-
BMC Cancer Apr 2024Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective...
BACKGROUND
Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration.
METHODS
The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM.
RESULTS
The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01).
CONCLUSION
The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.
Topics: Animals; Small Cell Lung Carcinoma; Mice; Humans; Lung Neoplasms; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Podophyllotoxin; Cell Line, Tumor; Mice, Nude; Meningeal Carcinomatosis; Xenograft Model Antitumor Assays; Proteolysis
PubMed: 38644473
DOI: 10.1186/s12885-024-12244-3 -
Medicine Apr 2024Durvalumab plus etoposide-platinum (DEP) showed sustained overall survival improvements in patients with extensive-stage small-cell lung cancer (ES-SCLC) compared to...
BACKGROUND
Durvalumab plus etoposide-platinum (DEP) showed sustained overall survival improvements in patients with extensive-stage small-cell lung cancer (ES-SCLC) compared to etoposide-platinum (EP), but adding tremelimumab to DEP (DTEP) did not significantly improve outcomes. A third-party payer perspective is taken here to evaluate the cost-effectiveness of DTEP, DEP, and EP for ES-SCLC.
METHODS
The cost-effectiveness was evaluated by partitioning survival models into 3 mutually exclusive health states. In this model, clinical characteristics and outcomes were obtained from the CASPIAN. Model robustness was evaluated through 1-way deterministic and probabilistic sensitivity analyses. Outcome measurements included costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio, life-years, incremental net health benefit, and incremental net monetary benefit. The analysis was conducted with a 10-year lifetime horizon in a United States setting.
RESULTS
Compared with EP, DEP, and DTEP were associated with an increment of 0.480 and 0.313 life-years, and an increment of 0.247 and 0.165 QALYs, as well as a $139,788 and $170,331 increase in cost per patient. The corresponding ICERs were $565,807/QALY and $1033,456/QALY, respectively. The incremental net health benefit and incremental net monetary benefit of DEP or DTEP were -0.685 QALYs and -$102,729, or -0.971 QALYs and -$145,608 at a willingness to pay threshold of $150,000/QALY, respectively. Compared with DTEP, DEP was dominated. DTEP and DEP were 100% unlikely to be cost-effective if the willingness to pay threshold was $150,000/QALY. DEP was cost-effective compared to EP when durvalumab was priced below $0.994/mg. Compared with EP, DEP, and DTEP were unlikely to be considered cost-effective across all subgroups.
CONCLUSION
DEP and DTEP were not cost-effective options in the first-line treatment for ES-SCLC compared with EP, from the third-party payer perspective in the United States. Compared with DTEP, DEP was dominated.
Topics: Humans; United States; Small Cell Lung Carcinoma; Lung Neoplasms; Etoposide; Platinum; Cost-Effectiveness Analysis; Cost-Benefit Analysis; Quality-Adjusted Life Years; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized
PubMed: 38640325
DOI: 10.1097/MD.0000000000037836 -
Molecules (Basel, Switzerland) Mar 2024Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained...
Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,β-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans.
Topics: Humans; Podophyllotoxin; Antineoplastic Agents; Skeleton; Hypertrophy; Aldehydes; Lactones; Radiopharmaceuticals
PubMed: 38611722
DOI: 10.3390/molecules29071442 -
Scientific Reports Apr 2024Spatially Fractionated Radiotherapy (SFRT) has demonstrated promising potential in cancer treatment, combining the advantages of reduced post-radiation effects and...
Spatially Fractionated Radiotherapy (SFRT) has demonstrated promising potential in cancer treatment, combining the advantages of reduced post-radiation effects and enhanced local control rates. Within this paradigm, proton minibeam radiotherapy (pMBRT) was suggested as a new treatment modality, possibly producing superior normal tissue sparing to conventional proton therapy, leading to improvements in patient outcomes. However, an effective and convenient beam generation method for pMBRT, capable of implementing various optimum dose profiles, is essential for its real-world application. Our study investigates the potential of utilizing the moiré effect in a dual collimator system (DCS) to generate pMBRT dose profiles with the flexibility to modify the center-to-center distance (CTC) of the dose distribution in a technically simple way.We employ the Geant4 Monte Carlo simulations tool to demonstrate that the angle between the two collimators of a DCS can significantly impact the dose profile. Varying the DCS angle from 10 to 50 we could cover CTC ranging from 11.8 mm to 2.4 mm, respectively. Further investigations reveal the substantial influence of the multi-slit collimator's (MSC) physical parameters on the spatially fractionated dose profile, such as period (CTC), throughput, and spacing between MSCs. These findings highlight opportunities for precision dose profile adjustments tailored to specific clinical scenarios.The DCS capacity for rapid angle adjustments during the energy transition stages of a spot scanning system can facilitate dynamic alterations in the irradiation profile, enhancing dose contrast in normal tissues. Furthermore, its unique attribute of spatially fractionated doses in both lateral directions could potentially improve normal tissue sparing by minimizing irradiated volume. Beyond the realm of pMBRT, the dual MSC system exhibits remarkable versatility, showing compatibility with different types of beams (X-rays and electrons) and applicability across various SFRT modalities.Our study illuminates the dual MSC system's potential as an efficient and adaptable tool in the refinement of pMBRT techniques. By enabling meticulous control over irradiation profiles, this system may expedite advancements in clinical and experimental applications, thereby contributing to the evolution of SFRT strategies.
Topics: Humans; Proton Therapy; Protons; Radiation, Ionizing; Radiation Injuries; Monte Carlo Method; Etoposide; Dose Fractionation, Radiation; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted
PubMed: 38605022
DOI: 10.1038/s41598-024-55104-7 -
The Oncologist Jun 2024A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we...
BACKGROUND
A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy.
MATERIALS AND METHODS
Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy.
RESULTS
Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications.
CONCLUSION
EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.
Topics: Humans; Etoposide; Female; Male; Cytarabine; Aged; Central Nervous System Neoplasms; Consolidation Chemotherapy; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies; Middle Aged; Aged, 80 and over; Treatment Outcome; Lymphoma, Large B-Cell, Diffuse
PubMed: 38581718
DOI: 10.1093/oncolo/oyae059 -
BMC Cancer Apr 2024We designed this study based on both a physician practice survey and real-world patient data to: (1) evaluate clinical management practices in extensive-stage small cell...
BACKGROUND
We designed this study based on both a physician practice survey and real-world patient data to: (1) evaluate clinical management practices in extensive-stage small cell lung cancer (ES-SCLC) among medical centers located across France; and (2) describe first-line treatment patterns among patients with ES-SCLC following the introduction of immunotherapy into clinical practice.
METHODS
A 50-item questionnaire was completed by physicians from 45 medical centers specialized in SCLC management. Responses were collected from June 2022 to January 2023. The survey questions addressed diagnostic workup of ES-SCLC, chemoimmunotherapy in first-line and second-line settings, and use of prophylactic cranial irradiation (PCI) and radiotherapy. In parallel, using a chart review approach, we retrospectively analyzed aggregated information from 548 adults with confirmed ES-SCLC receiving first-line treatment in the same centers.
RESULTS
In ES-SCLC, treatment planning is based on chest computed tomography (CT) (as declared by 100% of surveyed centers). Mean time between diagnosis and treatment initiation was 2-7 days, as declared by 82% of centers. For detection of brain metastases, the most common imaging test was brain CT (84%). The main exclusion criteria for first-line immunotherapy in the centers were autoimmune disease (87%), corticosteroid therapy (69%), interstitial lung disease (69%), and performance status ≥ 2 (69%). Overall, 53% and 36% of centers considered that patients are chemotherapy-sensitive if they relapse within ≥ 3 months or ≥ 6 months after first-line chemoimmunotherapy, respectively. Among the 548 analyzed patients, 409 (75%) received chemoimmunotherapy as a first-line treatment, 374 (91%) of whom received carboplatin plus etoposide and 35 (9%) cisplatin plus etoposide. Overall, 340/548 patients (62%) received maintenance immunotherapy. Most patients (68%) did not receive radiotherapy or PCI.
CONCLUSIONS
There is an overall alignment of practices reflecting recent clinical guidelines among medical centers managing ES-SCLC across France, and a high prescription rate of immunotherapy in the first-line setting.
Topics: Adult; Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Etoposide; Retrospective Studies; Neoplasm Recurrence, Local; Carboplatin
PubMed: 38580937
DOI: 10.1186/s12885-024-12117-9 -
Annals of Agricultural and... Mar 2024Including additional compounds that disturb the energy metabolism of cancer cells in advanced cancer therapy regimens may be an approach to overcome the problem of drug...
INTRODUCTION AND OBJECTIVE
Including additional compounds that disturb the energy metabolism of cancer cells in advanced cancer therapy regimens may be an approach to overcome the problem of drug resistance and the therapeutic effectiveness of classic chemotherapeutics. One of the compounds that decouple oxidative phosphorylation, and thus alter the activity of energy-producing pathways, is 2,4-DNP (2,4- dinitrophenol).
OBJECTIVE
The aim of the study was to assess the ability of the 2,4-DNP to sensitize prostate cancer cells to the action of cisplatin and etoposide, or to intensify their action.
MATERIAL AND METHODS
The research was carried out on three prostate cancer cell lines (LNCaP, PC-3, DU-145. To assess the effect of cisplatin or etoposide with 2,4-DNP on prostate cancer cells, MTT assay, analysis of the cell cycle and apoptosis detection was performed. Oxidative stress was investigated by CellRox fluorescence staining and expression of genes related to antioxidant defence. In addition, analysis was conducted of the expression of genes related to cell cycle inhibition, transporters associated with multi-drug resistance and DNA repair.
RESULTS
The study showed that the simultaneous incubation of 2,4-DNP with cisplatin or etoposide enhances the cytotoxic effect of the chemotherapeutic agent only in LNCaP cells (oxidative phenotype).
CONCLUSIONS
The enhanced cytotoxic effect of chemotherapeutics by 2,4-DNP may be the result of disturbed redox balance, reduced ability of cells to repair DNA, and the oxidative metabolic phenotype of prostate cancer cells.
Topics: Male; Humans; Cisplatin; Etoposide; 2,4-Dinitrophenol; Antineoplastic Agents; Prostatic Neoplasms; Cell Line; Apoptosis; Cell Line, Tumor
PubMed: 38549475
DOI: 10.26444/aaem/174919 -
Journal of Functional Biomaterials Feb 2024Podophyllotoxin (PPT) is used in the industrial production of efficient anticancer, antiviral and other drugs. or are natural sources of PPT, but at present they are...
Podophyllotoxin (PPT) is used in the industrial production of efficient anticancer, antiviral and other drugs. or are natural sources of PPT, but at present they are considered as endangered species. Their PPT content is variable, depending on the growing conditions. Searching for new sources of PPT, some representatives of the genus were found to exhibit efficient PPT biosynthesis. However, PPT is highly toxic and poorly soluble in water compound, which limits its clinical applications. In this connection, amphiphilic polymer micelles are considered to be suitable PPT carriers, aimed at increase in water solubility and decrease in toxicity. The present research deals with the evaluation of MPEG-polycarbonate block copolymer micelles loaded with PPT or juniper extracts. The active component-loaded polymer nanocarriers were characterized by dynamic and electrophoretic light scattering, as well as by transmission electron microscopy. The active component loading efficiency and loading capacity were also determined. Highly efficient antiproliferative activity of the loaded micelles was determined in a panel of cancer cell lines. The obtained amphiphilic nanocarriers, loaded with PPT-containing bioactive components, have application in future in vivo preclinical trials of their pharmacokinetics and pharmacodynamics as potential therapeutical agents in the prospective nanomedicine.
PubMed: 38535246
DOI: 10.3390/jfb15030053 -
Frontiers in Immunology 2024Immune checkpoint blockade (ICB) with or without chemotherapy has a very modest benefit in patients with small cell lung cancer (SCLC). SCLC tumors are characterized by...
INTRODUCTION
Immune checkpoint blockade (ICB) with or without chemotherapy has a very modest benefit in patients with small cell lung cancer (SCLC). SCLC tumors are characterized by high tumor mutation burden (TMB) and low PD-L1 expression. Therefore, TMB and PD-L1 do not serve as biomarkers of ICB response in SCLC. CD38, a transmembrane glycoprotein, mediates immunosuppression in non-small cell lung cancer (NSCLC). In this brief report, we highlight the potential role of CD38 as a probable biomarker of immunotherapy response in SCLC.
METHODS
We evaluated the role of CD38 as a determinant of tumor immune microenvironment in SCLC with bulk and single-cell transcriptomic analyses and protein assessments of clinical samples and preclinical models, including CD38 blockade.
RESULTS
In SCLC clinical samples, levels were significantly correlated with the gene expression of the immunosuppressive markers , and . CD38 expression was significantly enhanced after chemotherapy and ICB treatment in SCLC preclinical models and clinical samples. A combination of cisplatin/etoposide, ICB, and CD38 blockade delayed tumor growth compared to cisplatin/etoposide.
CONCLUSION
Our study provides a preliminary but important direction toward exploring CD38 as a potential biomarker of ICB response and CD38 blockade as a combination strategy for chemo-immunotherapy in SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; B7-H1 Antigen; Cisplatin; Etoposide; Biomarkers; Tumor Microenvironment
PubMed: 38533509
DOI: 10.3389/fimmu.2024.1348982 -
FEBS Open Bio Jun 2024Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system, catalysing the formation...
Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system, catalysing the formation of reactive oxygen species that are important in anti-microbial action, but MPO also oxidatively transforms the topoisomerase II (TOP2) poison etoposide to chemical forms that have elevated DNA damaging properties. TOP2 poisons such as etoposide are widely used anti-cancer drugs, but they are linked to cases of secondary acute myeloid leukaemias through a mechanism that involves DNA damage and presumably erroneous repair leading to leukaemogenic chromosome translocations. This leads to the possibility that myeloperoxidase inhibitors could reduce the rate of therapy-related leukaemia by protecting haematopoietic cells from TOP2 poison-mediated genotoxic damage while preserving the anti-cancer efficacy of the treatment. We show here that myeloperoxidase inhibition reduces etoposide-induced TOP2B-DNA covalent complexes and resulting DNA double-strand break formation in primary ex vivo expanded CD34 progenitor cells and unfractionated bone marrow mononuclear cells. Since MPO inhibitors are currently being developed as anti-inflammatory agents this raises the possibility that repurposing of these potential new drugs could provide a means of suppressing secondary acute myeloid leukaemias associated with therapies containing TOP2 poisons.
Topics: Etoposide; Humans; Peroxidase; DNA Damage; DNA Topoisomerases, Type II; Poly-ADP-Ribose Binding Proteins; Topoisomerase II Inhibitors; Antineoplastic Agents; DNA Breaks, Double-Stranded; Bone Marrow Cells; Leukocytes, Mononuclear
PubMed: 38531625
DOI: 10.1002/2211-5463.13799