Potential applications for sigma receptor ligands in cancer diagnosis and therapy

Van Waarde and colleagues outline the biology and pharmacology of two distinct sigma receptor classes, sigma-1 and sigma-2. The introduction summarises uncertainties about endogenous ligands (possible candidates include steroid hormones such as progesterone, sphingolipid-derived amines and the tryptamine DMT), highlights major functional distinctions (sigma-1 functions as a ligand-regulated chaperone, while sigma-2 was identified as the progesterone receptor membrane component 1, PGRMC1), and notes that both receptor subtypes are frequently overexpressed in rapidly proliferating normal tissues and in many cancers. The paper sets out to review evidence supporting diagnostic and therapeutic applications of sigma receptor ligands in oncology. Key themes include receptor overexpression in tumours, development of subtype-selective radioligands for PET/SPECT imaging, strategies for sigma-ligand-mediated targeted drug delivery, preclinical antitumour activity of sigma ligands (including conjugates and derivatives), and the molecular mechanisms by which sigma ligands influence tumour cell survival and invasiveness. The authors emphasise unresolved questions such as exact endogenous ligands, the pharmacological classification of agonists versus antagonists at sigma receptors, and remaining molecular details about sigma-2/PGRMC1 that affect translation to clinical use.

Both sigma-1 and sigma-2 receptor subtypes are repeatedly reported to be overexpressed in rapidly dividing normal cells and across a range of human and animal tumours. The sigma-2 subtype is particularly noted as a marker of proliferative status, with expression reported about 10-fold higher in proliferating versus quiescent tumour cells. In human cell lines and tumour specimens, examples include very high sigma-2 density in the RT-4 bladder tumour cell line (reported densities: sigma-2 ~2,108 fmol/mg protein versus sigma-1 ~279 fmol/mg protein) and significant overexpression of sigma-2 in small cell lung carcinoma (up to 6-fold in 12/15 samples) and adenocarcinomas (up to 4-fold in 6/15 samples). Plasma levels of sigma-2 protein were elevated in lung cancer patients (up to 7-fold), leading authors to propose sigma-2/PGRMC1 as a potential tumour and serum biomarker. Additional associations were described: knockdown of PGRMC1 in A549 lung cancer cells reduced NGAL expression and MMP9 activity, implicating PGRMC1 in invasion and progression. Sigma-1 receptor overexpression is documented in other contexts: the hematopoietic multiple myeloma cell line RPMI 8226 had a reported Bmax of 477 fmol/mg protein (≈122,000 sites/cell), and several oesophageal squamous cell carcinoma (ESCC) lines and patient samples showed sigma-1 overexpression correlated with TNM stage and lymph node metastasis. In an animal example, spontaneous pituitary tumours in aged rats showed increased uptake and binding potential of the sigma-1 tracer 11C-SA4503, enabling microPET visualisation of very small tumours (an example specimen of 17 mg was clearly visualised). Diagnostic imaging efforts have produced multiple subtype-directed radioligands for PET and SPECT. For sigma-1 receptors, notable candidates include [18F]fluspidine (high affinity, Ki 0.59 nM, favourable brain uptake and metabolic profile), [18F]FTC-146 (high specific binding in brain and peripheral organs, substantial blockade by haloperidol), and re-evaluations of [11C]SA4503 that support sigma-1 selectivity in vivo. For sigma-2 receptors, promising tracers include [11C]RHM-1 and [18F]ISO-1. [18F]ISO-1 in rodent tumour models produced tumour-to-background signals that tracked the fraction of proliferating cells and correlated with changes in tumour volume during therapy. Importantly, a first human study of [18F]ISO-1 in thirty cancer patients reported that tracer uptake measures correlated significantly with Ki-67, a proliferation marker. The authors also report multiple tracer failures or limitations: some analogues failed due to rapid metabolism, radiometabolites entering brain, low target-to-nontarget ratios, or P-glycoprotein-mediated efflux. The review summarises SPECT and radiobromine/radioiodine tracer work as well, including a 99mTc-labelled sigma-2 candidate that produced specific binding in receptor-expressing organs and visualised C6 glioma brain tumours in rats with a tumour-to-brain ratio ≈2 at 2 h post injection. Two broad strategies for sigma-ligand-mediated targeted drug delivery have been evaluated preclinically: (1) nanoparticles (liposomes, calcium phosphate particles, gold nanocages, etc.) surface-decorated with sigma ligands to deliver cytotoxic drugs or nucleic acids, and (2) direct covalent conjugation of sigma ligands to therapeutic peptides or antisense/siRNA oligonucleotides. Conjugation methods typically used a PEG spacer or long alkyl linkers. In many reported models, targeted constructs achieved substantially greater uptake in sigma-expressing tumour cells and tumours, increased delivery efficiency (examples: 4-to 7-fold or greater), and produced improved antitumour outcomes such as inhibited tumour growth, reduced metastases (70–80% reduction in one model), prolonged survival, and sensitisation to chemotherapy. The authors emphasise that targeted nanoparticles and peptide/oligonucleotide conjugates retained receptor specificity (blocking with haloperidol or DTG reduced uptake) but note that, to date, translation into clinical trials has not been reported. Preclinical cytotoxicity studies show that sigma ligands can induce tumour cell death via multiple, ligand- and cell type-dependent mechanisms. Sigma-1 antagonists were reported to reduce cellular protein synthesis by repressing cap-dependent translation and to induce ER stress, unfolded protein response, autophagy and eventual apoptosis in some breast cancer cell lines. Sigma-2 ligands can trigger caspase-dependent or caspase-independent cell death; examples include lysosomal membrane permeabilisation and oxidative stress (SW43) independent of caspase-3, and mitochondrial destabilisation and caspase activation in other cell types. Some sigma ligands (e.g., PB28) bind nuclear histones, suggesting direct nuclear effects. The sigma-2/PGRMC1 complex is implicated in autophagy machinery interactions and in regulating factors (NGAL, MMP9) relevant to invasion. Several chemically modified sigma ligands and hybrids have shown potent antiproliferative effects in vitro and antitumour activity in vivo: cationic lipid-haloperidol conjugates (HP-C8) produced substantially greater cytotoxicity than parent haloperidol and reduced tumour growth in mice; rimcazole injections reduced A375M xenograft weight by more than 4-fold; and combinations of sigma ligands with standard chemotherapies (e.g., gemcitabine + SW43) produced better outcomes than single agents in pancreatic tumour models. Across studies, the authors emphasise that responses are heterogeneous: different ligands, their selectivity, and tumour cell type determine whether cell death is caspase-dependent, caspase-independent, autophagic or apoptotic, which explains apparently conflicting reports in the literature.

The authors interpret the collected evidence as indicating substantial potential for sigma receptor ligands in both cancer diagnostics and therapy. They propose that subtype-selective radioligands can inform tumour biology, enable non-invasive measurement of proliferative status, aid in tumour detection and staging, and serve in evaluating therapeutic response in drug development. The identification of PGRMC1 as the sigma-2 binding site is highlighted as particularly important because it provides a defined molecular target that may also serve as a serum biomarker and a regulator of invasion-related pathways (for example via NGAL and MMP9). Relative to earlier research, the review consolidates advances in tracer chemistry (noting several promising sigma-1 and sigma-2 PET tracers and a first human [18F]ISO-1 study), and summarises a growing preclinical literature on sigma-ligand-directed drug delivery and chemically modified sigma ligands with direct antitumour properties. Nevertheless, the authors acknowledge unresolved issues: the biochemical identity of sigma-2/PGRMC1 has open questions (reported molecular mass differences, potential splice variants or post-translational modifications), the operational definitions of "agonist" and "antagonist" at sigma receptors remain unclear, and some reported pharmacology appears contradictory (for example differing functional outcomes when ligands are classified differently). They also note practical limitations encountered in tracer development, including rapid metabolism, radiometabolites crossing the blood-brain barrier, nonselective binding, and P-glycoprotein-mediated efflux which can preclude brain entry. Key uncertainties and gaps stressed by the authors include the need for more subtype-selective tools to resolve mechanism, further validation of PGRMC1/sigma-2 as a clinical biomarker, and the absence of clinical trials for sigma-ligand-targeted nanoparticles or conjugates despite encouraging preclinical efficacy. Their stated implications are cautious: improved radioligands may permit clinical PET studies that inform patient selection and therapeutic monitoring, and continued preclinical study of subtype-selective ligands and conjugates could lead to translational applications. The authors recommend further research to reconcile molecular discrepancies, define pharmacological action at sigma receptors more precisely, and advance promising imaging agents and targeted therapeutics into clinical evaluation.

The authors conclude that novel, potent and subtype-selective radioligands for PET imaging of sigma receptors are now available and that in vivo studies with these agents can advance understanding of sigma receptor biology and support PET applications in tumour detection, staging, therapeutic evaluation and drug development. They further state that preclinical treatment studies using targeted and subtype-selective non-radioactive sigma ligands have improved understanding of sigma ligand-induced cell death and hold promise for eventual clinical applications, but translation from animal models to patients remains to be achieved.