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Cancer Chemotherapy and Pharmacology Jun 2024Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages...
Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.
PURPOSE
Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC.
METHODS
In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo.
RESULTS
Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses.
CONCLUSION
RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.
PubMed: 38913118
DOI: 10.1007/s00280-024-04691-3 -
BMC Cancer Jun 2024Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best...
PURPOSE
Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best efforts of surgery, radiation, and other therapies. For better therapy, we explored the efficacy and toxicity of a novel therapy that combines apatinib and temozolomide in DMG.
METHODS
A retrospective analysis of 32 patients with DMG who underwent apatinib plus temozolomide treatment was performed. Apatinib was given 500 mg in adults, 250 mg in pediatric patients once daily. Temozolomide was administered at 200 mg/m/d according to the standard 5/28 days regimen. The main clinical data included basic information of patients, radiological and pathological characteristics of tumors, treatment, adverse reactions, prognosis.
RESULTS
The objective response rate was 24.1%, and the disease control rate was 79.3%. The median PFS of all patients was 5.8 months, and median OS was 10.3 months. A total of 236 cycles of treatment were available for safety assessment and the toxicity of the combination therapy was relatively well tolerated. The most common grade 3 toxicities were myelosuppression including leukopenia (5.08%), neutropenia (4.24%), lymphopenia (2.12%), thrombocytopenia (1.69%) and anemia (1.27%). Grade 4 toxicities included neutropenia (2.12%), thrombocytopenia (2.12%) and proteinuria (1.69%). All the adverse events were relieved after symptomatic treatment or dose reduction.
CONCLUSIONS
Apatinib plus temozolomide could be an effective regimen with manageable toxicities and favorable efficacy and may outperform temozolomide monotherapy, particularly in newly diagnosed adults with tumors located outside the pons. The novel therapy deserves further investigation in adult DMG patients.
Topics: Humans; Temozolomide; Female; Male; Adult; Pyridines; Glioma; Adolescent; Retrospective Studies; Child; Brain Neoplasms; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Middle Aged; Treatment Outcome
PubMed: 38907215
DOI: 10.1186/s12885-024-12373-9 -
Scientific Reports Jun 2024Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients...
Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of MMP9 mRNA and MMP9 promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells.
Topics: Temozolomide; Glioblastoma; Matrix Metalloproteinase 9; Humans; p38 Mitogen-Activated Protein Kinases; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Antineoplastic Agents, Alkylating; Animals; Brain Neoplasms; Transcription Factor AP-1; Up-Regulation; Mice
PubMed: 38906916
DOI: 10.1038/s41598-024-65398-2 -
Nature Communications Jun 2024Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for...
Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
Topics: Humans; Ataxia Telangiectasia Mutated Proteins; Glioblastoma; Tumor Suppressor Protein p53; DNA Breaks, Double-Stranded; Temozolomide; Cell Line, Tumor; Mutation; Drug Resistance, Neoplasm; DNA Repair; Brain Neoplasms; Animals; DNA End-Joining Repair; Mice; Phosphorylation
PubMed: 38906885
DOI: 10.1038/s41467-024-49316-8 -
The Medical Letter on Drugs and... Jun 2024
Topics: Humans; Melanoma; Uveal Neoplasms; Antineoplastic Agents; Treatment Outcome
PubMed: 38905528
DOI: 10.58347/tml.2024.1705f -
Cancers May 2024The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the... (Review)
Review
The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the introduction of the international prognostic scoring (IPS) system; therapeutic decision-making based on both IPS and interim PET/CT data; the finding that a negative interim PET/CT result could be safely used for treatment de-escalation; the introduction of intensive combination chemotherapy like escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin (vincristine), procarbazine, and prednisone); and further modification of this protocol with the incorporation of a conjugated anti-CD30 antibody brentuximab vedotin (BV) into first-line regimens, like BV-AVD (BV+ adriamycin, vinblastine and dacarbazine) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). The accruing data about the toxicity of the escalated BEACOPP protocol have led to decreasing the number of therapeutic cycles, substitution of toxic agents like procarbazine with dacarbazine (e.g., BEACOPDac), and reduction/omission of radiation therapy. Lately, a significant advancement has been made by the integration of checkpoint inhibitors in the first-line treatment, with preliminary results demonstrating the superiority of anti-PD1 combined with chemotherapy (nivolumab-AVD) compared to the BV-AVD regimen. This review aims to analyze recently published studies whose findings could change the treatment practice in advanced-stage HL.
PubMed: 38893177
DOI: 10.3390/cancers16112059 -
International Journal of Molecular... Jun 2024Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated...
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.
Topics: STAT5 Transcription Factor; Glioblastoma; Humans; Animals; Quinazolines; Benzodioxoles; Mice; ErbB Receptors; Phosphorylation; Cell Line, Tumor; Temozolomide; Cell Proliferation; Xenograft Model Antitumor Assays; Signal Transduction; Brain Neoplasms; Apoptosis; src-Family Kinases; Tumor Suppressor Proteins
PubMed: 38892466
DOI: 10.3390/ijms25116279 -
Cells May 2024Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced...
Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell's fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O vs. 21% O). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft () as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors.
Topics: Glioblastoma; Humans; Animals; Cell Line, Tumor; Neurons; Mice; Cellular Reprogramming; Brain Neoplasms; Temozolomide; Basic Helix-Loop-Helix Transcription Factors
PubMed: 38891029
DOI: 10.3390/cells13110897 -
Journal of Minimally Invasive Gynecology Jun 2024Pelvic exenteration (PE) is an aggressive surgical procedure that implies a large hard-to-fill pelvic defect. Different reconstruction techniques were proposed to...
STUDY OBJECTIVE
Pelvic exenteration (PE) is an aggressive surgical procedure that implies a large hard-to-fill pelvic defect. Different reconstruction techniques were proposed to improve abdominal organ support and reduce complications (infections, pelvic organs herniation, vaginal stump dehiscence, bowel prolapse and obstruction) [1], with conflicting results [2]. Because of young age and survival greater than 50% at 5 years in patients with no residual tumor after surgery [3], a new approach with better clinical results to pelvic reconstruction is needed.
DESIGN
The aim of this surgical film is to present an unusual presentation of vaginal sarcoma, successfully managed with a minimally invasive approach, and to illustrate our contextual multilayer technique of pelvic reconstruction using a combination of pedicled omental flap (POF) and human acellular dermal matrix (HADM).
SETTING
Tertiary level academic hospital. A 42-year-old obese patient with recurrent and symptomatic myxoid leiomyosarcoma, previously underwent vaginal-assisted laparoscopic surgery at a primary care center for the removal of a vaginal swelling.
INTERVENTIONS
The multidisciplinary board determined anterior PE as the optimal therapeutic approach. Given the patient's body mass index (33 kg/m), young age, and the favorable outcomes of robotic surgery in obese patients compared with other approaches [3,4], we proposed a combined robotic and vaginal surgery for both exenteration and reconstructive procedures [5]. During surgery, we initially explored the abdominal cavity to exclude macroscopic metastasis, followed by anterior PE. Urinary diversion was achieved with a Bricker ileal conduit by means of an ileoileal laterolateral anastomosis and an uretero-ileo-cutaneostomy. The pelvic dead space was partially filled with a POF on the left gastroepiploic artery. Subsequently, the pelvic defect was covered by a 15 × 10 mm HADM inlay inserted circumferentially at the pelvic brim, fixed with a barbed thread suture on residual pelvic structures. The final pathology confirmed the recurrence of myxoid leiomyosarcoma and indicated tumor-free resection margins. The intraoperative and postoperative periods were uneventful. The patient was discharged 14 days after surgery and underwent adjuvant doxorubicin- and dacarbazine-based chemotherapy, which was initiated 45 days after the surgery. Currently the patient is asymptomatic and disease free at the sixth month of follow-up.
CONCLUSION
Robotic PE proves to be a feasible technique in obese patients, reducing postoperative hospital stay and complications. The contextual pelvic floor reconstruction with a POF and HADM supports abdominal viscera, diminishing interorgan adhesions and bowel prolapse. VIDEO ABSTRACT.
PubMed: 38866099
DOI: 10.1016/j.jmig.2024.06.003 -
Molecular Pharmaceutics Jul 2024Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent...
Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.
Topics: Solubility; Crystallization; X-Ray Diffraction; Dacarbazine; Photolysis; Spectroscopy, Fourier Transform Infrared; Magnetic Resonance Spectroscopy; Calorimetry, Differential Scanning
PubMed: 38858241
DOI: 10.1021/acs.molpharmaceut.4c00393