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Clinical and Translational Science Dec 2023Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper...
Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5-aminoimidazole-4-carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m ) was administered to patients with LMS via 1-hour intravenous (IV) infusion on Day 1 of every 21-day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (BIW), starting on Day 2 of every cycle, except for Cycle 2 (C2), where unesbulin was dosed either on Day 1 together with DTIC or on Day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in Cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached C immediately or shortly after end of infusion at 1.0 and 1.4 hours (T ), respectively. Coadministration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2-mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC C by 69.4% and AUC by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m IV DTIC q21d and 300 mg unesbulin BIW in a staggered regimen is well tolerated in patients with LMS.
PubMed: 38129988
DOI: 10.1111/cts.13709 -
Journal of Clinical Oncology : Official... Jan 2024JCO We analyzed long-term results of the response-adapted trial for adult patients with advanced-stage Hodgkin lymphoma. The aim was to confirm noninferiority of...
JCO We analyzed long-term results of the response-adapted trial for adult patients with advanced-stage Hodgkin lymphoma. The aim was to confirm noninferiority of treatment de-escalation by omission of bleomycin from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for interim fluorodeoxyglucose positron emission tomography (iPET)-negative patients and assess efficacy and long-term safety for iPET-positive patients who underwent treatment intensification with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP/BEACOPP14). The median follow-up is 7.3 years. For all patients, the 7-year progression-free survival (PFS) and overall survival (OS) are 78.2% (95% CI, 75.6 to 80.5) and 91.6% (95% CI, 89.7 to 93.2), respectively. The 1.3% difference in 3-year PFS (95% CI, -3.0 to 4.7) between ABVD and doxorubicin, vinblastine, and dacarbazine (AVD) now falls within the predefined noninferiority margin. Among 172 patients with positive iPET, the 7-year PFS was 65.9% (95% CI, 58.1 to 72.6) and the 7-year OS was 83.2% (95% CI, 76.2 to 88.3). The cumulative incidence of second malignancies at 7 years was 5.5% (95% CI, 4.0 to 7.5) for those receiving ABVD/AVD and 2.5% (95% CI, 0.8 to 7.7) for those escalated to BEACOPP. With extended follow-up, these results confirm noninferiority of treatment de-escalation after a negative iPET. Escalation with BEACOPP for iPET-positive patients is effective and safe, with no increase in second malignancies.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dacarbazine; Doxorubicin; Follow-Up Studies; Hodgkin Disease; Neoplasms, Second Primary; Prednisone; Vinblastine; Vincristine
PubMed: 37883739
DOI: 10.1200/JCO.23.01177 -
Advanced Science (Weinheim,... May 2024Temozolomide (TMZ) resistance remains the major obstacle in the treatment of glioblastoma (GBM). Lactylation is a novel post-translational modification that is involved...
Temozolomide (TMZ) resistance remains the major obstacle in the treatment of glioblastoma (GBM). Lactylation is a novel post-translational modification that is involved in various tumors. However, whether lactylation plays a role in GBM TMZ resistance remains unclear. Here it is found that histone H3K9 lactylation (H3K9la) confers TMZ resistance in GBM via LUC7L2-mediated intron 7 retention of MLH1. Mechanistically, lactylation is upregulated in recurrent GBM tissues and TMZ-resistant cells, and is mainly concentrated in histone H3K9. Combined multi-omics analysis, including CUT&Tag, SLAM-seq, and RNA-seq, reveals that H3K9 lactylation is significantly enriched in the LUC7L2 promoter and activates LUC7L2 transcription to promote its expression. LUC7L2 mediates intron 7 retention of MLH1 to reduce MLH1 expression, and thereby inhibit mismatch repair (MMR), ultimately leading to GBM TMZ resistance. Of note, it is identified that a clinical anti-epileptic drug, stiripentol, which can cross the blood-brain barrier and inhibit lactate dehydrogenase A/B (LDHA/B) activity, acts as a lactylation inhibitor and renders GBM cells more sensitive to TMZ in vitro and in vivo. These findings not only shed light on the mechanism of lactylation in GBM TMZ resistance but also provide a potential combined therapeutic strategy for clinical GBM treatment.
Topics: Animals; Humans; Mice; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Glioblastoma; Histones; Introns; Mice, Nude; MutL Protein Homolog 1; Temozolomide; Female
PubMed: 38477507
DOI: 10.1002/advs.202309290 -
Journal of Controlled Release :... Jul 2023Infiltrative glioma growth makes surgical excision incomplete, and the residual tumor cells proliferate rapidly. Residual glioma cells evade phagocytosis by macrophages...
Infiltrative glioma growth makes surgical excision incomplete, and the residual tumor cells proliferate rapidly. Residual glioma cells evade phagocytosis by macrophages through upregulating anti-phagocytosis molecule CD47, which binds to the signal regulatory protein alpha (SIRPα) of macrophages. Specifically, blocking the CD47-SIRPα pathway is a potential strategy for post-resection glioma treatment. In addition, the anti-CD47 antibody (α-CD47) in combination with temozolomide (TMZ) caused an enhanced pro-phagocytic effect due to the TMZ not only destroying DNA but also inducing endoplasmic reticulum stress response of glioma cells. However, the obstruction of the blood-brain barrier makes systemic combination therapy not ideal for post-resection glioma treatment. Herein, we designed a temperature-sensitive hydrogel system based on a moldable thermosensitive hydroxypropyl chitin (HPCH) copolymer to encapsulate both α-CD47 and TMZ as α-CD47&TMZ@Gel for in situ postoperative cavity administration. Through the in vitro and in vivo evaluations, α-CD47&TMZ@Gel significantly inhibited glioma recurrence post-resection through enhancement of pro-phagocytosis of macrophages, recruitment, and activation of CD8 T cells and NK cells.
Topics: Humans; Glioblastoma; Temozolomide; CD8-Positive T-Lymphocytes; Receptors, Immunologic; Glioma
PubMed: 37290721
DOI: 10.1016/j.jconrel.2023.05.046 -
Lipids in Health and Disease Aug 2023Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with limited treatment options, such as the chemotherapeutic agent, temozolomide (TMZ). However, many... (Review)
Review
Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with limited treatment options, such as the chemotherapeutic agent, temozolomide (TMZ). However, many GBM tumors develop resistance to TMZ, which is a major obstacle to effective therapy. Recently, dysregulated lipid metabolism has emerged as an important factor contributing to TMZ resistance in GBM. The dysregulation of lipid metabolism is a hallmark of cancer and alterations in lipid metabolism have been linked to multiple aspects of tumor biology, including proliferation, migration, and resistance to therapy. In this review, we aimed to summarize current knowledge on lipid metabolism in TMZ-resistant GBM, including key metabolites and proteins involved in lipid synthesis, uptake, and utilization, and recent advances in the application of metabolomics to study lipid metabolism in GBM. We also discussed the potential of lipid metabolism as a target for novel therapeutic interventions. Finally, we highlighted the challenges and opportunities associated with developing these interventions for clinical use, and the need for further research to fully understand the role of lipid metabolism in TMZ resistance in GBM. Our review suggests that targeting dysregulated lipid metabolism may be a promising approach to overcome TMZ resistance and improve outcomes in patients with GBM.
Topics: Humans; Temozolomide; Glioblastoma; Antineoplastic Agents, Alkylating; Lipid Metabolism; Brain Neoplasms; Drug Resistance, Neoplasm; Cell Line, Tumor; Xenograft Model Antitumor Assays
PubMed: 37537607
DOI: 10.1186/s12944-023-01881-5 -
Supportive Care in Cancer : Official... Dec 2023This systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016-2017. HEC still includes cisplatin, carmustine,...
PURPOSE
This systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016-2017. HEC still includes cisplatin, carmustine, dacarbazine, mechlorethamine, streptozocin, and cyclophosphamide in doses of > 1500 mg/m and the combination of cyclophosphamide and an anthracycline (AC) in women with breast cancer.
METHODS
A systematic review report following the PRISMA guidelines of the literature from January 1, 2015, until February 1, 2023, was performed. PubMed (Ovid), Scopus (Google), and the Cochrane Database of Systematic Reviews were searched. The literature search was limited to randomized controlled trials, systematic reviews, and meta-analyses.
RESULTS
Forty-six new references were determined to be relevant. The main topics identified were (1) steroid-sparing regimens, (2) olanzapine-containing regimens, and (3) other issues such as comparisons of antiemetics of the same drug class, intravenous NK receptor antagonists, and potentially new antiemetics. Five updated recommendations are presented.
CONCLUSION
There is no need to prescribe steroids (dexamethasone) beyond day 1 after AC HEC, whereas a 4-day regimen is recommended in non-AC HEC. Olanzapine is now recommended as a fixed part of a four-drug prophylactic antiemetic regimen in both non-AC and AC HEC. No major differences between 5-HT receptor antagonists or between NK receptor antagonists were identified. No new antiemetic agents qualified for inclusion in the updated recommendations.
Topics: Female; Humans; Emetics; Antiemetics; Consensus; Olanzapine; Nausea; Vomiting; Antineoplastic Agents; Cyclophosphamide; Anthracyclines
PubMed: 38127246
DOI: 10.1007/s00520-023-08221-4 -
Metabolic Brain Disease Aug 2023Glioblastoma Multiforme (GBM) is the primary brain tumor and accounts for 200,000 deaths each year worldwide. The standard therapy includes surgical resection followed... (Review)
Review
Glioblastoma Multiforme (GBM) is the primary brain tumor and accounts for 200,000 deaths each year worldwide. The standard therapy includes surgical resection followed by temozolomide (TMZ)-based chemotherapy and radiotherapy. The survival period of GBM patients is only 12-15 months. Therefore, novel treatment modalities for GBM treatment are urgently needed. Mounting evidence reveals that non-coding RNAs (ncRNAs) were involved in regulating gene expression, the pathophysiology of GBM, and enhancing therapeutic outcomes. The combinatory use of ncRNAs, chemotherapeutic drugs, and tumor suppressor gene expression induction might provide an innovative, alternative therapeutic approach for managing GBM. Studies have highlighted the role of Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in prognosis and diagnosis. Dysregulation of ncRNAs is observed in virtually all tumor types, including GBMs. Studies have also indicated the blood-brain barrier (BBB) as a crucial factor that hinders chemotherapy. Although several nanoparticle-mediated drug deliveries were degrading effectively against GBM in vitro conditions. However, the potential to cross the BBB and optimum delivery of oligonucleotide RNA into GBM cells in the brain is currently under intense clinical trials. Despite several advances in molecular pathogenesis, GBM remains resistant to chemo and radiotherapy. Targeted therapies have less clinical benefit due to high genetic heterogeneity and activation of alternative pathways. Thus, identifying GBM-specific prognostic pathways, essential genes, and genomic aberrations provide several potential benefits as subtypes of GBM. Also, these approaches will provide insights into new strategies to overcome the heterogenous nature of GBM, which will eventually lead to successful therapeutic interventions toward precision medicine and precision oncology.
Topics: Humans; Glioblastoma; Prognosis; Precision Medicine; Temozolomide; MicroRNAs; Brain Neoplasms; Cell Line, Tumor
PubMed: 37249862
DOI: 10.1007/s11011-023-01234-2 -
Science Translational Medicine Sep 2023The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma...
The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial (number NCT04135807), we provide first-in-human evidence that drug-releasing intratumoral microdevices (IMDs) can be safely and effectively used to obtain patient-specific, high-throughput molecular and histopathological drug response profiling. These data can complement other strategies to inform the selection of drugs based on their observed antitumor effect in situ. IMDs are integrated into surgical practice during tumor resection and remain in situ only for the duration of the otherwise standard operation (2 to 3 hours). None of the six enrolled patients experienced adverse events related to the IMD, and the exposed tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Analysis of the specimens provided preliminary evidence of the robustness of the readout, compatibility with a wide array of techniques for molecular tissue interrogation, and promising similarities with the available observed clinical-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMDs allows characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor, and without affecting the standard surgical workflow.
Topics: Humans; Glioma; Glioblastoma; Drug Delivery Systems; Drug Liberation; Temozolomide
PubMed: 37672566
DOI: 10.1126/scitranslmed.adi0069 -
American Journal of Surgery Aug 2023Surgery is considered for patients without metastatic disease and with resectable primary tumor. Pre-operatively, high quality imaging is reviewed to determine the... (Review)
Review
Surgery is considered for patients without metastatic disease and with resectable primary tumor. Pre-operatively, high quality imaging is reviewed to determine the likely extent of resection, specifically including the need for potential en-bloc resection of adjacent organs. In cases where up-front surgical approach would expose the patient to excessive morbidity (such as bilateral nephrectomy, multi-visceral resection, or prohibitively high risk of positive margins), neoadjuvant chemotherapy and/or chemoradiotherapy is considered. Though data are sparse in LMS, a neoadjuvant regimen of doxorubicin and dacarbazine is typically considered for borderline resectable tumors at our institution; patients may be treated for up to 4 months with interval imaging every 2 months to evaluate for tumor response. Postoperatively, adjuvant systemic therapy or radiation may be considered for patients with positive surgical margins or high-grade tumors.
Topics: Humans; Vena Cava, Inferior; Leiomyosarcoma; Nephrectomy; Combined Modality Therapy; Plastic Surgery Procedures
PubMed: 36959023
DOI: 10.1016/j.amjsurg.2023.03.002 -
Biomedicine & Pharmacotherapy =... Sep 2023Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they... (Review)
Review
Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they have been proven to prolong overall survival. Within an optimal treatment regimen (incl. surgical resection, radiation therapy, and chemotherapy) temozolomide as the current anti-GBL first-line chemotherapeutic has increased the median overall survival to 14-15 months, and the percentage of patients alive at two years has been reported to rise from 10.4% to 26.5%. Though, the effectiveness of temozolomide chemotherapy is limited by the serious systemic, dose-related side effects. Therefore, the ponderation regarding novel treatment methods along with innovative formulations is crucial to emerging the therapeutic potential of the widely used drug simultaneously reducing the drawbacks of its use. Herein the complex temozolomide application restrictions present at different levels of therapy as well as, the currently proposed strategies aimed at reducing those limitations are demonstrated. Approaches increasing the efficacy of anti-GBL treatment are addressed. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for temozolomide delivery and their functionalization towards more effective blood-brain-barrier crossing and/or tumour targeting. Appropriate designing accounting for the physical and chemical features of formulations along with distinct routes of administration is also discussed. In addition, considering the multiple resistance mechanisms, the molecular heterogeneity and the evolution of tumour the purposely selected delivery methods, the combined therapeutic approaches and specifically focused on GBL cells therapies are reviewed.
Topics: Humans; Temozolomide; Dacarbazine; Brain Neoplasms; Glioblastoma; Glioma; Antineoplastic Agents, Alkylating
PubMed: 37459661
DOI: 10.1016/j.biopha.2023.115174