News and events from the Institute of Cancer Therapeutics

Black phosphorus (BP) is one of the most promising nanomaterials for cancer therapy. This 2D material is biocompatible and has strong photocatalytic activity, making it a powerful photosensitiser for combined NIR photothermal and photodynamic therapies. However, the fast degradation of BP in oxic conditions (including biological environments) still limits its use in cancer therapy. This work proposes a facile strategy to produce stable and highly concentrated BP suspensions using lysolipid temperature-sensitive liposomes (LTSLs). This approach also allows for co-encapsulating BP nanoflakes and doxorubicin, a potent chemotherapeutic drug. Finally, we demonstrate that our BP/doxorubicin formulation shows per se high antiproliferative action against an in vitro prostate cancer model and that the anticancer activity can be enhanced through NIR irradiance.

Dr Amalia Ruiz from the ICT

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AKR1C3 is an enzyme that is overexpressed in several types of radiotherapy- and chemotherapy-resistant cancers. Despite AKR1C3 is a validated target for drug development, no inhibitor has been approved for clinical use. In this manuscript, we describe our study of a new series of potent AKR1C3-targeting 3-hydroxybenzoisoxazole based inhibitors that display high selectivity over the AKR1C2 isoform and low micromolar activity in inhibiting prostate cancer cells in vitro. In silico studies initially suggested substituent needed to increase compound potency and provided with a mechanistic explanation that could clarify their different activity, later confirmed by X-ray crystallography. Both the in-silico studies and the crystallographic data highlight the importance of 90◦ rotation around the single bond of the biphenyl group, in ensuring that the inhibitor can adopt the optimal binding mode within the active pocket. The p-biphenyls that bear the meta-methoxy, and the ortho- and meta- trifluoromethyl substituents (in compounds 6a, 6e and 6f respectively) proved to be the best contributors to cellular potency as they provided the lowest IC50 values in the new series (2.3, 2.0 and 2.4 μM respectively); importantly with no toxicity towards human MRC-5 cells. Co-treatment with scalar dilutions of either compound 6 or 6e and the clinically used drug abiraterone led to a significant reduction in cell proliferation, and thus confirmed that treatment with both CYP171A1-and AKR1C3-targeting compounds possess the potential to intervene in key steps in the steroidogenic pathway. Taken together, the novel compounds display desirable biochemical potency and cellular target inhibition as well as good in-vitro ADME properties, which highlight their potential for further preclinical studies.

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Co-author Prof Klaus Pors Professor of Chemical Biology at the Institute of Cancer Therapeutics commented  “This study is our latest contribution to research carried out by a European team of investigators led by Prof Donatella Boschi and colleagues at the University of Turin focused on blocking AKR1C3 enzyme activity to halt prostate cancer cell proliferation. The current study provides mechanistic insight to how new inhibitors can be grown into more robust molecules with drug-like properties for clinical progression. We are very excited about this work, which also provides a basis for combining an AKR1C3 inhibitor with standard of care drugs. AKR1C3 is highly expressed in castration-resistant prostate cancer, which is a cancer with poor overall survival rates. Accordingly, targeting AKR1C3 for therapeutic intervention might provide a new approach to treating this aggressive disease.”

One of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC.

Lead author and Senior Lecturer in Cancer Biology at the ICT Dr Steve Shnyder commented “This study is part of ongoing work at the ICT to uncover novel mechanisms and biomarkers of drug resistance for colorectal cancer. The findings of this study will act as a springboard for more detailed investigations which it is hoped will eventually lead to new therapeutic interventions to overcome the drug resistance challenges for the disease. We are grateful to all the people in Bradford who contributed to the Bradford Crocus Appeal which enabled the purchase of the Orbitrap Mass Spectrophotometer which was central to the work in this study.”

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 Introduction: There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis.

Methods and analysis: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6 monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%.

Co-author Prof. Paul Loadman from the ICT said "This work evolves from our strong, long standing collaboration with Professor Mark Hull at the University of Leeds . The ICT in Bradford have spent many years developing specific and sensitive analytical methods (by Amanda Race and Jade Spencer) to show the influence of EPA on Patients. These methods include the analysis of a wide range of Fatty acids and Oxylipins via LC/MS/MS”

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Harnessing the differences between cancer and non-cancer tissues presents new opportunities for selective targeting by anti-cancer drugs. CD13, a heavily glycosylated protein, is one example with significant unmet clinical potential in cancer drug discovery. Despite its high expression and activity in cancers, CD13 is also expressed in many normal tissues. Here, we report differential tissue glycosylation of CD13 across tissues and demonstrate for the first time that the nature and pattern of glycosylation of CD13 in preclinical cancer tissues are distinct compared to normal tissues. We identify cancer-specific O-glycosylation of CD13, which selectively blocks its detection in cancer models but not in normal tissues. In addition, the metabolism activity of cancer-expressed CD13 was observed to be critically dependent on its unique glycosylation. Thus, our data demonstrate the existence of discrete cancer-specific CD13 glycoforms and propose cancer-specific CD13 glycoforms as a clinically useful target for effective cancer-targeted therapy.

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https://doi.org/10.1016/j.isci.2023.108219

Lead author, Dr. Francis M. Barnieh, a Research fellow at the ICT commented “This paper demonstrates for the first time the uniqueness of cancer-expressed CD13 compared to that expressed in normal tissues, which position CD13 as a potential target for cancer-targeted therapy. As an early career researcher, publishing my first independent and innovative research is critical for my career progression, and I am grateful to the UoB for the STARTER fellowship award”.

The Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the β3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvβ3 and αIIbβ3 are important anticancer targets, most integrin antagonists developed to target the β3 integrins are highly selective for αvβ3 or αIIbβ3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic β3 integrin antagonist. These new antagonists combine a high activity against αvβ3 with a moderate affinity for αIIbβ3, providing the first evidence for a new approach to integrin targeting in cancer.

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Dr Helen Sheldrake (pictured above) lecturer in Organic and Medicinal Chemistry at the Institute of Cancer Therapeutics and first author on this article recently published in “Cancers” said ”I am very pleased to finally be able to publish the beginning of our cyclobutane integrin antagonist story after filing a patent on the most exciting compounds discovered. The cyclobutane structure is underused in medicinal chemistry; this paper highlights an easy method to make functionalised cyclobutanes and their potential in drug molecules".