Recurrent Tumor Growth Research Articles

Osteopontin is a therapeutic target that drives breast cancer recurrence

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin’s multiaxial role in breast cancer progression and recurrence.

Bionic aggregation-induced emission photosensitizer for enhanced cancer immunotherapy

Cold exposure therapy (CE), as an inexpensive method, has shown great potential in cancer therapy. Exploring the combined anti-tumor mechanism of CE and traditional therapies (such as photodynamic therapy (PDT)) is exciting and promising. Here, a bionic aggregation-induced emission photosensitizer system (named THL) is designed for combined CE to enhance anti-tumor immunotherapy. THL inherits the homologous targeting ability of tumor derived exosomes, promoting the enrichment of THL at the tumor site. Under external illumination, THL generates hydroxyl radicals and superoxide anions through type I PDT. In addition, mice are pretreated with cold exposure, which promotes THL mediated PDT and reactive oxygen species (ROS) generation by reducing the production of ATP and GSH in tumor tissue. This combination therapy increases production of ROS within the tumor, inhibits the growth of distant tumors, recurrent and rechallenged tumors and increases the number of cytotoxic CD8+T cells and memory T cells. Compared to PDT alone, combination therapy shows greater advantages in tumor immunotherapy. The combination therapy strategy provides new ideas for cancer immunotherapy.

Molecular developments in parasellar tumors and potential therapeutic implications.

The parasellar region is the anatomical area around the sella turcica that represents a crucial crossroad for important adjacent structures. Several distinct tumors can primarily originate from this area, the most common being meningiomas, gliomas, embryonal cell tumors, germ cell tumors and craniopharyngiomas. In addition, a number of systemic and inflammatory disorders can also affect the parasellar region most commonly involving the pituitary. These lesions have different pathology characteristics and malignant potential according to the new WHO CNS5 2021 classification. Signs and symptoms may be non-specific and are mostly related to a mass effect on the surrounding anatomical structures and/or impairment of endocrine function whereas the vast majority lack a secretory component. The mutational signature analysis based on advances in molecular techniques, has recently enabled the identification of specific gene mutations or signalling pathway aberrations. These developments may serve as a powerful mean to delineate the pathophysiology of these lesions and serve as a diagnostic, prognostic and therapeutic tool, particularly for high-risk populations. Treatment options include surgery alone or in combination with radiotherapy, chemotherapy and disease-specific medical therapy in order to prevent recurrence or further tumor growth along with replacement of coexistent pituitary hormonal deficiencies. In this comprehensive review, we present current state-of-the-art developments in the histopathology and molecular biology of these lesions that may be utilized by a dedicated multidisciplinary team of relevant specialties for the diagnosis, monitoring and treatment of the parasellar lesions that often represent a diagnostic and therapeutic challenge.

Respiratory insufficiency after brain metastasectomy for extraskeletal Ewing sarcoma in an adult patient with mucopolysaccharidosis type II: a case report.

Mucopolysaccharidosis is a rare lysosomal storage disease caused by deficiencies in enzymes involved in the degradation of glycosaminoglycans. We report the case of an adult with mucopolysaccharidosis type II who developed respiratory insufficiency after brain metastasectomy for extraskeletal Ewing sarcoma. This report describes the case of a 35-year-old man with a mass on the left chest wall for 3months. Magnetic resonance imaging and computed tomography revealed a large mass on the chest wall. Positron emission tomography revealed multiple metastatic lesions in the lungs, ribs, and sternum. A needle biopsy specimen confirmed extraskeletal Ewing sarcoma, and the fusion gene EWS-FLI1 was positive. Subsequently, multidrug chemotherapy was administered. During radiotherapy for the primary lesion, progressive convulsions occurred suddenly. Computed tomography of the brain revealed metastasis in the frontal lobe. Brain metastasectomy was scheduled; however, endotracheal intubation was not possible because of the deformity of the glottis, and emergency tracheostomy was performed. Thereafter, granulation tissue proliferated in reaction to the tracheostomy cannulae in the trachea, and respiratory insufficiency persisted. Because of the rapid growth of an intrathoracic recurrent tumor, the patient passed away 2months after brain surgery. This is the first report of sarcoma in a patient with mucopolysaccharidosis. Respiratory management is difficult in patients with mucopolysaccharidosis, especially under general anesthesia. Orthopedic surgeons should be aware that surgical planning must be performed carefully when soft tissue sarcomas occur in patients with mucopolysaccharidosis.

Comparison the results of surgical treatment of metastatic lesions of the thoracic spine (systematic review)

Objective: to conduct a comparative analysis of the effectiveness of surgical treatment for patients with metastatic lesions of the thoracic spine from anterior and posterior approaches according to the literature. Methodology for writing a review. The search was carried out in the PubMed and Scopus databases. Search words and phrases: "thoracic spine", "metastatic lesion", "spinal cord", "management of thoracic spine metastasis". Search depth for the last 15 years. 13 publications were included in the final analysis. Conclusion. Both approaches are effective, but data such as blood loss, duration of surgery, neurological changes and pain intensity are significantly better in patients who underwent anterior approach. At the same time, in this group the development of respiratory failure is more common, and the 30-day mortality rate is higher compared to group of posterior approach. In the group of posterior interventions there was a significantly higher level of postoperative CSF leakage and wound infection, as well as worsening neurological deteriorations. The frequency of failure of implanted structures and revision interventions for wound hematomas and recurrent tumor growth is almost the same.

Abstract 458: Nanoparticle-mediated delivery of miR-590-3p decreases recurrent GBM tumor growth by inhibits multiple oncogenic nodes

Abstract Glioblastoma (GBM) is the most lethal and aggressive form of brain cancer. Despite aggressive therapy consisting of surgery followed by radio/chemotherapy GBM recurs in almost all patients and, currently, there are no proven therapies to treat recurrent GBM (rGBM). Recent developments in nanomedicine provide new and promising opportunities to develop new targeted therapeutics to treat brain tumors. We have recently developed PBAE nanoparticle formulations optimized for in vivo miRNA delivery to brain tumor stem cells, or GSCs. Carefully selecting one miRNA to target several mRNAs dysregulated within a pathway can allow the targeting of multiple nodes using a single agent, mimicking combinatorial therapies. To test this hypothesis, we performed bioinformatic analysis of RNA sequencing from GSCs and clinical rGBM specimens combined with gene set enrichment analysis (GSEA) and identified TGFBR2 signaling as a targetable pathway in rGBM. We show that SMAD2 signaling, a downstream effector of TGFBR2, is enriched in rGBM and that patients with elevated TGFBR2 transcripts respond poorly to current standard of care. Utilizing patient-derived xenograft lines from rGBM, we show that blocking TGFBR2 signaling using siRNAs or ITD1, a selective TGFBR2 inhibitor, decreases the stem cell capacity, cell viability and re-sensitizes clinical rGBM cells to temozolomide (TMZ) in-vitro. In vivo, we show that ITD1 is modestly effective in subcutaneous and ineffective in orthotopic rGBM models. Not surprisingly, these tumors exhibited classical growth patterns associated with acquisition of resistance. To overcome this obstacle, we performed a miRNA-based network analysis in rGBM and identified miR-590-3p as a putative tumor suppressor that targets SMAD2 signaling at multiple nodes in rGBM. In-vitro, transgenic miR-590-3p robustly decreased the expression of 37 putative oncogenes simultaneously concurrent with decreasing stem cell capacity, cell viability and re-sensitizing rGBM PDX cells to TMZ. In vivo delivery of miR-590-3p to established PDX-derived rGBM orthotopic tumors using novel PBAE nanocarriers robustly decreased tumor sizes and increased tumor necrosis. These results show that the promiscuous nature of miRNAs, in combination with cutting-edge nucleic acid delivery vehicles, can be leveraged as advanced targeted therapeutics for rGBM bypasses the resistance that is developed to standard of care and available small molecules. Citation Format: Hernando Lopez-Bertoni, Sophie Sall, Harmon Khela, Jack Korleski, Katherine Luly, Maya Johnson, Bachchu Lal, Amanda Johnson, Stephany Tzeng, Jordan Green, John Laterra. Nanoparticle-mediated delivery of miR-590-3p decreases recurrent GBM tumor growth by inhibits multiple oncogenic nodes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 458.

Metal coordination‐driven assembly of stimulator of interferon genes‐activating nanoparticles for tumor chemo‐immunotherapy

AbstractActivating the stimulator of interferon genes (STING) signaling pathway is critical for enhancing antitumor immunity and remodeling the immunosuppressive tumor microenvironment (TME). Herein, we report the preparation of STING‐activating nanoparticles via metal coordination‐driven assembly of a synthetic STING agonist (i.e., SR717) and a chemotherapeutic drug (i.e., curcumin). After intravenous administration, the assembled nanoparticles could efficiently accumulate in tumors to improve the bioavailability of SR717 and trigger potent STING pathway activation for effective immune responses. Meanwhile, the released curcumin evokes immunogenic cell death in tumors and regulates amino acid metabolism by inhibiting the activation of indoleamine 2,3‐dioxygenase 1, leading to the reversal of the immunosuppressive TME. The antitumor immunity induced by nanoparticles significantly inhibits the growth of primary, recurrent, and metastatic tumors. The assembled nanoparticles are promising for the co‐delivery of STING agonists and drugs in improved tumor chemo‐immunotherapy.

Hydrogel-immobilized nanotherapeutics: Inhibition of protective autophagy to amplify STING signals for postsurgical tumor immunotherapy

Activating the inherent stimulator of interferon gene (STING) pathway of cancer cells can inhibit tumor growth but can also induce protective autophagy of tumor cells to inhibit the STING-mediated immunotherapy. Therefore, amplification of STING activation and inhibition of autophagy could potentiate the cancer immunotherapy. Here, hydrogel-immobilized nanoparticles loaded with glucose oxidase (GOx), manganese ions (Mn2+) and hydroxychloroquine (HCQ) are prepared at the postsurgical site to enhance cancer therapy via activating the STING pathway and regulating the autophagy pathway. The delivered GOx and Mn2+ exert a chemo-dynamic therapy (CDT) to induce dsDNA damage, which can further initiate the STING pathway. HCQ can effectively inhibit protective autophagy associated with STING pathway activation, further amplify the antitumor immune responses. The synergistic delivery of CDT agents (i.e., GOx and Mn2+), STING agonists (i.e., Mn2+) and autophagy inhibitors (i.e., HCQ) results in a specific immune response, significantly inhibit tumor recurrence and metastatic tumor growth, which could extend the survival rate of mice suffered from the triple-negative breast cancer (TNBC).

Pterional approach for tuberculum sellae meningiomas: a 17-year single-center experience.

Tuberculum sellae meningiomas (TSMs) are typically in the proximity of the optic nerves and the optic chiasm, thus making the primary aim of surgery the enhancement or stabilization of the patients' visual acuity. The authors therefore undertook a retrospective review of their 17-year experience with the pterional approach to ascertain the resection rate, neurological outcome, and visual outcome. Patients who underwent TSM surgery between September 2003 and December 2020 at the authors' institution were retrospectively evaluated. Patient demographics, tumor characteristics, surgical parameters, postoperative visual outcomes, and complications were analyzed. Gross-total resection (GTR) and subtotal resection (STR) rates were assessed, along with the impact of surgical approach on visual outcomes. A total of 71 patients with a mean age of 56.9 ± 14.3 years were enrolled in the study. The mean tumor volume was 10.2 ± 12.8 cm3. Postoperatively, 38.7% of patients experienced visual improvement, 45.2% had stable visual acuity, and 16.1% showed visual deterioration. Ipsilateral or contralateral surgical approaches were performed based on the side of the most affected visual acuity. No significant difference in postoperative visual outcomes was observed between the two approaches. GTR was achieved in 84.0% and STR in 16.0%. Minor complications occurred in 3 patients (4.2%), while major complications were found in 4 patients (5.6%). Seven patients (9.8%) showed recurrent tumor growth after 53 months. Progression-free survival after GTR was 123.9 ± 12.9 months, and it was 59.3 ± 13.2 months after STR. This study highlighted the finding that TSMs can be successfully resected using a transcranial pterional approach with a low risk of complications and sufficient visual outcomes. Further studies with larger sample sizes are warranted to confirm these findings and optimize surgical strategies for TSM resection.

Pyk2/FAK Signaling Is Upregulated in Recurrent Glioblastoma Tumors in a C57BL/6/GL261 Glioma Implantation Model.

The majority of glioblastomas (GBMs) recur shortly after tumor resection and recurrent tumors differ significantly from newly diagnosed GBMs, phenotypically and genetically. In this study, using a Gl261-C57Bl/6 mouse glioma implantation model, we identified significant upregulation of proline-rich tyrosine kinase Pyk2 and focal adhesion kinase (FAK) phosphorylation levels-pPyk2 (579/580) and pFAK (925)-without significant modifications in total Pyk2 and FAK protein expression in tumors regrown after surgical resection, compared with primary implanted tumors. Previously, we demonstrated that Pyk2 and FAK are involved in the regulation of tumor cell invasion and proliferation and are associated with reduced overall survival. We hypothesized that the use of inhibitors of Pyk2/FAK in the postsurgical period may reduce the growth of recurrent tumors. Using Western blot analysis and confocal immunofluorescence approaches, we demonstrated upregulation of Cyclin D1 and the Ki67 proliferation index in tumors regrown after resection, compared with primary implanted tumors. Treatment with Pyk2/FAK inhibitor PF-562271, administered through oral gavage at 50 mg/kg daily for two weeks beginning 2 days before tumor resection, reversed Pyk2/FAK signaling upregulation in recurrent tumors, reduced tumor volume, and increased animal survival. In conclusion, the use of Pyk2/FAK inhibitors can contribute to a delay in GBM tumor regrowth after surgical resection.

Endoscopic far-lateral supracerebellar infratentorial approach for resection of dumbbell-shaped trigeminal schwannoma: surgical techniques and preliminary results.

Trigeminal schwannomas (TSs) are mostly benign tumors. However, dumbbell-shaped TSs are most challenging for surgeons and pose a high surgical risk. We describe the technique of the purely endoscopic far-lateral supracerebellar infratentorial approach (EFL-SCITA) for removing dumbbell-shaped TSs and further discuss the feasibility of this approach and our experience. EFL-SCITA was performed for resection of 5 TSs between January 2020 and March 2023. The entire procedure was performed endoscopically with the goal of total tumor resection. During the operation, the tumor was exposed in close proximity and multiple angles under the endoscope, and the peri-tumor nerves were carefully identified and protected, especially the normal trigeminal fiber bundles around the tumor. All the tumors of 5 patients involved the middle and posterior cranial fossa, of which total removal was achieved in 2 patients and near-total removal in 3 patients. The most common preoperative symptoms were relieved after surgery. Two patients had postoperative mild facial paralysis (House-Brackmann grade II), and 1 patient had abducens palsy; both recovered during the follow-up period. Two patients experienced new postoperative facial hypesthesia, and 1 experienced mastication weakness, which did not recover. There was no tumor recurrence or residual tumor growth during the follow-up period in any of the patients. EFL-SCITA is a new and effective alternative for the surgical treatment of TSs. For dumbbell-shaped TSs, this approach provides sufficient surgical field exposure and freedom of operation.

Sulfate-reducing bacteria loaded in hydrogel as a long-lasting H2S factory for tumor therapy

The continuous supply of hydrogen sulfide (H2S) gas at high concentrations to tumors is considered a promising and safe strategy for tumor therapy. However, the absence of a durable and cost-effective H2S-producing donor hampers its extensive application. Sulfate-reducing bacteria (SRB) can serve as an excellent H2S factory due to their ability to metabolize sulfate into H2S. Herein, a novel injectable chondroitin sulfate (ChS) hydrogel loaded with SRB (SRB@ChS Gel) is proposed to sustainably produce H2S in tumor tissues to overcome the limitations of current H2S gas therapy. In vitro, the ChS Gel not only supports the growth of encapsulated SRB, but also supplies a sulfate source to the SRB to produce high concentrations of H2S for at least 7 days, resulting in mitochondrial damage and immunogenic cell death. Once injected into tumor tissue, the SRB@ChS Gel can constantly produce H2S for >5 days, significantly inhibiting tumor growth. Furthermore, such treatment activates systemic anti-tumor immune responses, suppresses the growth of distant and recurrent tumors, as well as lung metastases, meanwhile with negligible side effects. Therefore, the injectable SRB@ChS Gel, as a safe and long-term, self-sustained H2S-generating factory, provides a promising strategy for anti-tumor therapy.

Meningioma involving the superior sagittal sinus: long-term outcome after robotic radiosurgery in primary and recurrent situation.

Treatment for meningiomas involving the superior sagittal sinus (SSS) is challenging and proved to be associated with higher risks compared to other brain locations. Therapeutical strategies may be either microsurgical (sub-)total resection or adjuvant radiation, or a combination of both. Thrombosis or SSS occlusion following resection or radiosurgery needs to be further elucidated to assess whether single or combined treatment is superior. We here present tumor control and side effect data of robotic radiosurgery (RRS) in combination with or without microsurgery. From our prospective database, we identified 137 patients with WHO grade I meningioma involving the SSS consecutively treated between 2005 and 2020. Treatment decisions were interdisciplinary. Patients underwent RRS as initial/solitary treatment (group 1), as adjuvant treatment after subtotal resection (group 2), or due to recurrent tumor growth after preceding microsurgery (group 3). Positive tumor response was assessed by MRI and defined as reduction of more than 50% of volume. Study endpoints were time to recurrence (TTR), time to RRS, risk factors for decreased survival, and side effects. Overall and specific recurrence rates for treatment groups were analyzed. Side effect data included therapy-related morbidity during follow-up (FU). A total of 137 patients (median age, 58.3 years) with SSS meningiomas WHO grade I were analyzed: 51 patients (37.2%) in group 1, 15 patients (11.0%) in group 2, and 71 patients (51.8%) in group 3. Positive MR (morphological response) to therapy was achieved in 50 patients (36.4%), no response was observed in 25 patients (18.2%), and radiological tumor progression was detected in 8 patients (5.8%). Overall 5-year probability of tumor recurrence was 15.8% (median TTR, 41.6 months). Five-year probabilities of recurrence were 0%, 8.3.%, and 21.5% for groups 1-3 (p = 0.06). In multivariate analysis, tumor volume was significantly associated with extent of SSS occlusion (p = 0.026) and sex (p = 0.011). Tumor volume significantly correlated with TTR (p = 0.0046). Acute sinus venous thrombosis or venous congestion-associated bleedings did not occur in any of the groups. RRS for grade I meningiomas with SSS involvement represents a good option as first-line treatment, occasionally also in recurrent and adjuvant scenarios as part of a multimodal treatment strategy.

Abstract 1656: Evexomostat: A novel therapeutic in development for the treatment of prostate cancer

Abstract Background: Prostate cancer (PCa) is the second-most diagnosed malignancy among men and is a leading cause of cancer death worldwide (WHO, 2020). Elevated expression of the enzyme methionine aminopeptidase type 2 (MetAP2) in prostate cancer was recently shown to be associated with higher grade tumors and with worse clinical outcomes (Xie, 2021). Evexomostat/SDX-7320 is a polymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor attached to a polymer backbone via a cleavable linker. This design alters biodistribution (limits CNS penetration) and improves pharmacokinetics relative to small molecule fumagillin-derived MetAP2 inhibitors. Evexomostat completed a phase I safety study in late-stage cancer patients and is in two phase 2 breast cancer studies (NCT05455619, NCT05570253). Methods: To evaluate the efficacy of evexomostat in a model of prostate cancer, NSG mice were injected subcutaneously with 2×106 LNCaP cells. When tumors reached ≈200 mm3, mice were randomized into 4 groups. A cohort of intact mice (Group 1; n=4/group) received treatment with SDX-7320 (12 mg/kg, s.c. Q4D) or vehicle (5% mannitol/water). Group 2 were castrated and randomized to SDX-7320 (6 mg/kg, 12 mg/kg) or Vehicle (5% mannitol) upon recovery (n=4/group). Group 3 (n=13/group) and Group 4 (n=14/group) were castrated and randomized to Vehicle or SDX-7320 at recurrence of tumor growth with Group 4 additionally receiving enzalutamide (10 mg/kg, p.o., QD). Tumor growth and body weight were assessed twice/week. Upon necropsy, tumors were dissected, weighed and snap frozen for RNAseq analysis or formalin fixed along with major organs for histological processing (H&E staining, and tumor CD31, CD34 IHC analysis). Results: Evexomostat elicited a significant reduction in tumor growth in the absence of significant changes in body weight. Survival in evexomostat-treated mice was doubled relative to vehicle-treated mice (12.5 vs 23.5 days). In castrated mice (Group 2), evexomostat (6 and 12 mg/kg) attenuated tumor growth with no change in body weight, and in CRPC mice (Group 3), evexomostat also significantly inhibited tumor growth. Treatment of CRPC mice (Group 4) with enzalutamide alone elicited a mixed response, with 6/14 mice showing sustained response to enzalutamide (responders). At endpoint, tumors from enzalutamide non-responders averaged 0.54g (± 0.09g) and enzalutamide responders 0.27g (± 0.07g), p&lt0.05, while tumors from SDX-7320 plus enzalutamide-treated mice weighed 0.19g (± 0.07g), p&lt0.005 compared to enzalutamide non-responders. Conclusions: MetAP2 inhibition has potential as a new approach for the treatment of prostate cancer. The clinical-stage MetAP2 inhibitor evexomostat/SDX-7320 significantly inhibited the growth of LNCaP tumors in intact, castrated and CRPC mice. Clinical evaluation of evexomostat in castration-sensitive as well as castration-resistant prostate cancer patients is warranted. Citation Format: Peter Cornelius, Benjamin Mayes, Bradley J. Carver, James Shanahan, Jennifer Gunter, Colleen Nelson. Evexomostat: A novel therapeutic in development for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1656.

Bioabsorbable nano-micelle hybridized hydrogel scaffold prevents postoperative melanoma recurrence.

The residual and scattered small tumor tissue or cells after surgery are the main reason for tumor recurrence. Chemotherapy has a powerful ability to eradicate tumors but always accompanied by serious side effects. In this work, tissue-affinity mercapto gelatin (GelS) and dopamine-modified hyaluronic acid (HAD) were employed to fabricate a hybridized cross-linked hydrogel scaffold (HG) by multiple chemical reactions, which could integrate the doxorubicin (DOX) loaded reduction-responsive nano-micelle (PP/DOX) into this scaffold via click reaction to obtain the bioabsorbable nano-micelle hybridized hydrogel scaffold (HGMP). With the degradation of HGMP, PP/DOX was slowly released and formed targeted PP/DOX with degraded gelatin fragments as target molecules, which increased the intracellular accumulation, and inhibited the aggregation of B16F10 cells in vitro. In mouse models, HGMP absorbed the scattered B16F10 cells and released targeted PP/DOX to suppress tumorigenesis. For another, implantation of HGMP at the surgical site reduced the recurrence rate of postoperative melanoma and inhibited the growth of recurrent tumors. Meanwhile, HGMP significantly relieved the damage of free DOX to hair follicle tissue. This bioabsorbable nano-micelle hybridized hydrogel scaffold provided a valuable strategy for adjuvant therapy after tumor surgery.

Carrier-Free Nanoplatform via Evoking Pyroptosis and Immune Response against Breast Cancer.

Pyroptosis, as a novel mode of cell death, has been proven to have impressive antitumor effects. Dying cells undergoing pyroptosis can elicit antitumor immunity by the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). Accordingly, developing an effective, stable, and controllable nanoplatform that can promote these two side effects is a promising option for cancer therapy. In this study, we designed a carrier-free chemo-photodynamic nanoplatform (A-C/NPs) using a co-assembly strategy with cytarabine (Ara-C) and chlorin e6 (Ce6) to induce pyroptosis and a subsequent immune response against breast cancer. Mechanistically, A-C/NPs can trigger GSDME-mediated pyroptosis in a controllable manner through reactive oxygen species (ROS) accumulation, causing immunogenic cell death (ICD), in which dying cells release high-mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and calcitonin (CRT). Additionally, Ara-C can stimulate the maturation of cytotoxic T lymphocytes to act synergistically with Ce6-mediated immunogenic cell death (ICD), collectively augmenting the anticancer effect of A-C/NPs. The A-C/NPs showed excellent suppressive effects on the growth of orthotopic, abscopal, and recurrent tumors in a breast cancer mouse model. The chemo-photodynamic therapy (PDT) using the proposed nanomedicine strategy could be a novel strategy for triggering pyroptosis and improving the global anticancer immune response.

ALDH1-Mediated Autophagy Sensitizes Glioblastoma Cells to Ferroptosis.

The fatal clinical course of human glioblastoma (GBM) despite aggressive adjuvant therapies is due to high rates of recurrent tumor growth driven by tumor cells with stem-cell characteristics (glioma stem cells, GSCs). The aldehyde dehydrogenase 1 (ALDH1) family of enzymes has been shown to be a biomarker for GSCs, and ALDH1 seems to be involved in the biological processes causing therapy resistance. Ferroptosis is a recently discovered cell death mechanism, that depends on iron overload and lipid peroxidation, and it could, therefore, be a potential therapeutic target in various cancer types. Since both ALDH1 and ferroptosis interact with lipid peroxidation (LPO), we aimed to investigate a possible connection between ALDH1 and ferroptosis. Here, we show that RSL3-induced LPO and ferroptotic cell death revealed RSL3-sensitive and -resistant malignant glioma cell lines. Most interestingly, RSL3 sensitivity correlates with ALDH1a3 expression; only high ALDH1a3-expressing cells seem to be sensitive to ferroptosis induction. In accordance, inhibition of ALDH1a3 enzymatic activity by chemical inhibition or genetic knockout protects tumor cells from RSL3-induced ferroptotic cell death. Both RSL-3-dependent binding of ALDH1a3 to LC3B and autophagic downregulation of ferritin could be completely blocked by ALDH inhibition. Therefore, ALDH1a3 seems to be involved in ferroptosis through the essential release of iron by ferritinophagy. Our results also indicate that ferroptosis induction might be a particularly interesting clinical approach for targeting the highly aggressive cell population of GSC.

Evaluating the Utilization of Ethylenediaminetetraacetic Acid as a Treatment Supplement for Gliomas.

Gliomas are the most common primary tumors of the nervous system, accounting for approximately 81% of brain tumors. The primary treatment for these primary brain tumors, especially those of high grade, is surgical resection with subsequent therapy such as targeted radiotherapy, chemotherapy, or supportive care. In an effort to devise nuanced ways to treat gliomas, studies have examined various chemical agents to expand therapeutic avenues for gliomas. In this study, we investigate the applications of ethylenediaminetetraacetic acid (EDTA) in the investigation and treatment of gliomas. Searches were conducted on PubMed to find studies about the use of EDTA in the treatment of glioma. We identified 36 studies that had the information needed for analysis. We collected information on the dosage of EDTA, the agent that EDTA was complexed with, the route of administration, the outcome of the EDTA usage, and the type of glioma cells that were involved. In addition, a one-way analysis of variance was performed to identify any relationships between the effect of cell type, study purpose, and year published on dosage. We identified 36 articles that met our inclusion criteria. In-vitro studies utilized EDTA in various complexes to evaluate cellular viability, including proliferation and toxicity, intracellular enzyme kinetics, and intercellular interactions such as chelation and cellular aggregation. In-vivo studies predominantly utilized the versatile nature of EDTA as a tracer for imaging studies involved in diagnostics and identifying recurrent tumor growth and localization in human patients. Our statistical analysis failed to identify any significant relationships between cell type, study purpose, and publication year on EDTA dosage. We identified a variety of uses for EDTA in the investigation hopefully providing physicians with information regarding the context and applications of EDTA to assist in exploring new treatment options for glioma patients.

Outcomes of fractionated CyberKnife radiosurgery in patients with choroidal malignant melanoma

Objective The aim of this study was to evaluate local tumor control and complication development rates of fractionated CyberKnife radiosurgery (CRS) in patients with choroidal melanoma. Methods A total of 29 patients with choroidal melanoma were treated with fractionated CRS at Ankara Oncology Research and Training Hospital, Department of Radiotherapy between May 2009 and December 2013. Patients were treated with CRS if the initial height of the choroidal melanoma was ≥ 6 mm, or juxtapapillary and/or juxtamacular tumors with a height of >2.5 mm. Ophthalmic examinations were performed at baseline and at months 3, 6, 9 and 15 after radiotherapy. Assessment of visual acuity and measurement of tumor base dimension and height using A-scan and B-scan echography were done at each visit. Results The mean age was 56 (27–75) years. Tumor was located on choroid in 23 and on ciliochoroid in 6 patients. 86.2% of all melanomas were classified as medium sized and 23.8% as large sized. A median total dose of 5000 cGy was applied. Median tumor height decreased from 7.5 mm at baseline to 4.4 mm at the last follow-up visit (p < 0.001). Median visual acuity decreased from 0.4 at baseline to hand motion (p < 0.001). One patient had been lost to the metastatic disease and one patient had been treated with enucleation due to recurrent tumor growth. Conclusion CRS is an effective and reliable local treatment modality in uveal melanoma.

Sustained Oncogenic Signaling in the Cytostatic State Enables Targeting of Nonproliferating Persistent Cancer Cells.

This study finds that sustained oncogenic signaling in therapy-induced cytostatic cancer cells confers targetable vulnerabilities to deplete persistent cancer cell populations and reduce cancer recurrence.