Effective Anticancer Therapy Research Articles

Harnessing the Therapeutic Potential of Exosomes: A Novel Strategy for Anticancer and Antiviral Therapy.

Exosomes are extracellular membrane bound vesicles released from almost all cell types and can be retrieved from all body fluids. The molecular constituents of these extracellular bodies vary depending on their cell of origin, from which they can transport molecules such as DNA, RNA, proteins lipids, and several metabolites. They have been shown to execute several functions such as in cell growth, migration, differentiation, neuronal signaling, immune cell modulation, and some diseases such as cancer through intercellular communication and signaling. They are also described to act as key players in viral persistence and dissemination. Due to their ability to elicit potent cellular responses, high level of tolerance in host cells, and high efficiency in penetrating other cells, they are proposed to be potential therapeutics as well as vehicles for drug delivery. In recent years, several studies have been conducted in quest for the development of an effective anticancer therapy or antiviral therapy against highly persistent viruses. However, most of these studies become halted due to failure to achieve desired therapeutic outcomes. Nevertheless, the in vitro/in vivo application of exosomes in tumor and infectious disease diagnosis and therapy is prospective. This review discusses the role of exosomes as predictive markers for immune activation and potential targets for anticancer/antiviral therapies.

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

Gut microbiota shed new light on the management of immune-related adverse events.

Immunotherapy has dramatically revolutionized the therapeutic landscape for patients with cancer. Although immune checkpoint inhibitors are now accepted as effective anticancer therapies, they introduce a novel class of toxicity, termed immune‐related adverse events, which can lead to the temporary or permanent discontinuation of immunotherapy and life‐threatening tumor progression. Therefore, the effective prevention and treatment of immune‐related adverse events is a clinical imperative to maximize the utility of immunotherapies. Immune‐related adverse events are related to the intestinal microbiota, baseline gut microbiota composition is an important determinant of immune checkpoint inhibitor‐related colitis, and antibiotics exacerbate these undesirable side‐effects. Supplementation with specific probiotics reduces immune checkpoint inhibitor‐related colitis in mice, and fecal microbiota transplantation has now been shown to effectively treat refractory immune checkpoint inhibitor‐related colitis in the clinic. Hence, modifying the microbiota holds great promise for preventing and treating immune‐related adverse events. Microbiomes and their metabolites play important roles in the potential underlying mechanisms through interactions with both innate and adaptive immune cells. Here we review the gut microbiota and immune regulation; the changes occurring in the microbiota during immune checkpoint inhibitor therapy; the relationship between the microbiota and immune‐related adverse events, antibiotics, probiotics/prebiotics, and fecal microbiota transplantation in immune checkpoint inhibitor‐related colitis; and the protective mechanisms mediated by the microbiome and metabolites in immune‐related adverse events.

Apoptosis-Sensing Xenograft Zebrafish Tumor Model for Anticancer Evaluation of Redox-Responsive Cross-Linked Pluronic Micelles

A suitable animal model for preclinical screening and evaluation in vivo could vastly increase the efficiency and success rate of nanomedicine development. Compared with rodents, the transparency of the zebrafish model offers unique advantages of real-time and high-resolution imaging of the whole body and cellular levels in vivo. In this research, we established an apoptosis-sensing xenograft zebrafish tumor model to evaluate the anti-cancer effects of redox-responsive cross-linked Pluronic polymeric micelles (CPPMs) visually and accurately. First, doxorubicin (Dox)-loaded CPPMs were fabricated and characterized with glutathione (GSH)-responsive drug release. Then, the B16F10 xenograft zebrafish tumor model was established to mimic the tumor microenvironment with angiogenesis and high GSH generation for redox-responsive tumor-targeting evaluation in vivo. The high GSH generation was first verified in the xenograft zebrafish tumor model. Compared with ordinary Pluronic polymeric micelles, Dox CPPMs had a much higher accumulation in zebrafish tumor sites. Finally, the apoptosis-sensing B16F10-C3 xenograft zebrafish tumor model was established for visual, rapid, effective, and noninvasive assessment of anti-cancer effects at the cellular level in vivo. The Dox CPPMs significantly inhibited the proliferation of cancer cells and induced apoptosis in the B16F10-C3 xenograft zebrafish tumor model. Therefore, the redox-responsive cross-linked Pluronic micelles showed effective anti-cancer therapy in the xenograft zebrafish tumor model. This xenograft zebrafish tumor model is available for rapid screening and assessment of anti-cancer effects in preclinical studies.

Contrasting regulation of live Bacillus cereus No.1 and its volatiles on Shiraia perylenequinone production

BackgroundFungal perylenequinones (PQs) are a class of photoactivated polyketide mycotoxins produced by plant-associated fungi. Hypocrellins, the effective anticancer photodynamic therapy (PDT) agents are main bioactive PQs isolated from a bambusicolous Shiraia fruiting bodies. We found previously that bacterial communities inhabiting fungal fruiting bodies are diverse, but with unknown functions. Bacillus is the most dominant genus inside Shiraia fruiting body. To understand the regulation role of the dominant Bacillus isolates on host fungus, we continued our work on co-culture of the dominant bacterium B. cereus No.1 with host fungus Shiraia sp. S9 to elucidate bacterial regulation on fungal hypocrellin production.ResultsResults from "donut" plate tests indicated that the bacterial culture could promote significantly fungal PQ production including hypocrellin A (HA), HC and elsinochrome A-C through bacterial volatiles. After analysis by gas chromatograph/mass spectrometer and confirmation with commercial pure compounds, the volatiles produced by the bacterium were characterized. The eliciting roles of bacterial volatile organic compounds (VOCs) on HA production via transcriptional regulation of host Shiraia fungus were confirmed. In the established submerged bacterial volatile co-culture, bacterial volatiles could not only promote HA production in the mycelium culture, but also facilitate the release of HA into the medium. The total production of HA was reached to 225.9 mg/L, about 1.87 times that of the fungal mono-culture. In contrast, the live bacterium suppressed markedly fungal PQ production in both confrontation plates and mycelium cultures by direct contact. The live bacterium not only down-regulated the transcript levels of HA biosynthetic genes, but also degraded extracellular HA quickly to its reductive product.ConclusionOur results indicated that bacterial volatile release could be a long-distance signal to elicit fungal PQ production. Biodegradation and inhibition by direct contact on fungal PQs were induced by the dominate Bacillus to protect themselves in the fruiting bodies. This is the first report on the regulation of Bacillus volatiles on fungal PQ production. These findings could be helpful for both understanding the intimate fungal–bacterial interactions in a fruiting body and establishing novel cultures for the enhanced production of bioactive PQs.Graphical

Poly-Lactide-Co-Glycolide-Polyethylene Glycol-Ginsenoside Rg3-Ag Exerts a Radio-Sensitization Effect in Non-Small Cell Lung Cancer

Radiotherapy is an effective anti-cancer therapy for patients with non-small cell lung cancer (NSCLC), however, the prognosis is unsatisfactory owing to radio-resistance and toxicity. It is crucial to improve radiotherapy efficacy. Ag nanoparticles (NPs) and ginsenoside Rg3 (Rg3) exerted antitumor and radio-sensitization effects. Therefore, we investigated whether poly-lactide-co-glycolide-polyethylene glycol (PLGA-PEG)-Rg3-Ag will function as a noninvasive, tracing, radiotherapy sensitizer. The morphology of NPs was visualized with transmission electron microscopy (TEM). The drug loading content, encapsulation efficiency, and cumulative drug release of Rg3 was determined by HPLC. Cellular uptake of NPs in A549 and SPCA-1 was measured by immunostaining. The radio-sensitization effect of PLGA-PEG-Rg3-Ag in vitro was determined in A549 by detecting proliferation, colony formation, and apoptosis with CCK-8, clonogenic survival assay, and flow cytometry, while in vivo was determined in nude mice by testing the body weight and tumor volume. PLGA-PEG-Rg3-Ag exerted radio-sensitization effect by reducing cell proliferation and colony formation while enhancing cell apoptosis in A549; reduced tumor volume in nude mice. PLGA-PEG-Rg3-Ag exhibits radio-sensitization effects in NSCLC.

Plants as a Source of Anticancer Agents: From Bench to Bedside.

Cancer is the second leading cause of death after cardiovascular diseases. Conventional anticancer therapies are associated with lack of selectivity and serious side effects. Cancer hallmarks are biological capabilities acquired by cancer cells during neoplastic transformation. Targeting multiple cancer hallmarks is a promising strategy to treat cancer. The diversity in chemical structure and the relatively low toxicity make plant-derived natural products a promising source for the development of new and more effective anticancer therapies that have the capacity to target multiple hallmarks in cancer. In this review, we discussed the anticancer activities of ten natural products extracted from plants. The majority of these products inhibit cancer by targeting multiple cancer hallmarks, and many of these chemicals have reached clinical applications. Studies discussed in this review provide a solid ground for researchers and physicians to design more effective combination anticancer therapies using plant-derived natural products.

Bromopropylate Imidazoliumyl Substituted Silicon Phthalocyanine for Mitochondria-Targeting, Two-Photon Imaging Guided in Vitro Photodynamic Therapy.

Maximization of phototoxic damage on tumor is essential for effective anticancer photodynamic therapy (PDT). Highly cancer-cell-organelle-specific delivery of efficient photosensitizers (PSs) in vitro and in vivo is in great demand. In this paper, a novel water-soluble mitochondria targeted cationic bromopropylate imidazoliumyl axially substituted silicon (IV) phthalocyanine (Br-ID-SiPc) is developed to improve PDT efficiency by enhancing the subcellular localization of photosensitizers. Benefiting from the targeting capability of bromopropylate imidazoliumyl, Br-ID-SiPc can selectively accumulate in mitochondria after cellular uptake, this process could be tracked by two-photon imaging. Br-ID-SiPc effectively damaged the circular plasmid DNA of mitochondria and induced HO-8910 cells apoptosis. Our results indicate that Br-ID-SiPc is a potential photosensitizer which can be used as a mitochondria-targeting and two-photon fluorescent imaging molecule for PDT of cancers.

Coordination-Driven Metal-Polyphenolic Nanoparticles toward Effective Anticancer Therapy.

Stabilization of bioactive components, especially for hydrophobic functional factors, is a promising approach for improving their biological activity. Here, a metal-phenolic coordination chemistry that synthesizes biocompatible and biodegradable thin film based on tannic acid and trivalent metal ion (Fe3+ or Al3+ ) is addressed, and the results also demonstrate its use for encapsulating a hydrophobic drug (nobiletin) and triggering drug release for cancer treatment both in vitro and in vivo. This assembled system provides drug-loaded nanoparticles (NPs) with small, but uniform, size (≈200nm). It displays beneficial potential in enhancing colloidal stability and preventing premature drug leakage. Moreover, the metal-phenolic coating is found to possess high cell biocompatibility as a delivery vector for controlled drug delivery, while the final fabricated drug NPs have effective anti-tumor activity by both inducing higher tumor apoptosis and inhibiting tumor metastasis, which is superior to naked drug formulations. Overall, these findings propose an effective and straightforward way for coating hydrophobic drugs employing interfacial adhesion and assembly, which can be a highly promising vehicle for controlled-release biomedical applications for cancer therapy.

Abstract 1303: FAP-targeted molecular radiotherapy attenuates tumor growth and synergizes with immunotherapy for the treatment of malignant melanoma

Abstract Immunotherapy has drastically improved outcomes in many patients with melanoma, however the majority do not attain a durable response to treatment and therefore additional agents are desperately needed. Here, we tested the efficacy of 177Lu-FAPI-04, a novel FAP-targeted radiotherapy, alone and in combination with anti-PD-1 and anti-CTLA-4 immunotherapy in a mouse model of melanoma to attenuate tumor growth. Using B16F10 murine melanoma cells, we implanted tumors in C57BL/6 mice. Animals were divided into four groups: untreated control, molecular targeted 177Lu-FAPI-04 radiotherapy treatment, immunotherapy treatment, and combined radio- and immunotherapy treatment. We assessed tumor growth over time and animals were sacrificed at 21 days. After sacrifice, tumors were dissected out and preserved for immunohistochemistry and flow cytometry. Growth curves demonstrated that immunotherapy and radiotherapy each individually attenuated tumor growth, but together they resulted in tumor regression in the majority of animals. Immunohistochemistry demonstrated increased caspase-3 staining in tumors treated with combined 177Lu-FAPI-04 radiotherapy and immunotherapy compared to untreated tumors or tumors treated with either therapy alone indicating an increase in apoptotic cell death. Ki67 expression exhibited inverse staining with moderate expression in untreated samples, low expression in immunotherapy and radiotherapy treated samples, and no staining in tumors treated with combined therapy. Flow cytometric analysis demonstrated that tumors treated with either therapy exhibited an increase in M2 macrophages, however this population was obliterated in dual-treated tumors. Together, these data support that targeting FAP with targeted radiotherapy is an effective treatment which synergizes with immunotherapy to modulate cells of the myeloid lineage as an effective anticancer therapy for melanoma. Future translational studies are needed to further study the synergies between FAP-targeted radiotherapies and immunotherapy. Citation Format: Kathleen M. Capaccione, Mikhail Doubrovin, Brian Braumuller, Dvora Leibowiz, Nikunj Bhatt, Andrei Molotkov, Michael Kissner, Fatemeh Momen-Heravi, Akiva Mintz. FAP-targeted molecular radiotherapy attenuates tumor growth and synergizes with immunotherapy for the treatment of malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1303.

Interconnected Adaptive Responses: A Way Out for Cancer Cells to Avoid Cellular Demise

Simple SummaryOne of the major obstacles to anti-cancer therapy is the development of drug resistance that allows the cancer cell to adapt to the treatments and keep surviving. In this mini-review we attempt to give an overview of the adaptive responses and the cross-talk between them that could be targeted to counteract cancer resistance to stress and improve the outcome of cancer treatment.Different from normal cells, cancer cells must hyperactivate a variety of integrated responses in order to survive their basal stress or its exacerbation caused by exposure to anti-cancer agents. As cancer cells become particularly dependent on these adaptive responses, namely UPR, DDR autophagy, anti-oxidant and heat shock responses, this turns out to be an Achille’s heel, which allows them to be selectively killed while sparing normal unstressed cells. Better knowledge of the cross-talk between these adaptive processes and their impact on the immune system is needed to design more effective anti-cancer therapies, as reviewed in this paper.

Recapitulated Crosstalk between Cerebral Metastatic Lung Cancer Cells and Brain Perivascular Tumor Microenvironment in a Microfluidic Co-Culture Chip.

Non‐small cell lung carcinoma (NSCLC), which affects the brain, is fatal and resistant to anti‐cancer therapies. Despite innate, distinct characteristics of the brain from other organs, the underlying delicate crosstalk between brain metastatic NSCLC (BM‐NSCLC) cells and brain tumor microenvironment (bTME) associated with tumor evolution remains elusive. Here, a novel 3D microfluidic tri‐culture platform is proposed for recapitulating positive feedback from BM‐NSCLC and astrocytes and brain‐specific endothelial cells, two major players in bTME. Advanced imaging and quantitative functional assessment of the 3D tri‐culture model enable real‐time live imaging of cell viability and separate analyses of genomic/molecular/secretome from each subset. Susceptibility of multiple patient‐derived BM‐NSCLCs to representative targeted agents is altered and secretion of serpin E1, interleukin‐8, and secreted phosphoprotein 1, which are associated with tumor aggressiveness and poor clinical outcome, is increased in tri‐culture. Notably, multiple signaling pathways involved in inflammatory responses, nuclear factor kappa‐light‐chain‐enhancer of activated B cells, and cancer metastasis are activated in BM‐NSCLC through interaction with two bTME cell types. This novel platform offers a tool to elucidate potential molecular targets and for effective anti‐cancer therapy targeting the crosstalk between metastatic cancer cells and adjacent components of bTME.

Single center real-world treatment and outcomes in patients with hepatocellular carcinoma receiving immunotherapy.

e16134 Background: Immune checkpoint inhibitor (ICI) based therapy has emerged as a therapeutic option in hepatocellular carcinoma (HCC), both in combination (IC-C) and as single agent (IC-SA). Approvals were based on clinical trials with strict eligibility criteria limiting generalizability to the entire spectrum of clinical practice. Survival outcomes have not been evaluated in a real-world population and there is no established post ICI treatment standard. Methods: Patients (pts) with advanced HCC treated with ICI across lines of therapy were included in this retrospective study. Data regarding demographics, comorbidities, HCC etiology, liver function (Child Pugh Score [CPS] and ALBI Grade [G]), tumor burden, AFP, treatments, reason for discontinuation (dc) and outcomes were collected. Descriptive statistics and survival analysis were performed using Stata with cox regression analysis. Results: The cohort consisted of 138 pts: median age 63 years (24,95); 83% male; 38% Hispanic/Latino, 27% Asian, 17% Non-Hispanic White, 4% Black and 14% other/unknown. Etiology of cirrhosis: 16% Hepatitis B, 38% Hepatitis C, 12% alcohol liver disease, 9% NAFLD and 24 % mixed/other; Baseline CPS were 74% CPA, 23% CPB, and 2% CPC; ALBI Scores were G1 in 35%, G2 in 53%, and G3 in 12% pts; 62% had extrahepatic disease and/or portal invasion; AFP was ≥ 400ng/mL in 30% of pts. 88% of pts had prior local therapy. For the entire cohort, first line systemic therapy consisted of 52% ICI (18% IC-C and 34% IC-SA) and 48% TKI. mOS was 12 months (mo) (0,74) for first line ICI group and 19.5 mo (3,78) in those with first line TKI. In CPA pts, first line therapy was 51% ICI (24% IC-C and 27% IC-SA) and 39% TKI. 79% of CPA patients received ≥ 2 lines of therapy with second line consisting of 65% ICI and 20% TKI. First line therapy for pts with CPB cirrhosis was 58% ICI (2% IC-C and 55% IC-SA) and 42% TKI. 55% of CPB patients received ≥ 2 lines of therapy and second line therapy for CPB pts included 71% ICI and 18% TKI. mOS was 18 mo in CPA pts and 10 mo in CPB pts. Cirrhosis related complications resulted in treatment discontinuation in 2% of CPA pts vs. 14% of CPB pts. On multivariable analysis, Asian ethnicity (HR 0.41 p = 0.006), CPS (HR 1.64 p = 0.027), and number of treatment lines (HR 0.74 p = 0.005) were associated with OS. Conclusions: This single institution real-world cohort highlights the reality of sequential therapy in pts with advanced HCC. Survival outcomes in our CPA cohort are comparable to data from recent phase 3 trials. The survival in our CPB cohort in a tertiary care setting compares favorably with available data from clinical trials and suggests the feasibility of sequential and effective anti-cancer therapy in this population. Liver function, Asian ethnicity, and number of treatment lines are independent predictors of OS in this cohort of HCC patients receiving ICI. Prospective studies related to optimal treatment sequence and to CPB pts are needed.

Unusual dimeric flavonoids (brachydins) induce ultrastructural membrane alterations associated with antitumor activity in cancer cell lines

Notwithstanding the advances in molecular target-based drugs, chemotherapy remains the most common cancer treatment, despite its high toxicity. Consequently, effective anticancer therapies with fewer adverse effects are needed. Therefore, this study aimed to determine the anticancer activity of the dichloromethane fraction (DCMF) isolated from Arrabidae brachypoda roots, whose components are three unusual dimeric flavonoids. The toxicity of DCMF was investigated in breast (MCF-7), prostate (DU145), and cervical (HeLa) tumor cells, as well as non-tumor cells (PNT2), using sulforhodamine B (cell viability), Comet (genotoxicity), clonogenicity (reproductive capacity) and wound healing (cell migration) assays, and atomic force microscopy (AFM) for ultrastructural cell membrane alterations. Molecular docking revealed affinity between albumin and each rare flavonoid, supporting the impact of fetal bovine serum in DCMF antitumor activity. The IC50 values for MCF7, HeLa, and DU145 were 2.77, 2.46, and 2.51 µg/mL, respectively, and 4.08 µg/mL for PNT2. DCFM was not genotoxic to tumor or normal cells when exposed to twice the IC50 for up to 24 h, but it inhibited tumor cell migration and reproduction compared to normal cells. Additionally, AFM revealed alterations in the ultrastructure of tumor nuclear membrane surfaces, with a positive correlation between DCMF concentration and tumor cell roughness. Finally, we found a negative correlation between roughness and the ability of DCMF-treated tumor cells to migrate and form colonies with more than 50 cells. These findings suggest that DCFM acts by causing ultrastructural changes in tumor cell membranes while having fewer toxicological effects on normal cells.

Harnessing Unconventional T Cells and Innate Lymphoid Cells to Prevent and Treat Hematological Malignancies: Prospects for New Immunotherapy.

Unconventional T cells and innate lymphoid cells (ILCs) make up a heterogeneous set of cells that characteristically show prompt responses toward specific antigens. Unconventional T cells recognize non-peptide antigens, which are bound and presented by diverse non-polymorphic antigen-presenting molecules and comprise γδ T cells, MR1-restricted mucosal-associated invariant T cells (MAITs), and natural killer T cells (NKTs). On the other hand, ILCs lack antigen-specific receptors and act as the innate counterpart to the T lymphocytes found in the adaptive immune response. The alteration of unconventional T cells and ILCs in frequency and functionality is correlated with the onset of several autoimmune diseases, allergy, inflammation, and tumor. However, depending on the physio-pathological framework, unconventional T cells may exhibit either protective or pathogenic activity in a range of neoplastic diseases. Nonetheless, experimental models and clinical studies have displayed that some unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic markers. In fact, cell-mediated immune response in tumors has become the focus in immunotherapy against neoplastic disease. This review concentrates on the present knowledge concerning the function of unconventional T cell sets in the antitumor immune response in hematological malignancies, such as acute and chronic leukemia, multiple myeloma, and lymphoproliferative disorders. Moreover, we discuss the possibility that modulating the activity of unconventional T cells could be useful in the treatment of hematological neoplasms, in the prevention of specific conditions (such as graft versus host disease), and in the formulation of an effective anticancer vaccine therapy. The exact knowledge of the role of these cells could represent the prerequisite for the creation of a new form of immunotherapy for hematological neoplasms.

Nanoparticles Loaded with Docetaxel and Resveratrol as an Advanced Tool for Cancer Therapy.

A growing interest in the use of a combination of chemosensitizers and cytostatics for overcoming cancer resistance to treatment and the development of their delivery systems has been observed. Resveratrol (Res) presents antioxidant, anti-inflammatory and chemopreventive properties but also limits multidrug resistance against docetaxel (Dtx), which is one of the main causes of failure in cancer therapy with this drug. However, the use of both drugs presents challenges, including poor bioavailability, the unfavourable pharmacokinetics and chemical instability of Res and the poor water solubility and dose-limiting toxicity of Dtx. In order to overcome these difficulties, attempts have been made to create different forms of delivery for both agents. This review is focused on the latest developments in nanoparticles for the delivery of Dtx, Res and for the combined delivery of those two drugs. The aim of this review was also to summarize the synergistic mechanism of action of Dtx and Res on cancer cells. According to recent reports, Dtx and Res loaded in a nano-delivery system exhibit better efficiency in cancer treatment compared to free drugs. Also, the co-delivery of Dtx and Res in one actively targeted delivery system providing the simultaneous release of both drugs in cancer cells has a chance to fulfil the requirements of effective anticancer therapy and reduce limitations in therapy caused by multidrug resistance (MDR).

Circulating Factors Provoke Endothelial Dysfunction in the Human Microcirculation Following Doxorubicin Chemotherapy

RationaleAnthracyclines (e.g., doxorubicin) are among the most effective anti‐cancer therapies (CTx), yet their use is limited by cardiotoxic side effects. We sought to characterize the impact of anthracycline‐based CTx on microvascular endothelial function in breast cancer patients and determine if circulating factors are sufficient to induce endothelial dysfunction.MethodsWe assessed microvascular endothelium‐dependent vasodilation and its underlying mechanisms in two groups of breast cancer patients: 1) CTx‐naïve controls and 2) CTx‐treated patients (one month post‐CTx). Adipose samples were obtained at the time of surgical procedures. Freshly‐dissected arterioles were cannulated and pressurized, then flow‐induced production of nitric oxide (NO) and mitochondria‐derived hydrogen peroxide (H2O2) were visualized with fluorescent indicator probes. Next, we assessed whether plasma obtained from breast cancer patients one month following completion of CTx would evoke endothelial dysfunction. Adipose arterioles from healthy donors were exposed to diluted plasma from either CTx patients or healthy controls. Vessels were cannulated and filled with 10% plasma for overnight incubation prior to assessing flow‐mediated dilation (FMD; videomicroscopy). Data are expressed as area under the curve (AUC) for percentage change in diameter across five flow gradients and are shown as mean ± SE for n = 3–9 per condition.ResultsIn the cross‐sectional study, FMD was ~65% lower in vessels from breast cancer patients who had undergone CTx compared to those who were CTx‐naïve (AUC: 23 ± 10 vs. 61 ± 6, P = 0.004). Preliminary results suggest flow‐induced NO production is abolished in vessels from patients one month after CTx (Panel A, fold change in NO: −0.2 ± 0.2 vs. CTx‐naïve group: 11.3 ± 5.6; P = 0.08), whereas mitochondrial H2O2 production is elevated (Panel B, fold change in mtH2O2: 0.52 ± 0.25 vs. −0.51 ± 0.23; P = 0.03). FMD was also ~40% lower in vessels exposed to CTx plasma vs. healthy plasma (Panels C & D, AUC: 45 ± 7 vs. 75 ± 7, P = 0.049). Degradation of hydrogen peroxide (H2O2) with PEG‐catalase further reduced FMD in vessels exposed to CTx plasma (AUC: 22 ± 12), whereas PEG‐catalase did not affect dilation in vessels exposed to healthy plasma (AUC: 62 ± 17). Inhibition of NO synthase (NOS) with L‐NAME restored FMD in vessels exposed to CTx plasma (AUC: 77 ± 6), while L‐NAME had minimal impact on dilation in vessels exposed to healthy plasma (AUC: 60 ± 9). Future studies are needed to determine whether this reflects NOS uncoupling.Summary & ConclusionsMicrovascular endothelial function is impaired in breast cancer patients following doxorubicin chemotherapy. This is accompanied by a loss of NO and elevation of H2O2. Plasma obtained from breast cancer patients one month after cessation of CTx recapitulates these effects in otherwise healthy vessels, which suggest that circulating factors may contribute to endothelial dysfunction following treatment. Our preliminary findings reveal long‐term defects in the microcirculation that may contribute to adverse cardiovascular outcomes associated with doxorubicin chemotherapy.

Targeting Estrogen Non‐Genomic Signaling in a Three‐Dimensional (3D) in VitroModel of Inflammatory Breast Cancer

Inflammatory Breast Cancer (IBC) is the most aggressive form of breast cancer with a low overall 5‐year survival rate of ~30‐60%. To this date the molecular signature associated with IBC has not been fully characterized, which lead to a lack of effective targeted therapeutics, especially for those patients that account for the 20‐40% of triple‐negative (TNBC) IBC cases. Several studies established that molecular signature of IBC shows important differences from the other breast cancer subtypes, such as overexpression of ErbB receptors, RhoC GTPase and Cox‐2, E‐cadherin aberrant expression, and loss of WISP3, among others. However, these molecular alterations do not explain completely the aggressive and rapid IBC progression. Recently, several studies have shown that estrogen can exert non‐genomic effect in triple‐negative IBC and other TNBCs, mediated by the expression of alternate estrogen receptors, including ERα36 and GPR30. Estrogen non‐genomic signaling refers to the rapid action of these alternate estrogen receptors that upon estrogen binding activates protein‐kinase cascades in the cytoplasm. We hypothesize that estrogen can elicit a specific non‐genomic signaling cascade that promotes the acquisition of aggressive oncogenic phenotypes in IBC and that targeting this pathway can be an effective anticancer therapy for IBC. To test this hypothesis, we used pharmacological inhibitors of the Epidermal Growth Factor Receptor (EGFR) alone and GPR30 alone or in combination. The first approach was to determine if inhibiting estrogen non‐genomic signaling by targeting one of the alternate receptors, GPR30, affects cell proliferation in a 3D colony formation assay using Matrigel. Preliminary observations showed that after G15 treatment (GPR30 inhibitor), there was a slight reduction in cell proliferation compared to E2, but when combined with IRESSA (EGFR inhibitor) there was a further decreased on proliferation when compared to IRESSA alone. Ongoing experiments include the effects of Icaritin (modulator of ERα36) and knockdown of ERα36 using siRNA experiments to test the effects in cell proliferation, migration and invasion. Also, we are in the process of determining the half‐maximal inhibitory concentration (IC50) of G15, IRESSA and IRESSA + G15 by performing a dose response curve (Alamar Blue cell viability assay) of SUM149 cell line, to observe if there is an additive effect when combined the pharmacological inhibitors of EGFR and GPR30. This study will provide the foundation for further characterization of the role estrogen non‐genomic signaling in the progression of IBC and to test its potential as a therapeutic target.

The Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery.

Simple SummaryThe biopharmaceutical industry increasingly focuses on the development of new anticancer drugs for effective cancer therapy. Despite these efforts, the success rate is low, and thereby, greater efficacy and better safety properties are required. The high failure rate in drug discovery may be due to limitations of preclinical cancer models that inappropriately recapitulate human cancer biology. To date, patient-derived cancer organoids (PDCOs) have emerged as a model system to recapitulate human cancer biology. In this review, we discuss the advantages and applications of PDCO as a model to investigate anticancer drug efficacy and precision medicine. We also describe the challenges that must be overcome so that PDCOs can substantially represent human cancer biology.The cancer burden is rapidly increasing in most countries, and thus, new anticancer drugs for effective cancer therapy must be developed. Cancer model systems that recapitulate the biological processes of human cancers are one of the cores of the drug development process. PDCO has emerged as a unique model that preserves the genetic, physiological, and histologic characteristics of original cancer, including inter- and intratumoral heterogeneities. Due to these advantages, the PCDO model is increasingly investigated for anticancer drug screening and efficacy testing, preclinical patient stratification, and precision medicine for selecting the most effective anticancer therapy for patients. Here, we review the prospects and limitations of PDCO compared to the conventional cancer models. With advances in culture success rates, co-culture systems with the tumor microenvironment, organoid-on-a-chip technology, and automation technology, PDCO will become the most promising model to develop anticancer drugs and precision medicine.

Tumor intracellular microenvironment-responsive nanoparticles for magnetically targeted chemotherapy

Nanoparticles (NPs) with responsive modalities in biological microenvironments and external stimuli have received great attention as highly efficient and precise cancer therapy agents. In this study, tumor intracellular microenvironment-responsive NPs co-assembled from poly(ethylene glycol)-poly(aspartic acid) [PEG-P(Asp)] copolymer, doxorubicin (DOX), and superparamagnetic iron oxide NPs (SPIONs), termed as PEG-P(Asp)/DOX/SPIONs, were prepared for tumor intracellular microenvironment (enzyme and pH)-responsive and magnetically targeted chemotherapy. The NPs exhibited not only enzyme-responsive degradation in the presence of protease, but also triggered release of DOX at pH 5, which is an acidity similar to endolysosomal microenvironments in tumor cells. Furthermore, the PEG-P(Asp)/DOX/SPIONs showed a contrast effect in magnetic resonance imaging. In vitro viability assays showed that PEG-P(Asp)/DOX/SPIONs could effectively augment the cytocompatibility of DOX compared to free DOX without a change in magnetic forces. Fluorescence microscopy images indicated that the fabricated NPs efficiently increased the targeted uptake and release of DOX within cells. Overall, this hybrid NP system could be a favorable biomedical agent for effective tumor-targeted anti-cancer therapy.