a journal cover

Lead author Dr. Francis Barnieh explores the importance of aminopeptidase-N (CD13) in cancer in a newly-published review in 'BBA reviews on cancer' and considers whether the tumour-expressed protein is a unique isoform. The article forms the backdrop to his University of Bradford STARTER fellowship.

 To read the full article

Cytochrome P450 isoforms as targets for therapeutic intervention in head and neck cancer

Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.

To read the full article

Journal logo for news itemICT staff  Klaus Pors

Co-Lead author Dr Klaus Pors Senior Lecturer at the Institute of Cancer Therapeutics commented "Cytochrome P450 (CYP) enzymes are remarkable in their capacity to metabolise a wide variety of endogenous and xenobiotic compounds. Profiling CYPs in solid tumours helps us to understand their potential as targets for therapeutic intervention. In our latest study we show how CYP isoforms expressed in head and neck cancer cells can be exploited for therapeutic gain using a duocarmycin-based prodrug that can be safely administered in vivo.”