Current Standard Therapy Research Articles

Evaluating the impact of Sacubitril/valsartan on diastolic function in patients with heart failure: A systematic review and meta-analysis.

Heart failure is a common and severe condition, often complicated by diastolic dysfunction. Current standard therapies such as ACEIs and ARBs have limited efficacy in managing diastolic function. Sacubitril/Valsartan, an emerging therapy, warrants rigorous investigation to elucidate its impact on diastolic function in heart failure patients. This systematic review and meta-analysis were conducted adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and utilized the PICO schema. Searches were performed on 4 databases-PubMed, Embase, Web of Science, and Cochrane Library-without temporal restrictions. Inclusion and exclusion criteria were strictly defined, and quality assessments were conducted using the Cochrane Collaboration Risk of Bias tool. Both fixed-effects and random-effects models were used for statistical analysis, depending on inter-study heterogeneity assessed by I2 statistics and Chi-square tests. Out of 1129 identified publications, 8 studies met the criteria and were included in the meta-analysis. These studies consisted of both randomized controlled trials and cohort studies and featured diverse global populations. Significant reductions were found in the echocardiographic parameter E/e' ratio and LAVi upon treatment with Sacubitril/Valsartan compared to standard therapies, with mean differences of -1.38 and -4.62, respectively, both with P values < .01. This meta-analysis demonstrates that Sacubitril/Valsartan significantly improves diastolic function parameters in heart failure patients compared to standard treatments. These findings underscore the potential benefits of Sacubitril/Valsartan in the management of heart failure, particularly for patients with diastolic dysfunction.

Lactobacillus gasseri KBL697 ameliorates psoriatic inflammation through the modulation of gut-skin axis

Abstract Psoriasis is a chronic inflammatory disease arising from aberrant interactions between various immune cells and cytokines. The current standard therapy includes topical steroids, methotrexate or anti-IL-17A/IL-23 antibodies. However, due to the limited efficacy and associated side effects, there is still an unmet medical need for the development of novel therapeutic agents for this disease. KBL697 is a strain of Lactobacillus gasseri, isolated from the vaginal samples of healthy donors. We previously reported that KBL697 ameliorated the symptoms of an inflammatory bowel disease mouse model. At the molecular level, KBL697 decreased pro-inflammatory cytokines including IFN-gamma, IL-6, and IL-17A, while an anti-inflammatory cytokine IL-10 was increased. In the current study, we tested KBL697 in pre-clinical models for psoriasis. Oral administration of KBL697 showed a significant beneficial effect in imiquimod-induced mouse models, judged by the skin inflammation, PASI score and immune profile change. Further studies revealed that IL-10 is induced by lipoteichoic acid (LTA) of KBL697, indicating the critical role of LTA/IL-10 in the anti-inflammatory function of KBL697. In the skin analysis, key cytokines in psoriasis, such as IL-17A, IL-23, and IL-36, are downregulated while genes for skin regeneration are upregulated, supporting the model for KBL697 working in the gut-skin axis. Therefore, KBL697 has great potential as a novel therapeutic agent for the treatment of psoriasis.

Statement of the Uterus Commission of the Gynecological Oncology Working Group (AGO) on Neoadjuvant Chemotherapy Prior to Definitive Radiochemotherapy in Patients with Locally Advanced Cervical Cancer.

The presentation of the results of the prospective randomized international multicenter GCIG INTERLACE trial at the 2023 congress of the European Society of Medical Oncology (ESMO) is likely to change the therapy for locally advanced cervical cancer. In the GCIG INTERLACE trial, six cycles of neoadjuvant chemotherapy administered weekly and consisting of carboplatin AUC2 and paclitaxel 80 mg/m 2 followed by definitive radiochemotherapy with pelvic radiotherapy (40 - 50.4Gray) and cisplatin (40 mg/m 2 once a week for 5 weeks) and brachytherapy (total dose EQD2 at least 78 Gy at point A) (experimental arm) were compared with definitive radiochemotherapy alone (standard arm) in patients with locally advanced cervical cancer (Fédération Internationale de Gynécologie et d'Obstétrique [FIGO] 2008 stage IB1/node positive, IB2, II, IIIB and IVA) and was found to be significantly superior with significantly longer recurrence-free survival (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.64 - 0.91; p = 0.013) and significantly longer overall survival rates (HR 0.61; 95% CI: 0.40 - 0.91; p = 0.04) after 5 years' follow-up. After considering the results of the GCIG INTERLACE trial published at the congress, the Uterus Commission of the AGO is of the opinion that neoadjuvant chemotherapy with carboplatin AUC2 and paclitaxel 80 mg/m 2 d1, q7, x6 may be offered to patients with locally advanced cervical cancer (FIGO stage IB1/node positive, IB2, II, IIIB and IVA) in addition to the current standard therapy after the patient has been informed about the risks, with the decision taken on a case-by-case basis. However, before this approach can be discussed at guideline level or defined as the new therapy standard, it will be necessary to wait until the data from the full publication are available.

Anti-inflammatory and Apoptotic Effects of Levisticum Officinale Koch Extracts on HT 29 and Caco-2 Human Colorectal Carcinoma Cell Lines.

Colorectal cancer is among the deadliest cancers in the world. Due to the occurrence of side effects related to current standard therapy, researchers are seeking better alternative treatments. For many years, herbs have been a promising source for discovering therapeutic compounds. Therefore, the primary objective of this research was to examine the distinctive apoptotic and anti-inflammatory properties exhibited by Levisticum officinale Koch (lovage) on HT-29 and Caco-2 cell lines. The maceration method was used to prepare different extracts (ethanol, dichloromethane, petroleum, and residues) from the plant. These extracts were then tested on two colon cancer cell lines - HT-29 and Caco-2 - using the MTT assay to determine the half-maximal inhibitory concentration (IC50) values. In addition, we evaluated the expression levels of several inflammatory genes (IKKb, IKKa, and REIB) using real-time PCR. We also assessed Cox-2 protein expression using western blot analysis. The western blot was also used to analyze apoptosis-related proteins, including Caspase-3, BAX, and Bcl-2. The dichloromethane extract of Levisticum officin (DELO) exhibited a high cytotoxic effect on Caco-2 and HT-29 cell lines, with IC50 values of 106.0±2 μg/mL in HT-29 cells and 175.3±4 μg/mL in Caco-2 cells after 72 hours. None of the lovage extracts showed a significant cytotoxic effect on non-cancerous cells (3T3 cell line). Furthermore, the group treated with DELO showed a lower expression level of inflammatory genes and COX-2 protein compared to the control group. Notably, treatment with DELO resulted in an increase in Caspase-3 protein and BAX/Bcl-2 ratio in both HT-29 and Caco-2 cells. According to this study, DELO has the potential to act as an anti-inflammatory and anti-cancer agent. Further research on the compounds present in DELO and their effect on various signaling pathways could help in the development of new drugs for diseases where inflammation or cells escape from apoptosis play a crucial role.

Abstract 3205: MicroRNA-peptide polyelectrolyte complex nanoparticle-hydrogel composite attenuates mesothelioma growth

Abstract Diffuse pleural mesothelioma (DPM) is a biologically unusual, aggressive asbestos-associated cancer affecting the entire pleura surface. DPM defies current standard multimodal therapies due to intrinsic chemoresistance and inability to achieve negative-margin resection of complex surface anatomy. Hence, current non-specific drug regimens ultimately fail because the biology of this tumor is poorly understood and even if surgically resected, tumor inevitably recurs from residual microscopic tumor foci. These various clinical challenges led us to develop a therapeutic platform delivering microRNA (miRNA), a novel anti-cancer agent therapeutic regimen, with the goal of eradicating residual microscopic tumor foci thereby improving the efficacy of multimodal therapy. We engineered a peptide-based biodegradable hydrogel that can be injected or sprayed directly to coat anatomic surfaces (surface-fill hydrogel; SFH), functioning as a therapeutic depot. Properties of SFH allow us to specify critical composition parameters such as biopersistence time, therapeutic payload, cell-specific targeting etc. In the first step of SFH formulation, miRNA complexed with different amphiphilic cationic peptides varying in length (19-26 amino acids) and amines (9-17), to form stable nanoparticles. Flash nanocomplexation (FNC) were used to produce highly scalable and kinetically controlled assembly of miRNA-peptide polyelectrolyte complex (PEC) nanoparticles (NPs), which utilizes a confined impinging jet (CIJ) mixer to achieve turbulent micromixing of the NPs components, yielding highly uniform and stable NPs. Next, NPs were encapsulated into another peptide hydrogel, formed via self-assembly of amphiphilic cationic peptide HLT2, thus forming a surface-fill hydrogel NPs composite. The SFH-NPs composite was not toxic to DPM cells and demonstrated efficient release of miRNA-peptide NPs from the SFH matrix in-vitro. The uptake of FAM-labeled miRNA-peptide NPs was confirmed by flowcytometry. Biodistribution analysis of NPs in mice bearing luciferase-positive DPM xenografts treated locally with Cy3-miRNA-SFH composite showed that Cy3-miRNA was concentrated in tumor cells but not in other organs. Furthermore, miR-215 exhibiting potent anti-tumor activity in DPM was used to study the therapeutic efficacy of SFH miRNA-nanoparticle composites. Subcutaneous DPM xenografts treated locally with miR-215 SFH composite shrank tumor significantly. Thus, delivery of specific miRNA-peptide PEC nanoparticles via SFH therapeutic platform in preclinical models of DPM displayed potent anti-cancer effects. Together, this new generation microRNA-peptide polyelectrolyte complex nanoparticles-SFH composite is a very promising delivery platform that could be extended for a diverse array of locoregional therapies. Citation Format: Anand Singh, Anderson Caleb, Joel P. Schneider, Chuong D. Hoang. MicroRNA-peptide polyelectrolyte complex nanoparticle-hydrogel composite attenuates mesothelioma growth [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 3205.

Abstract 4565: Reckless mitotic entry as a chemosensitization approach for alkylating agents

Abstract The cell cycle is tightly regulated by checkpoints, playing a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anti-cancer treatments, allowing for DNA repair prior to cell division. Therefore, manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies such as alkylating agents and radiation. In this study, we conducted a forward genome scale CRISPR/Cas9 chemogenomic screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. Our findings revealed that canonical DNA repair pathways, including ATM/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of the membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, known as Myt1 (encoded by PKMYT1), in ensuring cell survival. Analysis on patient cohort demonstrated that PKMYT1 is not only highly presented in malignancy, but also predisposes an unfavorable disease outcome. Genetic depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between TMZ and other clinically used alkylating agents, such as carmustine, busulfan, and dacarbazine, when combined with a novel Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage, as indicated by a substantial increase in γH2AX-positive cells in mitosis. Moreover, RP-6306 dramatically altered cell cycle timing, reducing the threshold time for mitotic entry. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities, including unaligned and partially condensed chromosomes, lagging chromosomes, chromosome bridges, and multipolar spindles. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Importantly, preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as an effective strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes. Citation Format: Fengchao Lang, James A. Cornwell, Karambir Kaur, Mirit I. Aladjem, Michael Aregger, Steven D. Cappell, Chunzhang Yang. Reckless mitotic entry as a chemosensitization approach for alkylating agents [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 4565.

Abstract 7129: DNA polymerase beta expression in head &amp; neck cancer modulates the poly-ADP-ribose-mediated replication checkpoint

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) impose a significant health burden, necessitating innovative therapeutic strategies to enhance treatment efficacy. Current standard treatments, including surgery, radiation therapy, and chemotherapy, often exhibit limited effectiveness and cause substantial side effects. This underscores the critical need for novel therapies that selectively target cancer cells, sparing normal tissue. Survival from HNSCC is poor, and importantly, a racial disparity between African Americans (AfAm) and European Americans (EuAm) has been known for some time. Ancestry Informative Markers (AIMs) are associated with altered mRNA expression of Polβ where higher expression of Polβ was observed among AfAm patients in comparison to EuAm patients. Our research focuses on DNA polymerase beta (Polβ) and its role in replication stress and response to chemotherapy and DNA damage response modifiers. Elevated expression of Polβ is linked to increased DNA damage and genomic instability, contributing to treatment resistance. In this regard, our investigations reveal a regulatory role for base excision repair (BER) proteins, including Polβ, in the cellular response to inhibitors of poly(ADP-ribose) glycohydrolase (PARG), an enzyme involved in poly(ADP-ribose) (PAR) degradation. Inhibition of PARG triggers a robust intra-S phase response, activating ATR and CHK1 signaling. Exploiting the synthetic lethality between PARG inhibition and ATR/CHK1 inhibition, we have demonstrated the ability to overcome Polβ overexpression mediated treatment resistance in HNSCC cells. Specifically, our in vitro studies demonstrate that the response to a combination of an ATR inhibitor and PARG inhibitor is impacted by Polβ expression in HNSCC cells, with synergistic effects surpassing the efficacy of the individual inhibitors. Similarly, the combination of a CHK1 inhibitor and PARG inhibitor proves effective in cells with elevated Polβ expression, offering a potential dual therapeutic strategy. These combinations exhibit promising potential for HNSCC treatment when Polβ expression is elevated. In conclusion, our findings propose a novel therapeutic paradigm for HNSCC, employing combination therapy with ATR or CHK1 inhibitors and PARG inhibitors. This approach offers a targeted strategy, presenting a promising avenue for the development of more effective and less toxic treatment modalities in the management of HNSCC and may help overcome resistance from elevated expression of Polβ. Citation Format: Md Maruf Khan, Anusha Angajala, Denise Y. Gibbs, Jeffrey C. Liu, Camille Ragin, Robert W. Sobol. DNA polymerase beta expression in head &amp; neck cancer modulates the poly-ADP-ribose-mediated replication checkpoint [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 7129.

Abstract 5471: Ribosome heterogeneity and RNA polI inhibition in osteosarcoma heterogeneity

Abstract Osteosarcoma is the most common primary bone tumour in adolescents and young adults, with an incidence rate of 3.8 per million. These tumors affect the long bones of the body such as femur. Current standard therapy includes tumour resection associated with multi-drug chemotherapy. The 5-year survival rate can reach 65% but is significantly reduced to 30% when pulmonary metastases are detected at the time of diagnosis. As this rate has not improved in the last 50 years, it is necessary to identify new therapeutic strategies. Inhibition of ribosomal biogenesis is one of the strategies developed in many cancer studies. This can be obtained by inhibition of RNA pol I, and in particular by BMH-21. The objective of this study was to analyze the complexity and heterogeneity of osteosarcomas through the ribosomal spectrum. The effect of BMH-1 on survival was also studied in osteosarcoma cell lines. The data obtained showed that there was no difference in ribosome protein composition in the “core” ribosome in different osteosarcoma cell lines. In addition, BMH-21 decreased cell viability in all osteosarcoma and chemoresistant cell lines. However, any activation of the apoptotic pathway by caspases was detected, nor any impact on the formation of new colonies after treatment with BMH-21. These results suggest a rather cytostatic mechanism. Moreover, a G0/G1 arrest in cell cycle was shown for U2OS cells. Finally, BMH-21 does not appear to have any impact on migration in HOS and U2OS cells. The different molecular mechanisms involved in the regulation of proliferation need to be further investigated. Citation Format: Marc Baud'huin, Elvina Colleville, Rose Anne Thepault, Emilien Orgebin, Francois Lamoureux, Benjamin Ory. Ribosome heterogeneity and RNA polI inhibition in osteosarcoma heterogeneity [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 5471.

Integrating and optimizing tonabersat in standard glioblastoma therapy: A preclinical study.

Glioblastoma (GB), a highly aggressive primary brain tumor, presents a poor prognosis despite the current standard therapy, including radiotherapy and temozolomide (TMZ) chemotherapy. Tumor microtubes involving connexin 43 (Cx43) contribute to glioma progression and therapy resistance, suggesting Cx43 inhibition as a potential treatment strategy. This research aims to explore the adjuvant potential of tonabersat, a Cx43 gap junction modulator and blood-brain barrier-penetrating compound, in combination with the standard of care for GB. In addition, different administration schedules and timings to optimize tonabersat's therapeutic window are investigated. The F98 Fischer rat model will be utilized to investigate tonabersat's impact in a clinically relevant setting, by incorporating fractionated radiotherapy (three fractions of 9 Gy) and TMZ chemotherapy (29 mg/kg). This study will evaluate tonabersat's impact on tumor growth, survival, and treatment response through advanced imaging (CE T1-w MRI) and histological analysis. Results show extended survival in rats receiving tonabersat with standard care, highlighting its adjuvant potential. Daily tonabersat administration, both preceding and following radiotherapy, emerges as a promising approach for maximizing survival outcomes. The study suggests tonabersat's potential to reduce tumor invasiveness, providing a new avenue for GB treatment. In conclusion, this preclinical investigation highlights tonabersat's potential as an effective adjuvant treatment for GB, and its established safety profile from clinical trials in migraine treatment presents a promising foundation for further exploration.

Abstract A006: Reckless mitotic entry as a novel chemosensitization approach for alkylating agents

Abstract The cell cycle is tightly regulated by checkpoints, playing a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anti-cancer treatments, allowing for DNA repair prior to cell division. Therefore, manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies such as alkylating agents and radiation. In this study, we conducted a forward genome wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. Our findings revealed that canonical DNA repair pathways, including ATM/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of the membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, known as Myt1 (encoded by PKMYT1), in ensuring cell survival. Depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between TMZ and other clinically used alkylating agents, such as carmustine, busulfan, and dacarbazine, when combined with a novel Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage, as indicated by a substantial increase in γH2AX-positive cells in mitosis. Moreover, RP-6306 dramatically altered cell cycle timing, reducing the threshold time for mitotic entry. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities, including unaligned and partially condensed chromosomes, lagging chromosomes, chromosome bridges, and multipolar spindles. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Importantly, preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as a novel strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes. Citation Format: Fengchao Lang, James Cornwell, Karambir Kaur, Omar Elmogazy, Wei Zhang, Meili Zhang, Hua Song, Zhonghe Sun, Xiaolin Wu, Mirit I. Aladjem, Michael Aregger, Steven Cappell, Chunzhang Yang. Reckless mitotic entry as a novel chemosensitization approach for alkylating agents [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A006.

A pilot trial of neoadjuvant pyrotinib plus trastuzumab, dalpiciclib, and letrozole for triple-positive breast cancer.

Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan-human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II-III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%-84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0-I was 75% (95% CI, 46.8%-91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%-98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5%-70.5%) at baseline to 17.2% (95% CI, 0.7%-33.7%) after neoadjuvant therapy (p=0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment-related deaths occurred. This four-drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.

Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets.

Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.

In Vitro Glioblastoma Model on a Plate for Localized Drug Release Study from a 3D-Printed Drug-Eluted Hydrogel Mesh.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that has limited treatment options. Current standard therapies, including surgery followed by radiotherapy and chemotherapy, are not very effective due to the rapid progression and recurrence of the tumor. Therefore, there is an urgent need for more effective treatments, such as combination therapy and localized drug delivery systems that can reduce systemic side effects. Recently, a handheld printer was developed that can deliver drugs directly to the tumor site. In this study, the feasibility of using this technology for localized co-delivery of temozolomide (TMZ) and deferiprone (DFP) to treat glioblastoma is showcased. A flexible drug-loaded mesh (GlioMesh) loaded with poly (lactic-co-glycolic acid) (PLGA) microparticles is printed, which shows the sustained release of both drugs for up to a month. The effectiveness of the printed drug-eluting mesh in terms of tumor toxicity and invasion inhibition is evaluated using a 3D micro-physiological system on a plate and the formation of GBM tumoroids within the microenvironment. The proposed in vitro model can identify the effective combination doses of TMZ and DFP in a sustained drug delivery platform. Additionally, our approach shows promise in GB therapy by enabling localized delivery of multiple drugs, preventing off-target cytotoxic effects.

Transcranial Magnetic Stimulation of Dorsolateral Prefrontal Cortex in Treatment-Resistant Obsessive Compulsive Disorder: A Mini-Review

Introduction: Approximately two-thirds of patients with Obsessive-Compulsive Disorder (OCD) exhibit inadequate responses to current standard therapies. A previous meta-analysis has shown the potential benefit of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) area in patients with OCD. However, the analysis also included patients who had not previously failed first-line treatments. This mini-review aims to explore the therapeutic effects of rTMS applied to the dlPFC area in patients with treatment-resistant OCD. Methods: We conducted a comprehensive search for randomized controlled trials (RCTs) and observational studies across various databases (PubMed, EMBASE, Ebsco, Web of Science, and Cochrane Central). Eligible studies encompassed rTMS administered to the dlPFC area in cases of treatment-resistant OCD. Studies that did not focus on using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to assess the efficacy of rTMS were excluded. Quality assessments were conducted based on the Cochrane risk-of-bias tool. Results: Our review identified five RCTs involving 132 patients that met the established criteria. The application of high-frequency (HF) and low-frequency (LF) rTMS to the dlPFC region yielded controversial post-treatment Y-BOCS findings due to factors such as small sample sizes, short-term study durations, variations in rTMS protocols, and four studies exhibiting a high risk of bias. Discussion: The available data is constrained by a scarcity of high-quality, large-scale trials with extended follow-up periods and optimized protocols. Further research is warranted to establish the efficacy of rTMS administered to the dlPFC in this patient population.

KRAS is a molecular determinant of platinum responsiveness in glioblastoma

BackgroundKRAS is the undisputed champion of oncogenes, and despite its prominent role in oncogenesis as mutated gene, KRAS mutation appears infrequent in gliomas. Nevertheless, gliomas are considered KRAS-driven cancers due to its essential role in mouse malignant gliomagenesis. Glioblastoma is the most lethal primary brain tumor, often associated with disturbed RAS signaling. For newly diagnosed GBM, the current standard therapy is alkylating agent chemotherapy combined with radiotherapy. Cisplatin is one of the most effective anticancer drugs and is used as a first-line treatment for a wide spectrum of solid tumors (including medulloblastoma and neuroblastoma) and many studies are currently focused on new delivery modalities of effective cisplatin in glioblastoma. Its mechanism of action is mainly based on DNA damage, inducing the formation of DNA adducts, triggering a series of signal-transduction pathways, leading to cell-cycle arrest, DNA repair and apoptosis.MethodsLong-term cultures of human glioblastoma, U87MG and U251MG, were either treated with cis-diamminedichloroplatinum (cisplatin, CDDP) and/or MEK-inhibitor PD98059. Cytotoxic responses were assessed by cell viability (MTT), protein expression (Western Blot), cell cycle (PI staining) and apoptosis (TUNEL) assays. Further, gain-of-function experiments were performed with cells over-expressing mutated hypervariable region (HVR) KRASG12V plasmids.ResultsHere, we studied platinum-based chemosensitivity of long-term cultures of human glioblastoma from the perspective of KRAS expression, by using CDDP and MEK-inhibitor. Endogenous high KRAS expression was assessed at transcriptional (qPCR) and translational levels (WB) in a panel of primary and long-term glioblastoma cultures. Firstly, we measured immediate cellular adjustment through direct regulation of protein concentration of K-Ras4B in response to cisplatin treatment. We found increased endogenous protein abundance and involvement of the effector pathway RAF/MEK/ERK mitogen-activated protein kinase (MAPK) cascade. Moreover, as many MEK inhibitors are currently being clinically evaluated for the treatment of high-grade glioma, so we concomitantly tested the effect of the potent and selective non-ATP-competitive MEK1/2 inhibitor (PD98059) on cisplatin-induced chemosensitivity in these cells. Cell-cycle phase distribution was examined using flow cytometry showing a significant cell-cycle arrest in both cultures at different percentage, which is modulated by MEK inhibition. Cisplatin-induced cytotoxicity increased sub-G1 percentage and modulates G2/M checkpoint regulators cyclins D1 and A. Moreover, ectopic expression of a constitutively active KRASG12V rescued CDDP-induced apoptosis and different HVR point mutations (particularly Ala 185) reverted this phenotype.ConclusionThese findings warrant further studies of clinical applications of MEK1/2 inhibitors and KRAS as ‘actionable target’ of cisplatin-based chemotherapy for glioblastoma.

Targeting ferroptosis opens new avenues in gliomas.

Gliomas are one of the most challenging tumors to treat due to their malignant phenotype, brain parenchymal infiltration, intratumoral heterogeneity, and immunosuppressive microenvironment, resulting in a high recurrence rate and dismal five-year survival rate. The current standard therapies, including maximum tumor resection, chemotherapy with temozolomide, and radiotherapy, have exhibited limited efficacy, which is caused partially by the resistance of tumor cell death. Recent studies have revealed that ferroptosis, a newly defined programmed cell death (PCD), plays a crucial role in the occurrence and progression of gliomas and significantly affects the efficacy of various treatments, representing a promising therapeutic strategy. In this review, we provide a comprehensive overview of the latest progress in ferroptosis, its involvement and regulation in the pathophysiological process of gliomas, various treatment hotspots, the existing obstacles, and future directions worth investigating. Our review sheds light on providing novel insights into manipulating ferroptosis to provide potential targets and strategies of glioma treatment.

Current status and future perspective of clinical trials for patients with multiple myeloma

There are two main types of clinical trials: industry-sponsored trials and investigator-initiated trials. Both of these, like the two sets of wheels on a car, are essential to development of treatments. Numerous clinical trials have been conducted in multiple myeloma, contributing to the development of new drugs and the current treatment landscape. Highly effective novel immunotherapies, such as bispecific antibodies and chimeric antigen receptor T-cell therapy, have emerged, and could be incorporated into the treatment landscape in the near future. However, given the improved performance of current standard therapies, the drawbacks (e.g., toxicity) of immunotherapy can be expected to outweigh the benefits (efficacy) in some patients. Therefore, clinical trials are designed to evaluate treatments stratified based on factors such as post-treatment efficacy and disease risk, and stratified treatment approaches are increasingly being considered as well as one-size-fits-all approaches to treatment development. In addition, the use of real-world data is being explored to make clinical trials more efficient. These approaches are expected to further improve the individualization and efficiency of multiple myeloma treatment.

The Regulation of FOXP3 Expression and Its Therapeutic Potential in Non-Small Lung Cancer

Non-small cell cancer (NSCLC) is today one of the most threatening malignant tumors, and it is still rarely cured by current standard therapies with a high mortality rate. The transcription factor Forkhead box p3 (FOXP3) is a potential molecular target for NSCLC since it has been identified with an oncogenic effect in the tumor microenvironment (TME). It is well known that FOXP3 expression could characterize the regulatory T cells (Treg), which plays a critical role in regulating anti-tumor immune responses in TME. Through analyzing the basic mechanisms of FOXP3 and Treg in distinct tumor tissues, they have been found with contradictory expression and the frequency in different TME. In NSCLC, the suppressive function of Treg to immune systems and frequency of FOXP3 is accumulated to promote the development of tumors. Most recently, accumulating evidence reveals the therapeutic potential of targeting FOXP3 and the related signaling pathways in the treatment of NSCLC patients. Although unsolved side effects and limitations that still must be considered when targeting FOXP3 and FOXP3-related proteins, there is no doubt that they are potential therapeutic applications for NSCLC treatment. The main objective of this review is to mention the structure, function and recent progress in treatment targeting FOXP3 and FOXP3-related signaling pathways, especially to therapies with immune checkpoint inhibitors.

AChE reactivation in precision-cut lung slices following organophosphorus compound poisoning

Precision-cut lung slices (PCLS) are a suitable model for analyzing the acetylcholinesterase (AChE) activity and subsequent effects after exposure to organophosphorus (OP) compounds. In this study, the AChE activity was determined in intact PCLS for the first time. Since the current standard therapy for OP poisoning (atropine + oxime + benzodiazepine) lacks efficiency, reliable models to study novel therapeutic substances are needed. Models should depict pathophysiological mechanisms and help to evaluate the beneficial effects of new therapeutics. Here PCLS were exposed to three organophosphorus nerve agents (OPNAs): sarin (GB), cyclosarin (GF), and VX. They were then treated with three reactivators: HI-6, obidoxime (OBI), and a non-oxime (NOX-6). The endpoints investigated in this study were the AChE activity and the airway area (AA) change. OPNA exposure led to very low residual AChE activities. Depending on the reactivator properties different AChE reactivation results were measured. GB-inhibited PCLS-AChE was reactivated best, followed by VX and GF. To substantiate these findings and to understand the connection between the molecular and the functional levels in a more profound way the results were correlated to the AA changes. These investigations underline the importance of reactivator use and point to the possibilities for future improvements in the treatment of OPNA-exposed victims.

Abrogation of the G2/M checkpoint as a chemosensitization approach for alkylating agents.

The cell cycle is tightly regulated by checkpoints, which play a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anticancer treatments, allowing for DNA repair prior to cell division. Manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies. In this study, we conducted a forward genome-wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. Our findings revealed that canonical DNA repair pathways, including the Ataxia-telangiectasia mutated (ATM)/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of PKMYT1, in ensuring cell survival. Depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between alkylating agents and a Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as an effective strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes.