Current Standard Chemotherapy Research Articles

DDDR-18. TARGETTING GLIOBLASTOMA MULTIFORME USING A MULTIACTION ANTICANCER ANTI-INFLAMMATORY THERAPEUTIC STRATEGY

Abstract Glioblastoma multiforme (GBM) represents a significant challenge in adult brain tumor management, characterized by its aggressive nature and poor prognosis despite multimodal therapies. Current standard chemotherapy, Temozolomide (TMZ), offers limited survival benefits. In a recent breakthrough, the cyclic peptide cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) acetate (c2), initially developed for prostate cancer, demonstrates remarkable promise against GBM. By selectively inhibiting the inflammatory phospholipase enzyme sPLA2IIA, c2 significantly impedes GBM cell proliferation, surpassing TMZ efficacy in multiple resistant cell lines. Moreover, c2 exhibits potential to inhibit tumor growth and metastasis, confirmed in 3D tumoroid and wound healing assays. Mechanistic insights reveal modulation of crucial cellular pathways, including viral entry, cytoskeletal structure, and signaling cascades. Preclinical investigations demonstrate c2’s ability to penetrate the blood-brain barrier and attenuate tumor progression markers. At multiple levels, c2 is shown to target inhibition of ERBB2 and EGFR signalling and also have impacts on HIF1-NF-kB axis. This study proposes c2 as a potent anti-GBM candidate, warranting evaluations for its pharmacological profile, safety, and efficacy. With its potential to address the urgent need for effective GBM therapies, c2 holds promise as a significant advancement in GBM treatment, offering hope for improved patient outcomes.

DDDR-16. SORTING TO ENRICH FOR CHEMOTHERAPEUTIC-RESISTANT GLIOMA CELLS BASED ON UNIQUE MEMBRANE PROPERTIES

Abstract Glioblastoma, astrocytoma, and oligodendroglioma comprise a class of aggressive and deadly brain tumors called diffuse gliomas. Around 20,000 glioma cases are diagnosed yearly in the US alone. The current standard chemotherapy treatment, temozolomide (TMZ), is insufficient as the 5-year survival rate of glioblastoma patients is as low as 8%. This is due to the presence of TMZ-resistant cells within tumors that lead to chemoresistance and tumor recurrence. Thus, studying the molecular properties of TMZ-resistant cells would enable more effective means of targeting them and thus improve patient outcomes. We leveraged dielectrophoresis (DEP), a phenomenon by which non-uniform electric fields induce differential movement of cells, as a novel label-free technique to sort glioma cells based on their membrane electrophysiological properties. We were able to successfully use DEP to sort cells from glioblastoma and oligodendroglioma established cell lines, which yielded fractions that differed in membrane capacitance, the membrane’s ability to store charge. Interestingly, the DEP-sorted cell fractions also exhibited significant differences in TMZ resistance, indicating that we were able to use DEP to enrich for TMZ-resistant cells. Further, the differences in TMZ resistance were coupled with their membrane capacitance differences. Because we previously found that changes in membrane capacitance were linked to differences in glycosylation, we utilized lectin analysis to assess glycan expression of DEP-sorted oligodendroglioma cells. Our data show that TMZ-resistant oligodendroglioma cells enriched from DEP sorting had reduced levels of mannose glycans compared to less TMZ-resistant fractions. Collectively, our novel findings demonstrate (a) TMZ-resistant glioma cells can be enriched by DEP, and (b) TMZ resistance is correlated with membrane capacitance and cell surface glycosylation. These findings could enable further characterization of TMZ-resistant cells to better understand molecular mechanisms of TMZ resistance and the development of more effective treatment strategies for gliomas through targeting membrane properties such as glycosylation.

Approaches in Adult Glioblastoma Treatment: A Systematic Review of Emerging Therapies.

Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults, characterized by complex genetic changes and a poor prognosis. Current standard therapies, including surgery, chemotherapy, and radiotherapy, have limited effectiveness. Emerging therapeutic strategies aim to address the high recurrence rate and improve outcomes by targeting glioblastoma stem cells (GSCs), the blood-brain barrier, and utilizing advanced drug delivery systems. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. An electronic search was conducted across several databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane, covering studies published from January 2019 to May 2024. The inclusion criteria encompassed primary research studies in English focusing on emerging therapies for treating GB in adults. Eligible studies included experimental and observational studies. Only peer-reviewed journal articles were considered. Exclusion criteria included non-human studies, pediatric studies, non-peer-reviewed articles, systematic reviews, case reports, conference abstracts, and editorials. The search identified 755 articles and, finally, 24 of them met the inclusion criteria. The key findings highlight various promising therapies. Despite advances in treatment approaches, the complexity and heterogeneity of GB necessitate ongoing research to optimize these innovative strategies. The study has limitations that should be considered. The inclusion of only English-language articles may introduce language bias, and the focus on peer-reviewed articles could exclude valuable data from non-peer-reviewed sources. Heterogeneity among studies, particularly in sample sizes and designs, complicates comparison and synthesis, while the reliance on preclinical models limits generalizability to clinical practice. Nonetheless, this review provides a comprehensive overview of the emerging therapies that hold promise for improving patient outcomes in GB treatment.

Long-term outcomes among survivors of childhood osteosarcoma: A report from the Childhood Cancer Survivor Study (CCSS).

Treatment strategies for osteosarcoma evolving between 1970 and 1999 improved 5-year survival and continue as standard of care today. This report evaluates the impact of these evolving therapies on long-term health outcomes. Five-year survivors of childhood osteosarcoma in CCSS treated from 1970 to 1999 were evaluated for late (>5years from diagnosis) mortality, chronic health conditions (CHCs), and health status using piecewise-exponential and logistical models. Comparisons were made between survivors and siblings without cancer, and among survivors examining historical and current standard chemotherapies (e.g., methotrexate/doxorubicin/cisplatin [MAP] vs. others), specific chemotherapy agents and surgical approaches (amputation vs. limb salvage [LS]). Models were evaluated adjusting for attained age, sex, race, ethnicity, and age at diagnosis. A total of 1257 survivors of osteosarcoma were followed on average for 24.4years. Twenty-year all-cause late mortality was 13.3% (95% confidence interval [CI]: 11.7%-14.9%) overall and 11.7% (95% CI: 6.9%-16.5%) for the subset treated with MAP plus LS. Survivors were at higher risk of CHCs (rate ratio [RR] 3.7, 95% CI: 3.2-4.3) than the sibling cohort, most notably having more serious cardiac, musculoskeletal, and hearing CHCs. Within the survivor cohort, the risk of severe CHCs was twice as high with MAP versus no chemotherapy (RR 2.1, 95% CI: 1.3-3.4). Compared with primary amputation, serious musculoskeletal CHCs were higher after LS (RR 6.6, 95% CI: 3.6-13.4), without discernable differences in health status. Contemporary osteosarcoma therapy with MAP plus LS, while improving 5-year disease-free survival, continues to be associated with a high burden of late mortality, CHCs, and health status limitations.

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell–mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Abstract 7129: DNA polymerase beta expression in head & 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 & 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.

A global phase II randomized trial comparing oral taxane ModraDoc006/r to intravenous docetaxel in metastatic castration resistant prostate cancer

Study aimModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450–3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone. Methods103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1.1 and PCWG3 guidelines were randomized 1:1 into two cohorts. In Cohort 1, 49 patients received docetaxel 75 mg/m2 i.v. every 3 weeks (Q3W). In Cohort 2, 52 patients received ModraDoc006/r; 21 patients with a starting dose of ModraDoc006 30 mg with ritonavir 200 mg in the morning and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30–20/200–100 mg) bi-daily-once-weekly (BIDW) on Days 1, 8, and 15 of a 21-day cycle. To alleviate tolerability, the starting dose was amended to ModraDoc006/r 20–20/200–100 mg in another 31 patients. All patients received prednisone 10 mg daily. Primary endpoint was rPFS. ResultsThere was no significant difference in rPFS between the 2 arms (p = 0.1465). Median rPFS was 9.5 months and 11.1 months (95% CI) for ModraDoc006/r and i.v. docetaxel, respectively. Partial response was noted in 44.1% and 38.7% measurable disease patients, and 50% decline of PSA was seen in 23 (50%) and 26 (56.5%) evaluable cases treated with ModraDoc006/r and i.v. docetaxel, respectively. The safety profile of ModraDoc006/r 20–20/200–100 mg dose was significantly better than i.v. docetaxel, with mild (mostly Grade 1) gastrointestinal toxicities, no hematologic adverse events, and neuropathy and alopecia incidence of 11.5% and 25%, respectively. ConclusionsModraDoc006/r potentially represents a widely applicable, convenient, effective, and better tolerated oral taxane therapy option for mCRPC. Further investigation of ModraDoc006/r in a large randomized trial is warranted.

IPIAD- an augmentation regimen added to standard treatment of pancreatic ductal adenocarcinoma using already-marketed repurposed drugs irbesartan, pyrimethamine, itraconazole, azithromycin, and dapsone.

This short note presents the data and rationale for adding five generic non-oncology drugs from general medical practice to gemcitabine, nab-paclitaxel, a current standard cytotoxic chemotherapy of pancreatic ductal adenocarcinoma. The regimen, called IPIAD, uses an angiotensin receptor blocker (ARB) irbesartan indicated for treating hypertension, an old antimicrobial drug pyrimethamine indicated for treating toxoplasmosis or malaria, an old antifungal drug itraconazole, an old broad spectrum antibiotic azithromycin and an old antibiotic dapsone. In reviewing selected growth driving systems active in pancreatic ductal adenocarcinoma then comparing these with detailed data on ancillary attributes of the IPIAD drugs, one can predict clinical benefit and slowing growth of pancreatic ductal adenocarcinoma by this augmentation regimen.

A phase II trial of CapeOX plus nivolumab for early relapsed HER2-negative gastric cancer (JACCRO GC-11: FirSTAR trial).

TPS423 Background: Fluoropyrimidine-based post-operative chemotherapy is one of the standard adjuvant therapies for curatively resected gastric cancer (GC).1,2 The current standard first-line chemotherapy consists of fluoropyrimidine and oxaliplatin combined with nivolumab in advanced HER2-negative GC patients including cases with a recurrence > 6 months after completion of post-operative chemotherapy, based on the CheckMate 649 and ATTRACTION-4 trials. However, in GC patients with early recurrence during or ≤ 6 months after completion of post-operative 5-FU based chemotherapy, optimal treatments remain to be established. A previous phase II study showed that capecitabine plus cisplatin is an active regimen for early relapsed GC after post-operative S-1 monotherapy.3 This trial aims to investigate the efficacy of capecitabine plus oxaliplatin (CapeOX) plus nivolumab for patients with early relapsed HER2-negative GC. Methods: This is a multicenter single-arm phase II trial. The main eligibility criteria include: histologically confirmed HER2-negative adenocarcinoma of stomach or esophagogastric junction; radiologically diagnosed recurrence during or ≤ 6 months after post-operative chemotherapy with S-1 or S-1 plus docetaxel conducted for stage II/III GC after curative resection; age ≥ 18 years; ECOG performance status 0-1; having measurable lesions according to RECIST ver. 1.1; and adequate oral intake and organ functions. Enrolled patients will receive 21-day cycles of nivolumab with CapeOX at the following dose until disease progression or unacceptable toxicities: capecitabine, 1000 mg/m2 twice per day on day 1-14; oxaliplatin, 130 mg/m2 on day 1; and nivolumab, 360 mg on day 1. The primary endpoint is objective response rate (ORR), and the secondary endpoints include overall survival, progression-free survival, disease control rate, duration of response, and safety. PD-L1 combined positive score will be tested for the association with efficacy. We assume null ORR of 20% and alternative ORR of 32%. With two-sided alpha level of 10% and 80% power, sample size would be calculated as 85. Thus, a total of 92 patients are planned for enrollment within a 2.5-year accrual period. Enrollment opened in March 2023. Clinical trial information: jRCTs031220572. 1. N Engl J Med. 2007;357:1810-20. 2. J Clin Oncol. 2019;37:1296-1304. 3. Gastric Cancer. 2018;21:811-8. Clinical trial information: jRCTs031220572 .

Decoding the secrets of small extracellular vesicle communications: exploring the inhibition of vesicle-associated pathways and interception strategies for cancer treatment.

Cancer disease is the second leading cause of death worldwide. In 2023, about 2 million new cancer cases and 609,820 cancer deaths are projected to occur in the United States. The driving forces of cancer progression and metastasis are widely varied and comprise multifactorial events. Although there is significant success in treating cancer, patients still present with tumors at advanced stages. Therefore, the discovery of novel oncologic pathways has been widely developed. Tumor cells communicate with each other through small extracellular vesicles (sEVs), which contribute to tumor-stromal interaction and promote tumor growth and metastasis. sEV-specific inhibitors are being investigated as a next-generation cancer therapy. A literature search was conducted to discuss different options for targeting sEV pathways in cancer cells. However, there are some challenges that need to be addressed in targeting sEVs: i) specificity and toxicity of sEV inhibitor, ii) targeted delivery of sEV inhibitors, iii) combination of sEV inhibitors with current standard chemotherapy to improve patients' clinical outcomes, and iv) data reproducibility and applicability at distinct levels of the disease. Despite these challenges, sEV inhibitors have immense potential for effectively treating cancer patients.

Targeting CDK8/CDK19 to Disrupt Leukemic Stem Cell-like Population in Acute Myeloid Leukemia: Exploring RVU120 As a Promising Frontline Therapy

Leukemic stem cells (LSCs) are implicated in the initiation, maintenance, and relapse of leukemia. The failure of current standard induction chemotherapy, which primarily targets dividing cells, has been linked to the quiescence of LSCs, leading to resistance to treatment. Consequently, there is an urgent need for novel therapies specifically aimed at eradicating LSCs to achieve more effective and durable treatment responses. CDK8 and its paralog CDK19 associate with the mediator complex and regulate gene expression programs linked to cancer and stem cell pluripotency. RVU120, a highly selective and potent CDK8/19 inhibitor, is currently undergoing clinical trials for AML and high-risk myelodysplastic syndrome (HR-MDS) (NCT04021368). Previous studies have demonstrated its potential mechanism of action on LSCs, wherein inhibition of CDK8/CDK19 led to the activation of lineage commitment genes in sensitive AML cells. Through recent gene expression analysis, it was discovered that inhibition of CDK8/CDK19 in transformed CD34+ cord blood cells resulted in the downregulation of stemness and quiescence-associated genes, while simultaneously upregulating genes associated with hematopoietic lineage-committed progenitors. Building on these findings, this study further investigates the potential of CDK8/CDK19 inhibition as a means to target LSCs, providing a rationale for RVU120 as a frontline treatment option in AML. The impact of RVU120 on LSCs has been investigated using an in vitro hierarchical AML-8227 model. This primary model maintains distinct populations in culture conditions, including CD34+CD38- cells with quiescent LSC potential, CD34+CD38+ cells enriched in progenitors, and CD34- more mature blasts (Lechman et al., 2016, Cancer Cell). The CD34+CD38- LSC population was further characterized by flow cytometry showing the expression of LSC surface markers, namely CD45RA, CD123, CD44, and negative expression for CD90, rendering it a suitable model for mechanistic studies. Next, AML-8227 cells were subjected to RVU120 treatment, resulting in a noticeable reduction in cell proliferation and viability. Flow cytometric analysis demonstrated a significant decrease in the percentage and total cell number of LSC-enriched/progenitor populations within the AML hierarchical model upon inhibition of CDK8/CDK19. Furthermore, RVU120 treatment induced the differentiation of cells, as evidenced by a sequential increase in the percentage of early myeloid differentiation marker, CD64, and late myeloid differentiation marker, CD14 (Fig. 1). In order to deconvolute the activity and mechanism of action of RVU120 in different cell populations, single-cell RNAseq analysis on AML-8227 cells has been performed at 24h and 3 days of treatment using technology from 10xGenomics. Additionally, analyzed AML-8227 cells have been enriched in the CD34+ population to evaluate the effect of RVU120 on stem and progenitor fraction at the single-cell level. The bioinformatic analysis of the performed experiment is ongoing and its results will be integrated into the data described above. CDK8 activity can be conveniently tracked by measuring specific phosphorylation of its target S726 on STAT5 protein. Dose and exposure-dependent inhibition of this marker has been established in cells exposed to RVU120. Levels of STAT5 S726 have been measured in different cell populations in patients from the first-in-human study of RVU120 in AML/HR-MDS. Consistent with established roles of CDK8 in LSCs, significantly elevated levels of pSTAT5 were observed in CD34+ stem/progenitor-enriched population when compared to CD34- blast cells measured at baseline before the start of the treatment (p<0.0001; ratio paired t-test; updated data from ASH 2022; Fig. 2). In summary, RVU120 displays cytotoxic and differentiating effects on well-characterized LSC populations in various models. Additionally, the CDK8 activity marker is directly associated with LSC-enriched bone marrow cells in AML patients, highlighting RVU120's potential as a promising therapeutic for targeting AML LSCs. Moreover, single-cell studies offer insights into its inhibitory effects on LSC-enriched populations and capacity for inducing differentiation. Overall, these results support RVU120 as a frontline candidate in AML therapy, countering therapeutic failure caused by persistent LSCs.

Metronomic and single high-dose paclitaxel treatments produce distinct heterogenous chemoresistant cancer cell populations

More than 75% of epithelial ovarian cancer (EOC) patients experience disease recurrence after initial treatment, highlighting our incomplete understanding of how chemoresistant populations evolve over the course of EOC progression post chemotherapy treatment. Here, we show how two paclitaxel (PTX) treatment methods- a single high dose and a weekly metronomic dose for four weeks, generate unique chemoresistant populations. Using mechanically relevant alginate microspheres and a combination of transcript profiling and heterogeneity analyses, we found that these PTX-treatment regimens produce distinct and resilient subpopulations that differ in metabolic reprogramming signatures, acquisition of resistance to PTX and anoikis, and the enrichment for cancer stem cells (CSCs) and polyploid giant cancer cells (PGCCs) with the ability to replenish bulk populations. We investigated the longevity of these metabolic reprogramming events using untargeted metabolomics and found that metabolites associated with stemness and therapy-induced senescence were uniquely abundant in populations enriched for CSCs and PGCCs. Predictive network analysis revealed that antioxidative mechanisms were likely to be differentially active dependent on both time and exposure to PTX. Our results illustrate how current standard chemotherapies contribute to the development of chemoresistant EOC subpopulations by either selecting for intrinsically resistant subpopulations or promoting the evolution of resistance mechanisms. Additionally, our work describes the unique phenotypic signatures in each of these distinct resistant subpopulations and thus highlights potential vulnerabilities that can be exploited for more effective treatment.

Review of Current Systemic Therapy and Novel Systemic Therapy for Pancreatic Ductal Adenocarcinoma.

This review aims to describe the systemic treatment options for pancreatic ductal adenocarcinoma and includes a summary of the current treatments as well as the ongoing clinical trials which may be efficacious in the treatment of this aggressive malignancy. A literature review was performed using MEDLINE/PubMed between August 1996 and February 2023. The reviewed studies are categorized into these categories: current standard of care treatments, targeted therapies, immunotherapy and clinical trials. The current treatment modality for the treatment of advanced pancreatic cancer is mainly systemic chemotherapy. The introduction of polychemotherapy regimens including gemcitabine/nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, folinic acid and fluorouracil) has improved the clinical outcome of advanced pancreatic cancer. For further improvement in clinical outcomes, several novel approaches have been extensively studied in pancreatic cancer. The review discusses the current standard chemotherapy regimen and the novel treatment options in the field. While there are novel treatments being explored for metastatic pancreatic, it remains a debilitating and aggressive disease with high mortality that warrants continued efforts to advance therapeutic options.

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis

BackgroundChemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance.MethodsWe established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism.ResultsHigh-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy.ConclusionsIrbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

BRAF Landscape and Its Implications among Patients with Pediatric Low-Grade Gliomas: A Comprehensive Review of the Literature

AbstractLow-grade gliomas are the most common intracranial tumor in the pediatric population. Pediatric low-grade gliomas represent a heterogeneous group of tumors. Genetic alterations that result in upregulation of the MAPK/ERK pathway represent most of the genetic landscape of pediatric low-grade gliomas. BRAF-V600E mutant pediatric low-grade gliomas may represent a unique and aggressive subset of tumors that require targeted therapy especially if gross total resection is not feasible. Many patients with pediatric low-grade gliomas have demonstrated successful clinical and radiological responses to BRAF and/or MEK inhibitors. Given the high proportion of patients who fail to respond to the current standard chemotherapy and radiotherapy, these targeted therapies should be considered in future trials and further investigations. In this review of the literature, we summarize the molecular status of BRAF alterations among patients with pediatric low-grade gliomas and provide an update on previous and current BRAF and MEK inhibitors clinical trials.

Therapy of BRCA-associated metastatic breast cancer. Efficacy and safety of talazoparib in the real-world clinical practice

Introduction. PARP inhibitors demonstrated high efficacy in BRCA1/2-associated Her2-negative metastatic breast cancer (BC). They were included in the current standard chemotherapy regimen and recognized as a priority option for the treatment of such tumours following the results of clinical studies.Aim. Review the experience with talazoparib (Talzenna) in the real-world clinical practice of 6 medical centers in Russia.Materials and methods. The review included data from 29 patients with HER2-negative metastatic breast cancer associated with a gBRCA mutation, who have been receiving talazoparib therapy in 6 medical centers of Russia since April 2021. Talazoparib was given at the standard dose 1 mg once daily, the dose was reduced, if any adverse event developed.Results. The median age of the patients was 50 years. 23 patients had a BRCA1 mutation, 5 patients had a BRCA2 mutation and one of the patients had a PALB2 mutation. Prior to starting talazoparib therapy, patients had received up to 9 lines of therapy for metastatic disease, the median was 1 line. The median follow-up period at that time was only 4.6 months. The median recurrence-free survival (RFS) was not reached. Progression was observed in 10 patients with a treatment period of 1 to 7.5 months, 19 patients continued to receive PARP inhibitor therapy without signs of disease progression, with a treatment period of 2 to 18 months. The objective response rate (ORR) was 57.2%, the clinical efficacy was confirmed in 85.7% of cases. The subgroup analysis showed that the lowest efficacy of therapy was reported in the group of patients, who had received prior therapy with platinum-based drugs, the median progression-free time (mPFT) was 4.5 months. (95% CI: 1.79-9.2). While for patients who had not received the prior platinum drug regimens, the median was not reached. Haematologic toxicities were common adverse events (AEs) for the talazoparib therapy, which were reported in 34.5% of cases. Transfusions of blood components were required in 3 patients, one of them required them repeatedly. All dose modifications were due to hematological toxicities. 7 patients (24.1%) required a dose reduction and 3 patients (10.3%) - repeated dose reduction.Conclusions. Testing for BRCA1/2 mutations in Her2-negative mBC should be a mandatory diagnostic procedure. Talazoparib therapy is an effective and safe treatment option for patients with gBRCAmut HER2-mBC.

PD-1 inhibitors plus nab-paclitaxel-containing chemotherapy for advanced gallbladder cancer in a second-line setting: A retrospective analysis of a case series.

Gallbladder cancer (GBC) is a fatal cancer, and the efficacy of the current standard second-line chemotherapy for GBC is limited. Novel therapies need to be explored. This retrospective analysis was aimed to investigate the outcomes of patients treated at West China Hospital with PD-1 inhibitors combined with nab-paclitaxel-based chemotherapy (nab-paclitaxel monotherapy or nab-paclitaxel plus other cytotoxic agents) in a second-line setting. Between April 2020 and May 2022, the patients with advanced GBC receiving PD-1 inhibitors combined with nab-paclitaxel-based chemotherapy after resistance to first-line gemcitabine-based chemotherapy at West China Hospital were retrospectively screened. Eleven patients were included, and all received gemcitabine-based chemotherapy as first-line therapy. Eight patients underwent next-generation sequencing (NGS), and all had microsatellite stability (MSS) and a low tumor mutation burden (TMB). Six patients were negative for PD-L1 expression and one patient was positive for PD-L1. Therapeutically relevant genetic alterations were not found. All patients received PD-1 inhibitors in combination with nab-paclitaxel-based chemotherapy as second-line therapy. Pembrolizumab was administered in 3 patients, and sintilimab was administered in eight patients. One patient had no measurable target lesion. Complete response (CR) was observed in one (10.0%) patient, partial response (PR) in four (40%) patients, and stable disease (SD) in four (40%) patients. The median progression-free survival (PFS) was 7.5 (95% CI: 2.5-12.5) months, and the median overall survival (OS) was 12.7 (95% CI: 5.5-19.9) months. The adverse events (AEs) were manageable. Our results suggest that PD-1 inhibitors combined with nab-paclitaxel-based chemotherapy as second-line therapy for advanced GBC might be a potential treatment and deserves further evaluation.

Vitamin D increases the efficacy of cisplatin on bladder cancer cell lines.

1,25(OH)2D3(Calcitriol), which is a broad regulatory molecule, plays a role in changing the efficacy of chemotherapeutic drugs. Cisplatin is one of a current standard chemotherapy regimen for bladder cancer. Increasing the effectiveness of the treatment and reducing the side effects to chemotherapeutics are of great importance in bladder cancer. We aimed to investigate the effect of the combination of cisplatin and calcitriol in order to create a possible advantage in treatment of bladder cancer. T24, ECV-304 and HUVEC cell lines were treated with calcitriol and cisplatin individually and in combination. Dose determination and combination treatments of calcitriol and cisplatin were evaluated using the MTT assay for cytotoxicity analysis on the cells. Annexin V-PI staining method was used for apoptosis determination by flow cytometry. Also the P-gp expression levels were determined by flow cytometry. The combination treatment increased the anti-proliferative efficacy compared to the efficacy in cisplatin alone in T24 cells and reduced the cytotoxicity in the HUVEC healthy cells compared to cisplatin alone. Combination treatment achieved significantly higher apoptosis rate in T24 cells compared with the rates in treatment of cisplatin alone. However apoptosis decreased in HUVEC cell line. P-gp ratios were increased in HUVEC and decreased in T24 cells with combination treatment compared to the numbers in the control cells. The rate of apoptosis and P-gp levels showed no significant change in ECV-304 cells. Our study revealed that the combination of calcitriol and cisplatin allows the use of cisplatin at lower doses in T24 bladder cancer cell line.

Clinical Implications of BRCA Mutations in Advanced Biliary Tract Cancer

Introduction: Current standard chemotherapy for biliary tract cancer (BTC) has limited survival benefits, and the need for targeted therapies is increasing. This study investigated the genetic profiles and clinical implications of BRCA mutations in patients with advanced BTC. Methods: Targeted high-throughput sequencing was performed on samples obtained from 25 patients with advanced BTC who had received palliative first-line platinum-based chemotherapy. Results: Of the 25 patients, 16 (64.0%) were younger than 65 years of age and 16 (64.0%) were male. The BTC cases consisted of intrahepatic cholangiocarcinoma (9, 36.0%), extrahepatic cholangiocarcinoma (5, 20.0%), and gallbladder cancer (11, 44.0%). The median overall survival (OS) and progression-free survival (PFS) of all patients were 11.9 months (95% confidence interval [CI]: 9.2–14.6) and 5.6 months (95% CI: 3.8–7.3), respectively. Genomic alterations in TP53 (52.0%), BRCA (36.0%), ATM (32.0%), ERBB2 (24.0%), NOTCH1 (20.0%), and FGFR3 (20.0%) were frequently reported. TP53 and ATM mutations were associated with OS (TP53: hazard ratio [HR] 2.719, 95% CI: 1.074–6.881, p = 0.035; ATM: HR 2.780, 95% CI: 1.091–7.082, p = 0.032). Patients with BRCA mutations had a slightly improved PFS compared to those with intact BRCA (6.7 months [range, 2.7–10.7 months] vs. 5.3 months [range, 3.6–7.0 months], p = 0.090). However, there was no significant difference in OS between groups (BRCA mutant vs. intact: 10.6 months [range, 3.6–17.6 months] vs. 11.9 months [range, 7.5–16.3 months], p = 0.252). BRCA mutations were significantly associated with PFS in the multivariate analysis (HR 0.150, 95% CI: 0.034–0.655, p = 0.012). Conclusion: This study demonstrated that BRCA mutations might have a role as predictive biomarkers for palliative first-line platinum-based chemotherapy in patients with advanced BTC.

Prospective approaches to enhancing CAR T cell therapy for glioblastoma.

Glioblastoma (GBM) is the most common malignant brain tumor. The poor clinical outcome and overall ineffectiveness of current standard treatments, including surgery, chemotherapy, and radiation, highlight the urgent need for alternative tumor-specific therapies for GBM. Chimeric antigen receptor (CAR) T cell therapy is a revolutionary therapeutic strategy for hematological malignancies, but the optimal potency of CAR T cell therapy for solid tumors, especially GBM, has not been achieved. Although CAR T cell therapeutic strategies for GBM have been assessed in clinical trials, the current antitumor activity of CAR T cells remains insufficient. In this review, we present our perspective on genetically modifying CAR constructs, overcoming T cell dysfunctions, and developing additional treatments that can improve CAR T cell effectiveness, such as functionality, persistence, and infiltration into tumor sites. Effectively improved CAR T cells may offer patients with GBM new treatment opportunities, and this review is intended to provide a comprehensive overview for researchers to develop potent CAR T cells using genetic engineering or combinatorial preparations.