Decoding the adaptive survival mechanisms of breast cancer dormancy.

Breast cancer (BC) recurrence remains a major clinical challenge, leaving patients in perpetual uncertainty about disease relapse after primary treatment. BC dormancy, an adaptive survival state of disseminated tumour cells, is a key driver of both early and late recurrence. However, the mechanisms regulating BC dormancy remain poorly understood.

Hypoxia-Responsive Prodrug of ATR Inhibitor, AZD6738, Selectively Eradicates Treatment-Resistant Cancer Cells.

Targeted therapy remains the future of anti-cancer drug development, owing to the lack of specificity of current treatments which lead to damage in healthy normal tissues. ATR inhibitors have in recent times demonstrated promising clinical potential, and are currently being evaluated in the clinic. However, despite the considerable optimism for clinical success of these inhibitors, reports of associated normal tissues toxicities remain a concern and can compromise their utility.

The DNA repair kinase ATM regulates CD13 expression and cell migration.

Classically, ATM is known for its role in sensing double-strand DNA breaks, and subsequently signaling for their repair. Non-canonical roles of ATM include transcriptional silencing, ferroptosis, autophagy and angiogenesis. Angiogenesis mediated by ATM signaling has been shown to be VEGF-independent via p38 signaling.

Cancer-specific glycosylation of CD13 impacts its detection and activity in preclinical cancer tissues.

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.

Trailblazers in cancer research: the next generation - the British Association of Cancer Research early-career conference.

The inaugural 'British Association of Cancer Research (BACR) Early Career Conference, Trailblazers in Cancer Research 2023', was a 2-day meeting held in Manchester, UK. Recognising the disruption caused by the COVID-19 pandemic to early-career researchers (ECRs), the BACR executive committee organised an in-person conference to address the lack of network and training opportunities during this time. The conference brought together PhD students and post-doctoral researchers from across the UK and beyond, who shared their outstanding contributions to cancer research.

Chemoselective Solution- and Solid-Phase Synthesis of Disulfide-Linked Glycopeptides.

Glycosylation of peptides and proteins is a widely employed strategy to mimic important post-translational modifications or to modulate the physicochemical properties of peptides to enhance their delivery. Furthermore, glycosylation a sulfur atom imparts increased chemical and metabolic stability to the resulting glycoconjugates. Herein, we report a simple and chemoselective procedure to prepare disulfide-linked glycopeptides.

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.

Progress towards a clinically-successful ATR inhibitor for cancer therapy.

The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades.

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.

Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds.

The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill.