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Anti‐angiogenic therapy has increased the progression‐free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6–8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table  1 ). Many mechanisms of resistance to anti‐VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti‐angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia‐inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre‐clinical studies combining anti‐angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti‐angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre‐clinical and clinical studies that have potential for producing synthetic lethality in combination with anti‐angiogenic therapy as a future therapeutic strategy. Graphical Abstract Improving progression‐free survival in cancer: the importance of combining anti‐angiogenic therapy with inhibitors of hypoxic and metabolic adaptation to target induced essentiality and overcome tumour adaption.

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α–positive (ERα⁺) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)–dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2’s cis-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.

The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model.

Inflammation has a crucial role in protection against various pathogens. The inflammasome is an intracellular multiprotein signaling complex that is linked to pathogen sensing and initiation of the inflammatory response in physiological and pathological conditions. The most characterized inflammasome is the NLRP3 inflammasome, which is a known sensor of cell stress and is tightly regulated in resting cells. However, altered regulation of the NLRP3 inflammasome is found in several pathological conditions, including autoimmune disease and cancer. expression was shown to be post-transcriptionally regulated and multiple miRNA have been implicated in post-transcriptional regulation of the inflammasome. Therefore, in recent years, miRNA based post-transcriptional control of NLRP3 has become a focus of much research, especially as a potential therapeutic approach. In this review, we provide a summary of the recent investigations on the role of miRNA in the post-transcriptional control of the NLRP3 inflammasome, a key regulator of pro-inflammatory IL-1β and IL-18 cytokine production. Current approaches to targeting the inflammasome product were shown to be an effective treatment for diseases linked to NLRP3 overexpression. Although utilizing NLRP3 targeting miRNAs was shown to be a successful therapeutic approach in several animal models, their therapeutic application in patients remains to be determined.

Background Ovarian cancer is one of the most common gynaecological cancers affecting more than 300,000 women worldwide each year. S100 calcium-binding protein A6 (S100A6) is a member of the S100 family of calcium-binding proteins. Upon activation by calcium (Ca 2+ ) signalling, S100A6 regulates numerous cellular processes including cell proliferation and metastasis. The role of S100A6 is well established across multiple tumour types where increased S100A6 expression contributes to tumourigenesis and worse patient outcome. However, the role of S100A6 in ovarian cancer is not well established. Methods The impact of cytoplasmic and nuclear S100A6 expression on overall survival and clinicopathological criteria was investigated in 462 ovarian tumours by immunohistochemistry. Additionally, S100A6 expression in an ovarian cancer cohort from The Cancer Genome Atlas (TCGA) PanCancer dataset ( n  = 299) was evaluated and associations with overall survival and progression-free survival were identified. Results Immunohistochemical staining revealed that high cytoplasmic expression of S100A6 was significantly associated with better overall survival ( p  = 0.014). Additionally, high nuclear expression was significantly associated with better overall survival ( p  = 0.036). In contrast, analysis of mRNA S100A6 suggests no significant association of mRNA levels for overall survival ( p  = 0.903) and progression free survival ( p  = 0.278). Conclusions Our data provides novel insights regarding the clinical implications of S100A6 expression in ovarian cancer, providing strong rationale for functional investigations of S100A6 in ovarian cancer.

Dysregulation of NLRP3 inflammasome complex formation can promote chronic inflammation by increased release of IL-1β. However, the effect of NLRP3 complex formation on tumor progression remains controversial. Therefore, we sought to determine the effect of NLRP3 modulation on the growth of the different types of cancer cells, derived from lung, breast, and prostate cancers as well as neuroblastoma and glioblastoma . The effect of Caspase 1 inhibitor (VX765) and combination of LPS/Nigericin on NLRP3 inflammasome activity was analyzed in A549 (lung cancer), MCF-7 (breast cancer), PC3 (prostate cancer), SH-SY5Y (neuroblastoma), and U138MG (glioblastoma) cells. Human fibroblasts were used as control cells. The effect of VX765 and LPS/Nigericin on NLRP3 expression was analyzed using western blot, while IL-1β and IL-18 secretion was detected by ELISA. Tumor cell viability and progression were determined using Annexin V, cell proliferation assay, LDH assay, sphere formation assay, transmission electron microscopy, and a multiplex cytokine assay. Also, angiogenesis was investigated by a tube formation assay. VEGF and MMPs secretion were detected by ELISA and a multiplex assay, respectively. Statistical analysis was done using one-way ANOVA with Tukey's analyses and Kruskal-Wallis one-way analysis of variance. LPS/Nigericin increased NRLP3 protein expression as well as IL-1β and IL-18 secretion in PC3 and U138MG cells compared to A549, MCF7, SH-SY5Y cells, and fibroblasts. In contrast, MIF expression was commonly found upregulated in A549, PC3, SH-SY5Y, and U138MG cells and fibroblasts after Nigericin treatment. Nigericin and a combination of LPS/Nigericin decreased the cell viability and proliferation. Also, LPS/Nigericin significantly increased tumorsphere size in PC3 and U138MG cells. In contrast, the sphere size was reduced in MCF7 and SH-SY5Y cells treated with LPS/Nigericin, while no effect was detected in A549 cells. VX765 increased secretion of CCL24 in A549, MCF7, PC3, and fibroblasts as well as CCL11 and CCL26 in SH-SY5Y cells. Also, VX765 significantly increased the production of VEGF and MMPs and stimulated angiogenesis in all tumor cell lines. Our data suggest that NLRP3 activation using Nigericin could be a novel therapeutic approach to control the growth of tumors producing a low level of IL-1β and IL-18.

ST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (i.v.) formulation may be required for some hospitalized patients who are unable to take oral medication. An i.v. formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation. The pharmacokinetics of ST-246 after i.v. infusions in mice, rabbits and nonhuman primates (NHP) were compared to those obtained after oral administration. Ten minute i.v. infusions of ST-246 at doses of 3, 10, 30, and 75 mg/kg in mice produced peak plasma concentrations ranging from 16.9 to 238 µg/mL. Elimination appeared predominately first-order and exposure dose-proportional up to 30 mg/kg. Short i.v. infusions (5 to 15 minutes) in rabbits resulted in rapid distribution followed by slower elimination. Intravenous infusions in NHP were conducted at doses of 1 to 30 mg/kg. The length of single infusions in NHP ranged from 4 to 6 hours. The pharmacokinetics and tolerability for the two highest doses were evaluated when administered as two equivalent 4 hour infusions initiated 12 hours apart. Terminal elimination half-lives in all species for oral and i.v. infusions were similar. Dose-limiting central nervous system effects were identified in all three species and appeared related to high C(max) plasma concentrations. These effects were eliminated using slower i.v. infusions. Pharmacokinetic profiles after i.v. infusion compared to those observed after oral administration demonstrated the necessity of longer i.v. infusions to (1) mimic the plasma exposure observed after oral administration and (2) avoid C(max) associated toxicity. Shorter infusions at higher doses in NHP resulted in decreased clearance, suggesting saturated distribution or elimination. Elimination half-lives in all species were similar between oral and i.v. administration. The administration of ST-246 was well tolerated as a slow i.v. infusion.

There is a consensus about the strong correlation between the elasticity of cells and tissue and their normal, dysplastic, and cancerous states. However, developments in cell mechanics have not seen significant progress in clinical applications. In this work, we explore the possibility of using phonon acoustics for this purpose. We used phonon microscopy to obtain a measure of the elastic properties between cancerous and normal breast cells. Utilising the raw time-resolved phonon-derived data (300 k individual inputs), we employed a deep learning technique to differentiate between MDA-MB-231 and MCF10a cell lines. We achieved a 93% accuracy using a single phonon measurement in a volume of approximately 2.5 μm 3 . We also investigated means for classification based on a physical model that suggest the presence of unidentified mechanical markers. We have successfully created a compact sensor design as a proof of principle, demonstrating its compatibility for use with needles and endoscopes, opening up exciting possibilities for future applications.

Background Testicular germ cell tumours (TGCTs) represent a clinical challenge; they are most prevalent in young individuals and are triggered by molecular mechanisms that are not fully understood. The origin of TGCTs can be traced back to primordial germ cells that fail to mature during embryonic development. These cells express high levels of pluripotency factors, including the transcription factor NANOG which is highly expressed in TGCTs. Gain or amplification of the NANOG locus is common in advanced tumours, suggesting a key role for this master regulator of pluripotency in TGCT stemness and malignancy. Methods In this study, we analysed the expression of microRNAs (miRNAs) that are regulated by NANOG in TGCTs via integrated bioinformatic analyses of data from The Cancer Genome Atlas and NANOG chromatin immunoprecipitation in human embryonic stem cells. Through gain-of-function experiments, MIR9-2 was further investigated as a novel tumour suppressor regulated by NANOG. After transfection with MIR9-2 mimics, TGCT cells were analysed for cell proliferation, invasion, sensitivity to cisplatin, and gene expression signatures by RNA sequencing. Results For the first time, we identified 86 miRNAs regulated by NANOG in TGCTs. Among these, 37 miRNAs were differentially expressed in NANOG-high tumours, and they clustered TGCTs according to their subtypes. Binding of NANOG within 2 kb upstream of the MIR9-2 locus was associated with a negative regulation. Low expression of MIR9-2 was associated with tumour progression and MIR9-2-5p was found to play a role in the control of tumour stemness. A gain of function of MIR9-2-5p was associated with reduced proliferation, invasion, and sensitivity to cisplatin in both embryonal carcinoma and seminoma tumours. MIR9-2-5p expression in TGCT cells significantly reduced the expression of genes regulating pluripotency and cell division, consistent with its functional effect on reducing cancer stemness. Conclusions This study provides new molecular insights into the role of NANOG as a key determinant of pluripotency in TGCTs through the regulation of MIR9-2-5p, a novel epigenetic modulator of cancer stemness. Our data also highlight the potential negative feedback mediated by MIR9-2-5p on NANOG expression, which could be exploited as a therapeutic strategy for the treatment of TGCTs.

Current strategies for early detection of breast and other cancers are limited in part because some lesions identified as potentially malignant do not develop into aggressive tumors. Acid pH has been suggested as a key characteristic of aggressive tumors that might distinguish aggressive lesions from more indolent pathology. We therefore investigated the novel class of molecules, pH low insertion peptides (pHLIPs), as markers of low pH in tumor allografts and of malignant lesions in a mouse model of spontaneous breast cancer, BALB/neu-T. pHLIP Variant 3 (Var3) conjugated with fluorescent Alexa546 was shown to insert into tumor spheroids in a sequence-specific manner. Its signal reflected pH in murine tumors. It was induced by carbonic anhydrase IX (CAIX) overexpression and inhibited by acetazolamide (AZA) administration. By using31P magnetic resonance spectroscopy (MRS), we demonstrated that pHLIP Var3 was retained in tumors of pH equal to or less than 6.7 but not in tissues of higher pH. In BALB/neu-T mice at different stages of the disease, the fluorescent signal from pHLIP Var3 marked cancerous lesions with a very low false-positive rate. However, only ∼60% of the smallest lesions retained a pHLIP Var3 signal, suggesting heterogeneity in pH. Taken together, these results show that pHLIP can identify regions of lower pH, allowing for its development as a theranostic tool for clinical applications.