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To investigate if radiographic imaging changes defined as necrosis correlate with regions in the brain with elevated linear energy transfer (LET) for proton radiation therapy treatments with partial brain involvement in central nervous system and patients with head and neck cancer.
The metastatic tumors of breast cancer lead to the mortality of patients in part due to the failure of chemotherapeutics to reach the brain and emergence of drug resistance. With the increase in drug resistance, we focused on targeting mitochondrial metabolism, which was recently found to be a viable and novel drug target in breast cancer. Here we screened several ligands for anticancer activity in a phenotypic screen using the MTT dye as a marker for cell proliferation. MCF-7 breast cancer cells were treated with compounds in the presence of galactose to ensure mitochondrial interaction by the compounds. The lead compound of our group, NL-1, a thiazolidinedione (TZD), was found to inhibit cell proliferation with an IC{sub 50} of 7.1 μM, whereas its unsaturated derivative CI-987 was more potent with a IC{sub 50} of 3.3 μM. The TZDs were affected by substitution on both the aromatic ring and the TZD warhead. Taken together, these compounds can serve as lead structures for mitochondrial targeted drug discovery programs in breast cancer.
Melanoma brain metastasis is linked to dismal prognosis and low overall survival and is detected in up to 80% of patients at autopsy. Circulating tumor cells (CTC) are the smallest functional units of cancer and precursors of fatal metastasis. We previously used an unbiased multilevel approach to discover a unique ribosomal protein large/small subunit (RPL/RPS) CTC gene signature associated with melanoma brain metastasis. In this study, we hypothesized that CTC-driven melanoma brain metastasis secondary metastasis (“metastasis of metastasis” per clinical scenarios) has targeted organ specificity for the liver. We injected parallel cohorts of immunodeficient and newly developed humanized NBSGW (huNBSGW) mice with cells from CTC-derived melanoma brain metastasis to identify secondary metastatic patterns. We found the presence of a melanoma brain–liver metastasis axis in huNBSGW mice. Furthermore, RNA sequencing analysis of tissues showed a significant upregulation of the RPL/RPS CTC gene signature linked to metastatic spread to the liver. Additional RNA sequencing of CTCs from huNBSGW blood revealed extensive CTC clustering with human B cells in these mice. CTC:B-cell clusters were also upregulated in the blood of patients with primary melanoma and maintained either in CTC-driven melanoma brain metastasis or melanoma brain metastasis CTC–derived cells promoting liver metastasis. CTC-generated tumor tissues were interrogated at single-cell gene and protein expression levels (10x Genomics Xenium and HALO spatial biology platforms, respectively). Collectively, our findings suggest that heterotypic CTC:B-cell interactions can be critical at multiple stages of metastasis.
Melanotransferrin (MTf) is an iron-binding member of the transferrin superfamily that can be membrane-anchored or secreted in serum. On cells, it can mediate transferrin-independent iron uptake and promote proliferation. In serum, it is a transcytotic iron transporter across the blood–brain barrier. MTf has been exploited as a drug delivery carrier to the brain and as an antibody-drug conjugate (ADC) target due to its oncogenic role in melanoma and its elevated expression in triple-negative breast cancer (TNBC). For treatment of TNBC, an MTf-targeting ADC completed a phase I clinical trial (NCT03316794). The structure of its murine, unconjugated Fab fragment (SC57.32) is revealed here in complex with MTf. The MTf N-lobe is in an active and iron-bound, closed conformation while the C-lobe is in an open conformation incompatible with iron binding. This combination of active and inactive domains displays a novel inter-domain arrangement in which the C2 subdomain angles away from the N-lobe. The C2 subdomain also contains the SC57.32 glyco-epitope, which comprises ten protein residues and two N-acetylglucosamines. Our report reveals novel features of MTf and provides a point of reference for MTf-targeting, structure-guided drug design.
Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference–based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial ( NCT03020017 ) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment–related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129–treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.
Radiation therapy is an important treatment component for patients with lung cancer. However, the survival time gained with clinical radiation therapy techniques is relatively short. Data from preclinical experiments suggest that synchrotron microbeam radiation therapy could be much better suited to control malignant brain tumors than current clinical concepts of radiation therapy. Even at peak doses of several hundred gray, the extent of functional deficits is low.
Chemotherapy remains a mainstay in the treatment of many types of cancer even though it is associated with debilitating behavioral side effects referred to as “chemobrain,” including difficulty concentrating and memory impairment. The predominant hypothesis in the field is that systemic inflammation drives these cognitive impairments, although the brain mechanisms by which this occurs remain poorly understood. Here, we hypothesized that microglia are activated by chemotherapy and drive chemotherapy-associated cognitive impairments. To test this hypothesis, we treated female C57BL/6 mice with a clinically-relevant regimen of a common chemotherapeutic, paclitaxel (6 i.p. doses at 30 mg/kg), which impairs memory of an aversive stimulus as assessed via a contextual fear conditioning (CFC) paradigm. In this work, paclitaxel increased the percent area of IBA1 staining in the dentate gyrus of the hippocampus. Moreover, using a machine learning random forest classifier we identified immunohistochemical features of reactive microglia in multiple hippocampal subregions that were distinct between vehicle- and paclitaxel-treated mice. Paclitaxel treatment also increased gene expression of inflammatory cytokines in a microglia-enriched population of cells from mice. Lastly, a selective inhibitor of colony stimulating factor 1 receptor, PLX5622, was employed to deplete microglia and then assess CFC performance following paclitaxel treatment. PLX5622 significantly reduced hippocampal gene expression of paclitaxel-induced proinflammatory cytokines and restored memory, suggesting that microglia play a critical role in the development of chemotherapy-associated neuroinflammation and cognitive impairments. This work provides critical evidence that microglia drive paclitaxel-associated cognitive impairments, a key mechanistic detail for determining preventative and intervention strategies for these burdensome side effects.
Fluorescence-guided surgery has emerged as a vital tool for tumour resection procedures. As well as intraoperative tumour visualisation, 5-ALA-induced PpIX provides an avenue for quantitative tumour identification based on ratiometric fluorescence measurement. To this end, fluorescence imaging and fibre-based probes have enabled more precise demarcation between the cancerous and healthy tissues. These sensing approaches, which rely on collecting the fluorescence light from the tumour resection site and its “remote” spectral sensing, introduce challenges associated with optical losses. In this work, we demonstrate the viability of tumour detection at the resection site using a miniature fluorescence measurement system. Unlike the current bulky systems, which necessitate remote measurement, we have adopted a millimetre-sized spectral sensor chip for quantitative fluorescence measurements. A reliable measurement at the resection site requires a stable optical window between the tissue and the optoelectronic system. This is achieved using an antifouling diamond window, which provides stable optical transparency. The system achieved a sensitivity of 92.3% and specificity of 98.3% in detecting a surrogate tumour at a resolution of 1 × 1 mm 2 . In conclusion, as well as addressing losses associated with collecting and coupling fluorescence light in the current ‘remote’ sensing approaches, the small size of the system introduced in this work paves the way for its direct integration with the tumour resection tools with the aim of more accurate interoperative tumour identification.
225 Ac-PSMA-617 targeted-therapy has demonstrated efficacy in 75-85% of patients; however, responses are not durable. We aimed to establish translatable mouse models of disseminated prostate cancer (PCa) to evaluate effectiveness of 225 Ac-PSMA-617 at various disease stages. Methods: C4-2, C4-2B, or 22Rv1 cells were injected into the left ventricle of male NSG mice. Disease progression was monitored using bioluminescence imaging (BLI). For treatment, mice were injected with 40 kBq 225 Ac-PSMA-617 at one (early treatment cohort) or three weeks (late treatment cohort) post-inoculation. Treatment efficacy was monitored by BLI of whole-body tumor burden. Mice were sacrificed based on body conditioning score. Results: C4-2 cells yielded metastases in liver, lungs, spleen, stomach, bones, and brain - achieving a clinically relevant model of widespread metastatic disease. The disease burden in the early treatment cohort was stable over 27 weeks in 5/9 mice and progressive in 4/9 mice. These mice were sacrificed due to brain metastases. Median survival of the late treatment cohort was superior to controls (13 vs. 7 weeks; p<0.0001) but inferior to that in the early treatment cohort (13 vs. 27 weeks; p<0.001). Late cohort mice succumbed to extensive liver involvement. The 22Rv1 and C4-2B systemic models were not used for treatment due to high kidney metastatic burden or low take rate, respectively. Conclusion: C4-2 cells reproduced metastatic cancer spread most relevantly. Early treatment with 225 Ac-PSMA-617 prevented liver metastases and led to significant survival benefit. Late treatment improved survival without reducing tumor burden in the liver, the main site of metastasis. The current findings suggest that early 225 Ac-PSMA-617 intervention is more efficacious in the setting of widespread metastatic PCa.
To this date, studies regarding the use of prophylactic cranial irradiation (PCI) versus standard of care (SoC) for patients with non-small cell lung cancer have shown limited benefit in survival outcomes, in addition to the potential effects on quality of life (QoL) and neurocognitive function (NCF). This randomized, phase II study evaluated the role of PCI in QoL and NCF, in a population comprised of subjects at a high risk for development of brain metastases (BM).
Background: Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. Methods: Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. Results: As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. Conclusions: We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.
Highlights: • Our findings demonstrates that HMGA2 promotes central arteries formation in zebrafish. • HMGA2 induces vascular development through modulation of IGFBP2 whatever in vivo or in vitro. • The mRNA expressions of HMGA2 and IGFBP2 increased significantly in peripheral blood of Hemangioma patients. • HMGA2-IGFBP2 are promising candidates towards therapeutical vascularization in vascular diseases like Hemangioma. Angiogenesis is the process by which new blood vessels form from preexisting vessels and regulates the processes of embryonic development, wound healing and tumorigenesis. HMGA2 is involved in the occurrence of several cancers, but its biological role and the exact downstream genes involved in vascular development and sprouting angiogenesis remain largely unknown. Here, we first found that HMGA2 knockdown in zebrafish embryos resulted in defects of central artery formation. RNA sequencing revealed that IGFBP2 was significantly downregulated by interference with HMGA2, and IGFBP2 overexpression reversed the inhibition of brain vascular development caused by HMGA2 deficiency. In vitro, we further found that HMGA2 knockdown blocked the migration, tube formation and branching of HUVECs. Similarly, IGFBP2 protein overexpression attenuated the impairments induced by HMGA2 deficiency. Moreover, the promotion of angiogenesis by HMGA2 overexpression was verified in a Matrigel plug assay. We next found that HMGA2 bound directly to a region in the IGFBP2 promoter and positively regulated IGFBP2 expression. Interestingly, the mRNA expression levels of HMGA2 and IGFBP2 were increased significantly in the peripheral blood of hemangioma patients, indicating that overexpression of HMGA2 and IGFBP2 results in vessel formation, consistent with the results of the in vivo and in vitro experiments. In summary, our findings demonstrate that HMGA2 promotes central artery formation by modulating angiogenesis via IGFBP2 induction.
Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)–mutant low-grade glioma (LGG). Here, we reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1 R132H -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.
The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant’s real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau’s synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.
Near-infrared (NIR) laser-induced phototherapy through NIR agents has demonstrated the great potential for cancer therapy. However, insufficient tumor killing due to the nonuniform heat or cytotoxic singlet oxygen ( 1 O 2 ) distribution over tumors from phototherapy results in tumor recurrence and inferior outcomes. To achieve high tumor killing efficacy, one of the solutions is to employ the combinational treatment of phototherapy with other modalities, especially with chemotherapeutic agents. In this paper, a simple and effective multimodal therapeutic system was designed via combining chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) to achieve the polytherapy of malignant glioma which is one of the most aggressive tumors in the brain. IR-780 (IR780) dye-labeled tube-forming peptoids (PepIR) were synthesized and self-assembled into crystalline nanotubes (PepIR nanotubes). These PepIR nanotubes showed an excellent efficacy for PDT/PTT because the IR780 photosensitizers were effectively packed and separated from each other within crystalline nanotubes by tuning IR780 density; thus, a self-quenching of these IR780 molecules was significantly reduced. Moreover, the efficient DOX loading achieved due to the nanotube large surface area contributed to an efficient and synergistic chemotherapy against glioma cells. Given the unique properties of peptoids and peptoid nanotubes, we believe that the developed multimodal DOX-loaded PepIR nanotubes in this work offer great promises for future glioma therapy in clinic.
Being the predominant cause of disability, neurological diseases have received much attention from the global health community. Over a billion people suffer from one of the following neurological disorders: dementia, epilepsy, stroke, migraine, meningitis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, prion disease, or brain tumors. The diagnosis and treatment options are limited for many of these diseases. Aptamers, being small and non-immunogenic nucleic acid molecules that are easy to chemically modify, offer potential diagnostic and theragnostic applications to meet these needs. This review covers pioneering studies in applying aptamers, which shows promise for future diagnostics and treatments of neurological disorders that pose increasingly dire worldwide health challenges.
Conducting polymers are promising due to their unique properties, such as excellent electrical and optical properties, physical and chemical stability, high conductivity, and effective redox properties with high-temperature stability and biocompatibility. Due to these properties, conducting polymers are useful in diverse applications like sensors, batteries, oil industries, biosensors, biomedicines, catalysis, cancer treatment, etc. This review article aims to discuss the recent trends and analysis of conducting polymer-based electrochemical sensors in diverse areas with all required sensor characteristics, such as the derived limit of detection, utilized techniques for the sensing analysis and derived linear dynamic range with the stability of the sensors. Conducting polymers and their nanocomposites-based electrochemical sensors have demonstrated exceptional capabilities towards detecting various biomolecules, heavy metals, pesticides, and viruses like SARS-COV-2. Incorporation of redox mediators, use of conducting hydrogels, and molecular imprinting are promising strategies for better performance of the derived sensor. The article has demonstrated the existing challenges and limitations and provided solutions in the field. In the future, conducting polymers-based electrochemical sensors can be utilized in wearable sensors and integrated with IoT devices for better reach in real-time applications. They can also be made more accessible with precise control and data output by following specific methodologies. Utilizing green and sustainable conducting polymers can be crucial in advancing eco-friendly practices in the future. Conducting polymer-based electrochemical sensors has affectivity in neurochemical and pathogen sensing, which is essential for brain function and mental health.