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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 -
International Journal of Molecular... Aug 2023The protein disulfide isomerase A3 (PDIA3) is directly or indirectly involved in various physiopathological processes and participates in cancer initiation, progression...
The protein disulfide isomerase A3 (PDIA3) is directly or indirectly involved in various physiopathological processes and participates in cancer initiation, progression and chemosensitivity. However, little is known about its involvement in glioblastoma. To obtain specific information, we performed cellular experiments in the T98G and U-87 MG glioblastoma cell lines to evaluate the role of PDIA3. The loss of PDIA3 functions, either through inhibition or silencing, reduced glioblastoma cells spreading by triggering cytotoxic phenomena. PDIA3 inhibition led to a redistribution of PDIA3, resulting in the formation of protein aggregates visualized through immunofluorescence staining. Concurrently, cell cycle progression underwent arrest at the G/S checkpoint. After PDIA3 inhibition, ROS-independent DNA damage and the activation of the repair system occurred, as evidenced by the phosphorylation of H2A.X and the overexpression of the Ku70 protein. We also demonstrated through a clonogenic assay that PDIA3 inhibition could increase the chemosensitivity of T98G and U-87 MG cells to the approved glioblastoma drug temozolomide (TMZ). Overall, PDIA3 inhibition induced cytotoxic effects in the analyzed glioblastoma cell lines. Although further in vivo studies are needed, the results suggested PDIA3 as a novel therapeutic target that could also be included in already approved therapies.
Topics: Humans; Glioblastoma; Protein Disulfide-Isomerases; Temozolomide; Phosphorylation; Biological Assay
PubMed: 37686085
DOI: 10.3390/ijms241713279 -
Clinical & Translational Oncology :... Dec 2023Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L)...
BACKGROUND
Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison.
METHODS
We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy).
RESULTS
Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma.
CONCLUSIONS
In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.
Topics: Humans; Ifosfamide; Retrospective Studies; Deoxycytidine; Sarcoma; Gemcitabine; Soft Tissue Neoplasms; Dacarbazine
PubMed: 37329429
DOI: 10.1007/s12094-023-03221-6 -
Cells Oct 2023Glioblastoma (GBM) stands as the most prevalent primary malignant brain tumor, typically resulting in a median survival period of approximately thirteen to fifteen...
Glioblastoma (GBM) stands as the most prevalent primary malignant brain tumor, typically resulting in a median survival period of approximately thirteen to fifteen months after undergoing surgery, chemotherapy, and radiotherapy. Nucleobindin-2 (NUCB2) is a protein involved in appetite regulation and energy homeostasis. In this study, we assessed the impact of NUCB2 expression on tumor progression and prognosis of GBM. We further evaluated the relationship between NUCB2 expression and the sensitivity to chemotherapy and radiotherapy in GBM cells. Additionally, we compared the survival of mice intracranially implanted with GBM cells. High NUCB2 expression was associated with poor prognosis in patients with GBM. Knockdown of NUCB2 reduced cell viability, migration ability, and invasion ability of GBM cells. Overexpression of NUCB2 resulted in reduced apoptosis following temozolomide treatment and increased levels of DNA damage repair proteins after radiotherapy. Furthermore, mice intracranially implanted with NUCB2 knockdown GBM cells exhibited longer survival compared to the control group. NUCB2 may serve as a prognostic biomarker for poor outcomes in patients with GBM. Additionally, NUCB2 not only contributes to tumor progression but also influences the sensitivity of GBM cells to chemotherapy and radiotherapy. Therefore, targeting NUCB2 protein expression may represent a novel therapeutic approach for the treatment of GBM.
Topics: Humans; Animals; Mice; Glioblastoma; Nucleobindins; Cell Line, Tumor; Temozolomide
PubMed: 37830634
DOI: 10.3390/cells12192420 -
Cellular Signalling Sep 2023Gliomas harbouring mutations in IDH1 (isocitrate dehydrogenase 1) are characterized by greater sensitivity to chemotherapeutics. These mutants also exhibit diminished...
Gliomas harbouring mutations in IDH1 (isocitrate dehydrogenase 1) are characterized by greater sensitivity to chemotherapeutics. These mutants also exhibit diminished levels of transcriptional coactivator YAP1 (yes-associated protein 1). Enhanced DNA damage in IDH1 mutant cells, as evidenced by γH2AX formation (phosphorylation of histone variant H2A.X) and ATM (serine/threonine kinase; ataxia telangiectasia mutated) phosphorylation, was accompanied by reduced FOLR1 (folate receptor 1) expression. Diminished FOLR1, concomitant with heightened γH2AX levels, was also observed in patient-derived IDH1 mutant glioma tissues. Chromatin immunoprecipitation, overexpression of mutant YAP1, and treatment with YAP1-TEAD (TEA domain transcription factors) complex inhibitor verteporfin demonstrated regulation of FOLR1 expression by YAP1 and its partner transcription factor TEAD2. TCGA (The Cancer Genome Atlas) data analysis demonstrated better patient survival with reduced FOLR1 expression. Depletion of FOLR1 rendered IDH1 wild-type gliomas more susceptible to temozolomide-mediated death. Despite heightened DNA damage, IDH1 mutants exhibited reduced levels of IL6 (interleukin 6) and IL8 (interleukin 8) - pro-inflammatory cytokines known to be associated with persistent DNA damage. While both FOLR1 and YAP1 influenced DNA damage, only YAP1 was involved in regulating IL6 and IL8. ESTIMATE and CIBERSORTx analyses revealed the association between YAP1 expression and immune cell infiltration in gliomas. By identifying the influence of YAP1-FOLR1 link in DNA damage, our findings suggest that simultaneous depletion of both could amplify the potency of DNA damaging agents, while concomitantly reducing the release of inflammatory mediators and potentially affecting immune modulation. This study also highlights the novel role of FOLR1 as a probable prognostic marker in gliomas, predicting responsiveness to temozolomide and other DNA damaging agents.
Topics: Humans; Interleukin-8; Temozolomide; Folate Receptor 1; Interleukin-6; Glioma; Mutation; Transcription Factors; Brain Neoplasms
PubMed: 37269960
DOI: 10.1016/j.cellsig.2023.110738 -
Orvosi Hetilap Jul 2023Anterior pituitary tumours, once considered benign neoplasms, may rarely have aggressive behaviour and can even metastasize. The current guideline of the European...
Anterior pituitary tumours, once considered benign neoplasms, may rarely have aggressive behaviour and can even metastasize. The current guideline of the European Society of Endocrinology defines aggressive pituitary adenomas as radiologically invasive tumours with an unusually rapid growth rate and frequent relapses despite the optimal use of standard therapies. Currently, there is not any single, well-defined pathological marker of malignancy. Pituitary carcinomas are thus clinically defined by the presence of craniospinal or distant metastases, typically developing several years after the first presentation. Histopathology may predict aggressive behaviour if the Ki67 index and mitotic rate are elevated and in case of positive p53 staining. These patients' short- and long-term therapy should be individualized and regularly discussed by a multidisciplinary pituitary team. Besides standard medical treatment administered in maximally tolerated doses, current recommendations suggest repeated surgery and radiotherapy. If this approach fails, the next choice of treatment is chemotherapy with temozolomide. After that, immune checkpoint inhibitors, bevacizumab, and peptide receptor radiotherapy are emerging therapies that should be used on a case-by-case basis. Orv Hetil. 2023; 164(30): 1167-1175.
Topics: Humans; Pituitary Neoplasms; Neoplasm Recurrence, Local; Adenoma; Temozolomide; Bevacizumab
PubMed: 37516994
DOI: 10.1556/650.2023.32832 -
Journal of Experimental & Clinical... Oct 2023Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) patients has been limited by resistance in the clinic. Currently, there are no clinically proven therapeutic...
BACKGROUND
Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) patients has been limited by resistance in the clinic. Currently, there are no clinically proven therapeutic options available to restore TMZ treatment sensitivity. Here, we investigated the potential of albumin-bound paclitaxel (ABX), a novel microtubule targeting agent, in sensitizing GBM cells to TMZ and elucidated its underlying molecular mechanism.
METHODS
A series of in vivo and in vitro experiments based on two GBM cell lines and two primary GBM cells were designed to evaluate the efficacy of ABX in sensitizing GBM cells to TMZ. Further proteomic analysis and validation experiments were performed to explore the underlying molecular mechanism. Finally, the efficacy and mechanism were validated in GBM patients derived organoids (PDOs) models.
RESULTS
ABX exhibited a synergistic inhibitory effect on GBM cells when combined with TMZ in vitro. Combination treatment of TMZ and ABX was highly effective in suppressing GBM progression and significantly prolonged the survival oforthotopic xenograft nude mice, with negligible side effects. Further proteomic analysis and experimental validation demonstrated that the combined treatment of ABX and TMZ can induce sustained DNA damage by disrupting XPC and ERCC1 expression and nuclear localization. Additionally, the combination treatment can enhance ferroptosis through regulating HOXM1 and GPX4 expression. Preclinical drug-sensitivity testing based on GBM PDOs models confirmed that combination therapy was significantly more effective than conventional TMZ monotherapy.
CONCLUSION
Our findings suggest that ABX has the potential to enhance TMZ treatment sensitivity in GBM, which provides a promising therapeutic strategy for GBM patients.
Topics: Animals; Mice; Humans; Temozolomide; Glioblastoma; Albumin-Bound Paclitaxel; Antineoplastic Agents, Alkylating; Ferroptosis; Mice, Nude; Proteomics; Drug Resistance, Neoplasm; DNA Damage; Cell Line, Tumor; Brain Neoplasms; Xenograft Model Antitumor Assays
PubMed: 37891669
DOI: 10.1186/s13046-023-02843-6 -
Hematology. American Society of... Dec 2023There has been a renewed effort globally in the study of older Hodgkin lymphoma (HL) patients, generating a multitude of new data. For prognostication, advancing age,...
There has been a renewed effort globally in the study of older Hodgkin lymphoma (HL) patients, generating a multitude of new data. For prognostication, advancing age, comorbidities, altered functional status, Hispanic ethnicity, and lack of dose intensity (especially without anthracycline) portend inferior survival. Geriatric assessments (GA), including activities of daily living (ADL) and comorbidities, should be objectively measured in all patients. In addition, proactive multidisciplinary medical management is recommended (eg, geriatrics, cardiology, primary care), and pre-phase therapy should be considered for most patients. Treatment for fit older HL patients should be given with curative intent, including anthracyclines, and bleomycin should be minimized (or avoided). Brentuximab vedotin given sequentially before and after doxorubicin, vinblastine, dacarbazine (AVD) chemotherapy for untreated patients is tolerable and effective, and frontline checkpoint inhibitor/AVD platforms are rapidly emerging. Therapy for patients who are unfit or frail, whether due to comorbidities and/or ADL loss, is less clear and should be individualized with consideration of attenuated anthracycline-based therapy versus lower-intensity regimens with inclusion of brentuximab vedotin +/- checkpoint inhibitors. For all patients, there should be clinical vigilance with close monitoring for treatment-related toxicities, including neurotoxicity, cardiopulmonary, and infectious complications. Finally, active surveillance for "postacute" complications 1 to 10 years post therapy, especially cardiac disease, is needed for cured patients. Altogether, therapy for older HL patients should include anthracycline-based therapy in most cases, and novel targeted agents should continue to be integrated into treatment paradigms, with more research needed on how best to utilize GAs for treatment decisions.
Topics: Humans; Aged; Aged, 80 and over; Hodgkin Disease; Brentuximab Vedotin; Activities of Daily Living; Antineoplastic Combined Chemotherapy Protocols; Vinblastine; Bleomycin; Doxorubicin; Anthracyclines
PubMed: 38066840
DOI: 10.1182/hematology.2023000449 -
Biomacromolecules Aug 2023Melanoma is resistant to conventional chemotherapy and radiotherapy. Therefore, it is essential to develop a targeted, low-toxic, and minimally invasive treatment. Here,...
Melanoma is resistant to conventional chemotherapy and radiotherapy. Therefore, it is essential to develop a targeted, low-toxic, and minimally invasive treatment. Here, DTIC/ICG-FeO@TpBD BSP/HA microneedles (MNs) were designed and fabricated, which can enhance targeting to melanoma and perform photothermal therapy (PTT) and chemotherapy simultaneously to synergistically exert anticancer effects. The system consisted of magnetic nanoparticles (DTIC/ICG-FeO@TpBD), dissoluble matrix (Bletilla polysaccharide (BSP)/hyaluronic acid (HA)), and a polyvinyl alcohol backing layer. Due to the good magnetic responsiveness of FeO@TpBD, dacarbazine (DTIC) and indocyanine green (ICG) can be better targeted to the tumor tissue and improve the therapeutic effect. BSP and HA have good biocompatibility and transdermal ability, so that the MNs can completely penetrate the tumor tissue, be dissolved by the interstitial fluid, and release DTIC and ICG. Under near-infrared (NIR) light irradiation, ICG converts light energy into thermal energy and induces ablation of B16-OVA melanoma cells. In vivo results showed that DTIC/ICG-FeO@TpBD BSP/HA MNs combined with chemotherapy and PTT could effectively inhibit the growth of melanoma without tumor recurrence or significant weight loss in mice. Therefore, DTIC/ICG-FeO@TpBD BSP/HA MNs are expected to provide new ideas and therapeutic approaches for the clinical treatment of melanoma.
Topics: Animals; Mice; Metal-Organic Frameworks; Hyperthermia, Induced; Melanoma; Phototherapy; Indocyanine Green; Dacarbazine; Cell Line, Tumor; Nanoparticles
PubMed: 37475132
DOI: 10.1021/acs.biomac.3c00488 -
Nature Communications Mar 2024Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause...
Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of OmG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.
Topics: Humans; Glioblastoma; Translesion DNA Synthesis; DNA Mismatch Repair; Drug Resistance, Neoplasm; Temozolomide; DNA-Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 38438348
DOI: 10.1038/s41467-024-45979-5