Tumor Reduction Research Articles

Case report of a dog treated with radioactive iodine (I131) and stereotactic body radiation therapy (SBRT) for metastatic ectopic thyroid carcinoma

BackgroundThyroid carcinoma is a rare malignancy in middle-aged to older, medium to large breed dogs. Most are carcinomas or adenocarcinomas and are often detected incidentally via palpation or advanced imaging, such as computed tomography. Up to 48% of dogs present with metastatic disease, primarily in lymph nodes and lungs. Preferred treatment is thyroidectomy, but many dogs are poor candidates due to tumour immobility and metastasis. Stereotactic body radiation therapy and radioactive iodine (I131) are emerging treatments with promising outcomes in these cases. This report describes a dog with metastatic ectopic thyroid carcinoma treated with both SBRT and I131.Case presentationThis case describes a 10-year-old Jack Russell Terrier mix presenting with an ectopic thyroid carcinoma at the heart base and pericardial effusion. Initial treatment involved stereotactic body radiation therapy in three fractions totalling 21 Gy. Seven weeks later, with persistent tumour-related signs, a subcutaneous injection of 1600 MBq of I131 was administered. The dog clinically improved, while showing initial tumour reduction on cardiac ultrasound and thoracic radiographs. 37 months later, the dog presented again with recurrent pericardial effusion. Thoracic radiographs and ultrasound revealed metastatic nodules and increased size of the primary heart-based mass, indicating disease progression. A second dose of I131 (1600 MBq) was administered, but restrictive pericarditis and effusion necessitated a subtotal pericardectomy. Nine months after the second I131 treatment, the dog presented with similar signs and further disease progression evident on imaging including pleural effusion. Though treatment options, including a third I131 dose and a second SBRT course, were discussed, the owners chose to humanely euthanise the dog.ConclusionsThis case highlights an unusually prolonged survival in a dog with metastatic ectopic thyroid carcinoma, suggesting the potential for extended disease control with multimodal external beam radiation and I131 therapies.

Development of an efficient NUPR1 inhibitor with anticancer activity

Pancreatic cancer is highly lethal and has limited treatment options available. Our team had previously developed ZZW-115, a promising drug candidate that targets the nuclear protein 1 (NUPR1), which is involved in pancreatic cancer development and progression. However, clinical translation of ZZW-115 was hindered due to potential cardiotoxicity caused by its interaction with the human Ether-à-go-go-Related Gene (hERG) potassium channel. To address this, we have performed a high-throughput screening of 10,000 compounds from the HitFinder Chemical Library, and identified AJO14 as a lead compound that binds to NUPR1, without having favorable affinity towards hERG. AJO14 induced cell death through apoptosis, necroptosis, and parthanatos (induced by the poly-ADP ribose polymerase (PARP) overactivation), driven by mitochondrial catastrophe and decreased ATP production. This process seemed to be mediated by the hyperPARylation (an excessive modification of proteins by PARP, leading to cellular dysfunction), as it could be reversed by Olaparib, a PARP inhibitor. In xenografted mice, AJO14 demonstrated a dose-dependent tumor reduction activity. Furthermore, we attempted to improve the anti-cancer properties of AJO14 by molecular modification of the lead compound. Among the 51 candidates obtained and tested, 8 compounds exhibited a significant increase in efficacy and have been retained for further studies, especially LZX-2-73. These AJO14-derived compounds offer potent NUPR1 inhibition for pancreatic cancer treatment, without cardiotoxicity concerns.

Special immune-related adverse events and subsequent photodynamic therapy in tislelizumab treatment for esophageal cancer: a case report

This case report highlights the immune-related adverse events (irAEs) that occurred during the treatment of esophageal cancer with Tislelizumab and discusses management strategies, indicating that photodynamic therapy (PDT) may be an optimal adjunctive treatment option. Following Tislelizumab therapy, the patient demonstrated significant tumor reduction; however, subsequent irAEs related to immunotherapy emerged, including eyelid muscle weakness and myocardial and skeletal muscle injury. Methylprednisolone successfully alleviated these symptoms, with early intervention being crucial for controlling irAEs. The patient then underwent PDT, which not only further helped manage irAEs but also inhibited tumor progression. This case underscores the specific adverse reactions, such as eyelid ptosis, skeletal muscle, and myocardial damage associated with Tislelizumab, and the importance of early corticosteroid intervention. It also emphasizes the significance of PDT as an adjunctive treatment for controlling tumors and alleviating immune-related adverse reactions.

Gamma Knife Radiosurgery for symptomatic eloquently deep-seated cystic pilocytic astrocytoma mural nodules: Retrospective case series of effective outcomes.

Although most pilocytic astrocytomas grow slowly, their progression in critical sites such as the brainstem or hypothalamus may prove fatal much more rapidly. Cystic progression may be more problematic than solid tumor. Patients with progressive cystic PAs located in eloquent deep areas of the brain are the best candidates for stereotactic radiosurgery. This retrospective case series aims to present the effective outcomes obtained from GKRS, targeting the mural nodules of symptomatic eloquently deep-seated cystic PAs in 9 consecutive patients treated at the IMC Gamma Knife Centre in Cairo, Egypt, between 2003 and 2021. The median follow-up period was 84months (range 24-240months). The median treated mural nodule volume was 1.25 cm3 (range 0.32-1.97 cm3), treated with a median peripheral prescription dose of 12Gy and a median maximum dose of 24Gy. The median cyst volume in treated patients was 7.64cm3(range 1.66-40.6cm3). At the last follow-up, 7 out of 9 patients (78%) achieved tumor control (marked reduction > 50% of the entire tumor volume in 6 patients and moderate tumor reduction < 50% in one patient) in addition to clinical improvement. The median time of confirmed tumor reduction was 18months (range 12-32months). Two patients reported progression of the treated tumor. The overall tumor control rates at 2, 5, and 7years of follow-up were 88.9%, 78%, and 78%, respectively. The encouraging results of this series indicate that limiting the GKRS to the mural nodule of eloquently deep-seated cystic PAs may be a practical and effective pattern in the salvage of its treatment. Our data do not support radiation for extensive, large symptomatic cysts in deep-seated cystic PA or patients where microsurgical removal is feasible.

Modeling the acute mucosal toxicity to fractionated radiotherapy combined with the ATM inhibitor WSD0628.

ATM inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk for normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of FVB mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose-escalation to maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose-volume limits for organs at risk.

Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens

Abstract Background Diffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach. Methods We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy. Results We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction. Conclusion Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.

Phase I clinical study of a multi-kinase inhibitor TG02 capsule for the treatment of recurrent high-grade gliomas with failed temozolomide treatment in Chinese patients

Introduction: Here, we report the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of a multi-kinase inhibitor (TG02 capsule) as a new therapy for patients with recurrent high-grade gliomas in China. Methods: This is a single-center, dose-escalation, open-label phase I study, which enrolled patients with recurrent high-grade gliomas who failed to temozolomide. Patients were assigned sequentially into different dose groups and received TG02 every 4 weeks. The dose was increased in a traditional 3+3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twelve patients (8 glioblastomas, 4 diffuse astrocytoma) were enrolled between May 2019 and November 2021. Three patients received 100 mg and 9 received 150 mg TG02 twice a week. The plasma concentration of TG02 reached the maximum at 2 hours after administration, and the elimination half-life was about 7 hours. No DLT occurred and MTD was not defined in this study. Eleven patients had one or more investigator-assessed treatment-related adverse events (TRAEs). The most frequent TRAEs were vomiting (91.7%) and diarrhea (75.0%), and 50% of the patients had grade 3 or 4 adverse events. There were no treatment-related deaths. The median progression-free survival and overall survival were 1.77 (95% confidence interval [CI]: 0.82-4.24) and 9.63 (95%CI: 2.66-not estimated) months, respectively. Conclusions: TG02 capsule 150mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy for recurrent gliomas warrant further investigation.

Abstract I008: Antisense Oligonucleotides as Therapeutics for Difficult-to-Drug Targets in Oncology

Abstract Many potential oncology targets are difficult to modulate by conventional classes of agents. Interfering with these targets at the level of RNA is a novel approach for difficult-to target proteins, as well as for non-coding RNAs, emerging targets that are part of the “dark matter’ of the genome. Antisense oligonucleotide (ASO) therapeutics are short sequences of 12- 30 DNA/RNA residues, designed to bind the cognate transcribed RNA. The ASO is chemically modified to increase stability, improve binding affinity, optimize pharmacokinetic properties and reduce immunostimulatory potential. The hybridization of ASO to cognate RNA results in cleavage of bound RNA by RNAse H1 and subsequent degradation. Several ASOs are marketed for treatment of rare diseases, but to date none have been approved for oncology indications. The long-noncoding RNA (lncRNA) MALAT1 is an example of an oncology target uniquely suited for an ASO therapeutic. This lncRNA is not translated and resides mostly in the nucleus, limiting access for most therapeutic approaches. MALAT1 is highly upregulated in various cancers, appears to play a role in epithelial to mesenchymal transition, and is associated with disease progression in patients. Inhibition of MALAT1 in preclinical breast cancer models, either genetic or pharmacologic using a murine ASO, leads to changes in tumor architecture and reduction in metastasis. FLM-7523 is a 16-mer ASO designed to bind to human MALAT1. It is a generation 2.5 design based on the constrained ethyl (cEt) modification to the 3 residues on the 3’ and 5’ ends of the ASO, and administered in a saline solution without any delivery vehicle. Preclinical studies have shown that FLM-7523 effectively inhibits MALAT1 expression in in vitro and in vivo models, and GLP toxicology studies have been completed to support a First-in-Human clinical trial. The signal transduction molecule STAT3 is another oncology target of interest that has, to date, been difficult to modulate. Danvatirsen is a 16-mer generation 2.5 ASO targeting human STAT3 mRNA and is currently in clinical trials. Preclinical in vivo studies in murine tumor models have demonstrated a reduction in STAT3 mRNA and protein following treatment with a STAT3 targeting ASO, along with tumor growth inhibition. Combination treatments with immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1, demonstrate improved tumor growth inhibition relative to monotherapy. In clinical trials, tumor uptake of danvatirsen is observed in post-treatment biopsies, with corresponding reduction in STAT3 protein. Danvatirsen is generally well tolerated with the most common adverse events being increased liver function tests and decreased myeloid hematologic parameters, both of which are easily monitored, manageable, and reversible. Clinical responses have been observed with the most robust being in combination with a PD-L1 inhibitor in recurrent/metastatic head and neck squamous cell carcinoma. In conclusion, ASOs are novel therapies that can inhibit oncology targets not tractable by traditional approaches. Citation Format: Andrew Denker. Antisense Oligonucleotides as Therapeutics for Difficult-to-Drug Targets in Oncology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I008.

Transarterial Chemoembolization in Locally Advanced Rectal Cancer: A Systematic Review

Background: Locally advanced rectal cancer (LARC) presents a significant treatment challenge. Transarterial chemoembolization (TACE) has emerged as a potential adjunctive treatment, offering targeted delivery of chemotherapeutic agents to the tumor site, minimizing systemic exposure. This systematic review aims to assess the current literature on this novel technique and evaluate the safety and efficacy profile of TACE in treating this complex cohort of patients. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, EMBASE, and Cochrane Library, to identify studies evaluating TACE in LARC. Inclusion criteria encompassed clinical trials, cohort studies, and case series reporting on outcomes such as tumor response rate, overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. Results: A total of eight studies involving 543 patients met the inclusion criteria. The studies varied in design, with five prospective and three retrospective studies. A higher prevalence of male participants (68.7%) was noted, with a median age of 60.3 years. The studies primarily evaluated the efficacy and safety of TACE in LARC treatment. Pathological response rates, tumor reduction, and survival outcomes varied across studies, with TACE showing promise in reducing tumor size, improving survival, and controlling metastasis. Major complications were rare, reported in 6.0% of cases. Conclusions: TACE is a promising therapeutic option for patients with LARC, demonstrating favorable tumor response rates and manageable toxicity profiles. Further large-scale, randomized controlled trials are warranted to confirm these findings and better define the role of TACE in the multimodal treatment of LARC.

BIOM-15. METASTATIC BIFOCAL GERMINOMA: A CASE HIGHLIGHTING DRAMATIC EARLY RADIOLOGICAL RESPONSE TO STEROIDS AND REBOUND FOLLOWING DISCONTINUATION, AND THE UTILITY OF CIRCULATING MIR-371A-3P QUANTIFICATION AND VINBLASTINE MONOTHERAPY PRIOR TO DEFINITIVE CRANIOSPINAL IRRADIATION

Abstract BACKGROUND In Europe, bifocal germinoma is diagnosed based on typical age (&amp;gt;8-10y), symptoms (diabetes insipidus), radiological appearances, and serum/CSF AFP/HCG markers below thresholds. A 12yo male presented with 4-month headaches, 3-month polyuria/polydipsia, visual and somnolence/memory issues. Weight=71.1kg; height=166cm. MRI head/spine revealed hydrocephalus and 19×14×15mm (volume=2.09cm3) enhancing pineal lesion with nodular suprasellar and septum-pellucidum soft tissue. CSF positive for malignant cells. Serum/CSF AFP/HCG markers below thresholds. Metastatic bifocal germinoma diagnosed. Dexamethasone (8mg/day=4.4mg/m2/day) commenced for raised pressure. Proton referral (craniospinal-irradiation) made, but 8 weeks to expected start; hence, external-ventricular-drain (EVD) placed and weekly vinblastine commenced (PMIDs:32642701/34520101). METHODS Serum/CSF placental-alkaline-phosphatase (PLAP) and miR-371a-3p measured at diagnosis and CSF longitudinally. MRI performed at d9+d19 post-vinblastine. RESULTS. At diagnosis, CSF miR-371a-3p PCR positive (raw-Cq=18.64) (PMID:37386046); serum miR-371a-3p and serum/CSF PLAP all negative. In follow-up, CSF miR-371a-3p levels fell with weekly vinblastine, consistent with treatment response; PLAP remained non-informative. Repeat CSF cytology after two vinblastine doses was negative. D9 MRI showed reduction in tumour size/enhancement [pineal lesion 13×7×12mm (0.57cm3) from 19×14×15mm] and reduced ventricular size. Dexamethasone switched to maintenance-dose hydrocortisone (10mg+5mg+2.5mg=9.7mg/m2/day). D19 MRI, however, showed increased tumour volume again (pineal=17×10×14mm; 1.25cm3), albeit less than at diagnosis, with CSF miR-371a-3p down to raw-Cq=26.92 (&amp;gt;300-fold reduction from diagnosis). EVD removed and septostomy performed; biopsy confirmed germinoma only (&amp;lt;5% cells) with &amp;gt;95% inflammatory cells (lymphocytes/macrophages). Vinblastine continued until protons without further tumour-associated comorbidity; MRI pre-protons showed pineal 10×10×12mm (0.63cm3; partial-remission) and post-protons complete-remission. Conclusion. Early radiological response to dexamethasone, with rebound on maintenance hydrocortisone, presumably secondary to lymphocytic re-infiltration of tumour (PMID:18000859). Reassuringly, circulating miR-371a-3p was informative for germinoma diagnosis (confirmed by biopsy) and treatment response. Weekly vinblastine useful bridge to definitive radiotherapy, explored in upcoming MonoGerm trial.

CSIG-04. ANTI-TUMOR RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy. PURPOSE The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro. We studied the cellular and molecular effects of Oncomagnetic monotherapy (OMT) on GBM cell lines and investigated immune response in a syngeneic mouse model. RESULTS OMT significantly reduces cell proliferation and cell survival in vitro. OMT induces persistent ROS primarily by increasing superoxide level in cancer cells and reduces mitochondrial-membrane potential in GBM cells. It also induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body Oncomagnetic stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from OMT-treated GBM cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group. CONCLUSION The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for OMT stimulation and provide a strong rationale for standalone OMT for GBM.

RADT-33. GAMMA KNIFE RADIOSURGERY FOR ORBITAL CAVERNOUS HEMANGIOMA: A SYSTEMATIC REVIEW AND SINGLE-ARM META-ANALYSIS

Abstract Gamma knife radiosurgery (GKRS) for orbital cavernous hemangioma (OCH) has emerged as a promising method due to its significant clinical improvement and low incidence of complications. This study aimed to evaluate the safety and efficacy of GKRS for the treatment of OCH. Following the PRISMA framework, we searched PubMed, Cochrane Central, and Embase for studies reporting outcomes of GKRS for OCH, including complications, visual improvement, proptosis, tumor reduction rate, and tumor progression rate. From 1856 search results, six studies with 100 patients were included. Only five minor complications related to GKRS were reported, including three with orbital pain and two with periorbital chemosis, resulting in a complication rate of 13% (95% CI: 7% - 25%). Visual acuity and visual field improvement rates after GKRS were 80% (95% CI: 63% - 96%) and 71% (95% CI: 47% - 95%), respectively. Proptosis improved in 94% of cases (95% CI: 83% - 100%). The tumor reduction rate was 77% after GKRS (95% CI: 69% - 85%). In conclusion, GKRS for OCH appears to be a safe technique, as evidenced by the rate of clinical improvement and radiological improvement. However, studies are limited by the absence of a control group, and additional studies are needed to evaluate the relative efficacy of GKRS compared with alternative surgical modalities for OCH.

CTNI-17. A PHASE 2 STUDY OF SAFETY AND EFFICACY OF CONCURRENT ACT001 AND RADIATION TREATMENT FOLLOWED BY ACT001 MAINTENANCE THERAPY IN NEWLY DIAGNOSED PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting NF-κB and STAT3 pathways, has shown activity in preclinical DIPG model and dose-finding study in patients with diffuse midline glioma. We further evaluated safety and activity of ACT001 in newly diagnosed DIPG patients and presented the interim data from exploratory stage of this phase 2 study. METHODS Eligible patients ≥ 5 and ≤ 15 years old were treated with concurrent ACT001 and standard radiation followed by ACT001 single agent treatment in this single arm, open label, multicenter phase 2 study. Tumor lesions were evaluated at baseline, 4 weeks and then every 8 weeks after the end of radiation therapy per RAPNO criteria with ORR as primary endpoint. Interim data analysis was performed when data from approximately 20 efficacy evaluable patients became available during the exploratory stage of this study. RESULTS Among 30 patients enrolled since Sept, 2023, 27 took at least one dose of ACT001 by April 30th, 2024, the data cutoff date (with exception for May 15th as the MRI cutoff date). While 3 patients were quickly taken off study due to a disease progression or consent withdrawal, 17 out of 27 patients finished at least one post-radiation MRI exam whereas MRI results are pending for 7 other patients by this interim analysis. Median age was 8 years old and male to female patient ratio is 17:10. The median LPS score is 70.0. Among 17 efficacy evaluable subjects, 8 patients exhibited partial response (6 confirmed) including one with a deep tumor reduction (-91.7%) noted three months after end of radiation. Among 9 other evaluable patients, 5 and 4 exhibited ongoing stable disease and progressive disease respectively. Subject 05001 was considered PD despite confirmed objective response for the target lesion upon development of new lesions. Two patients withdrew consent after finishing first post-radiation MRI scans despite initial tumor burden reduction which were both close to PR criteria. Patients tolerated concurrent ACT001 and radiation well. In total, 289 TEAE and 184 TRAE events were reported in 23 and 22 patients respectively. There were two ACT001-related grade 3 or 4 adverse events including one grade 4 hemorrhagic tumor necrosis (a SUSAR event and the only ACT001 related SAE) likely due to a therapeutic effect of ACT001 and one clinically insignificant grade 3 decreased lymphocyte count. Most common TRAE were manageable grade 1 or 2 events such as weight loss (15/184), vomiting (71/184), decreased lymphocyte count (13/184) and abdominal bloating (7/184). No study discontinuation occurred due to ACT001 or radiation related TRAEs. Conclusion. Concurrent ACT001 and radiation treatment was well tolerated. Preliminary evidence of anti-tumor activity was shown in about 50% efficacy evaluable DIPG patients. It is worthwhile to explore ACT001 and temozolomide combination in future study based on safety and efficacy signal from DIPG and recurrent GBM studies. The confirmatory stage of this study is in planning to further evaluate the anti-tumor efficacy signal of this NF-κB and STAT3 dual inhibitor.

081. Radiofrequency Ablation for Retrosternal Thyroid Tumour: A Rare Case Report

Background: Retrosternal thyroid tumours, though uncommon, present complex diagnostic and therapeutic challenges due to their location behind the sternum. These tumours can cause significant symptoms, such as difficulty breathing and chest pressure, which can impact patient quality of life. Radiofrequency ablation (RFA) has emerged as a minimally invasive treatment option, offering potential benefits over conventional surgical methods for retrosternal thyroid tumor. Case: A 54-year-old male with a history of right thyroid isthmolobectomy presented with a rapidly growing left-sided neck mass, causing increasing chest pressure and shortness of breath. Imaging studies, including ultrasound and CT scans, revealed a large tumour extending retrosternally and compressing the trachea. The patient opted for RFA over surgery. A core biopsy confirmed a benign struma adenomatosa. RFA was performed using the moving shoot technique, resulting in effective tumor ablation. Follow-up imaging showed a significant reduction in tumor size and symptom relief. Conclusion: This case demonstrates that RFA is a safe and effective alternative to conventional surgery for retrosternal thyroid tumours. It provides substantial symptom relief and tumour reduction with fewer complications. RFA should be considered a valuable treatment option for patients who are not ideal candidates for surgery or who prefer less invasive approaches. Continued research and long-term studies are needed to confirm its broader efficacy.

EGFR-mediated HSP70 phosphorylation facilitates PCNA association with chromatin and DNA replication.

Efficient DNA replication requires highly coordinated programs for the timely recruitment of protein complexes to DNA replication forks. Defects in this process result in replication stress, which in turn activates cell cycle checkpoints, suppresses cell proliferation and induces apoptosis. In response to persistent cell growth signals that speed up DNA replication processes, cells accelerate the recruitment of DNA replication proteins to avoid DNA replication stress. The mechanisms by which cell growth signals induce processes to facilitate the recruitment of DNA replication proteins onto the replication sites remain unclear. Here, we report that the epidermal growth factor receptor (EGFR) phosphorylates heat shock protein 70 (HSP70) for DNA replication. Such a modification promotes nuclear localization and chromatin association of HSP70, which interacts with the DNA replication coordinator, proliferating cell nuclear antigen (PCNA). HSP70 subsequently facilitates the loading of PCNA onto chromatin. Knockdown or chemical inhibition of HSP70 suppresses PCNA association with chromatin and impairs DNA synthesis and Okazaki fragment maturation, leading to replicative DNA double-strand breaks and apoptosis. Furthermore, chemical inhibition of HSP70 potentiates EGFR-tyrosine kinase inhibitor-induced tumor reduction in vivo. This work expands our understanding of oncogenesis-induced DNA replication processes and provides a foundation for improved treatments for EGFR-mutated lung cancer by simultaneously targeting HSP70.

Combining Phototherapy and Gold-Based Nanomaterials: A Breakthrough in Basal Cell Carcinoma Treatment.

Basal cell carcinoma (BCC) is the most common type of skin carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic, and genetic factors. While conventional treatments such as surgery and topical therapies have demonstrated variable efficacy (some of them with limited efficacy), they are not free of adverse side effects, most of them debilitating. Thus, there is a notable gap in the literature regarding alternative and non-invasive therapeutic options. This review aims to address this gap, exploring the potential of photothermal therapy (PTT) combined with metallic nanoparticles, namely gold nanoparticles (AuNPs), as a minimally invasive treatment approach. Through a comprehensive review of the literature in the period from 2014 to 2024, using experimental investigations, this review seeks to elucidate the intricate interplay between genetic factors, environmental influences, and the tumor microenvironment in BCC disease progression, with PTT as a potential therapeutic strategy. Those studies confirmed an enhanced targeting of cancer cells and selective ablation of tumor tissue, using emerging technologies like PTT. A significant tumor reduction, often exceeding 50%, was observed, with some studies reporting complete elimination of the tumor. The main adverse effects noted were localized skin irritation and transient hyperpigmentation, but these were generally minimal and manageable, highlighting the promise of PTT as an effective treatment. Thus, by leveraging the unique properties of AuNPs to enhance the effectiveness of PTT, the targeting of cancer cells can more precisely occur, reducing collateral damage to healthy tissues. This approach not only aims to achieve better clinical results, but also contributes to the broader knowledge base in the field of BCC research. Continued research and clinical trials will be crucial in refining those techniques and validating their efficacy, ultimately paving the way for more effective and less invasive treatments for BCC.

EFFICACY OF NEOADJUVANT TARGETED THERAPY IN TREATMENT OF PATIENTS WITH LOCALISED CLEAR-CELL RENAL CELL CARCINOMA

Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, accounting for approximately 75-80% of all renal malignancies. Objectives: The main objective of the study is to find the efficacy of neoadjuvant targeted therapy in the treatment of patients with localised clear-cell renal cell carcinoma. Methods: This prospective study was conducted at Mardan Medical Complex from June 2023 to January 2024. Data were collected from 85 patients. Patients aged&gt;18 years and have a histologically confirmed diagnosis of localized ccRCC were included in the study. Tumor size was required to be 4 cm or larger, but confined to the kidney, corresponding to Stage I to III disease. Results: Data were collected from 85 patients with an average baseline tumour size for the entire cohort was 7.5 cm, and after 12 weeks of treatment, tumours shrank to an average of 5.6 cm, resulting in a mean tumour reduction of 25%. In the sunitinib group, the tumour size decreased from 7.5 cm to 5.55 cm, reflecting a 26% reduction. Similarly, in the pazopanib group, the tumour size was reduced from 7.5 cm to 5.65 cm, with an average reduction of 24%. Conclusion: It is concluded that neoadjuvant targeted therapy, using agents such as sunitinib and pazopanib, effectively reduces tumour size and improves surgical outcomes in patients with localized clear-cell renal cell carcinoma.

Nanoparticles use magnetoelectricity to target and eradicate cancer cells.

We investigated the theranostic capabilities of magnetoelectric nanoparticles (MENPs) combined with MRI via a murine model of pancreatic adenocarcinoma. MENPs leverage the magnetoelectric effect to convert an applied magnetic field into local electric fields, which can induce irreversible electroporation of tumor cell membranes when activated by MRI. Additionally, MENPs modulate MRI relaxivity, which can be used to predict the degree of tumor ablation. Through a pilot study (n=21) and a confirmatory study (n=27), we demonstrated that, ≥300 µg of MRI-activated MENPs significantly reduced tumor volumes, averaging a three-fold decrease as compared to controls. Furthermore, there was a direct correlation between the reduction in tumor T 2 relaxation times and tumor volume reduction, highlighting the predictive prognostic value of MENPs. Six of 17 mice in the confirmatory study's experimental arms achieved a durable complete response, showcasing the potential for durable treatment outcomes. Importantly, the administration of MENPs was not associated with any evident toxicities. This study presents the first in vivo evidence of an externally controlled, MRI-based, theranostic agent that effectively targets and treats solid tumors via irreversible electroporation while sparing normal tissues, offering a new and promising approach to cancer therapy.

Real-World Clinical Outcomes of Treatment With Olaparib for BRCA1/2 Mutation-Positive Metastatic Breast Cancer in Japanese Patients.

Background Olaparib is effective in the treatment of metastatic breast cancer (MBC) patients, mainly confirmed by deleterious germline BRCA mutations. However, real-world data are scarce. Methodology A total of 10 cases from our institute and 17 cases from the relevant Japanese literature were reviewed. All 27 patients had MBC with confirmed deleterious germline BRCA mutations. Tumor reduction, response duration, disease-free interval (DFI), overall survival (OS), and safety were assessed. Additionally, exploratory research was conducted on the characteristics of a subgroup of patients who had a long-term response to olaparib. Results In the 10 cases from two Juntendo hospitals who received olaparib from July 2018 to December 2021, the median age was 48 years (range = 37-63 years). The same numbers of BRCA1 and BRCA2 mutations and the same ratios of luminal and triple negative (TN) breast cancer cases were observed. The metastatic sites, mainly visceral, included the lungs (n = 4), liver (n = 5), and bone (n = 6). The median duration of drug use was four months (range = 1-36 months). The median number of treatment regimens from metastasis to olaparib administration was 2.0 (range = 1-9 regimens). The median DFI was 21 months (range = 0-106 months). The median OS was not reached (range = 16-191 months). In the subgroup analysis of six cases in which olaparib was effective for four months or more, there was a case where DFI was longer than 100 months. Treatment-related toxicities (TRTs) included neutropenia (n = 5; 50%), anemia (n = 4; 40%), thrombocytopenia (n = 2; 20%), nausea (n = 1; 10%), and fatigue (n = 1; 10%). CTCAE (version 5.0) grade ≥3 TRTs included anemia (n = 1; 10%) and neutropenia (n = 5; 50%). On the other hand, neutropenia was previously said to be as low as 27.3%, lower than anemia (40.0%), in a population including various races. We additionally examined another 17 cases from the Japanese literature. Conclusions To our knowledge, this study reports the first real-world data of Japanese patients with MBC and confirmed deleterious germline BRCA mutations. Our data showed that olaparib is effective in the real world. The incidence of neutropenia seemed higher in Japanese patients.

Development and Evaluation of Indole-Based Phospholipase D Inhibitors for Lung Cancer Immunotherapy.

This study explored novel immunomodulatory approaches for cancer treatment, with a specific focus on lung cancer, the leading cause of cancer-related deaths worldwide. We synthesized indole-based phospholipase D (PLD) inhibitors with various substituents to improve anticancer efficacy. Through structure-activity relationship studies, the key compound was identified that significantly inhibiting PLD, suppressing cell growth, viability, and migration in vitro, while inducing apoptosis of lung cancer cells. In silico docking studies confirmed its binding to the PLD1 active site, highlighting the role of specific residues in inhibiting PLD1 activity. The inhibitor modulated oncogenic pathways and immune evasion in lung cancer cells, showing potential for immunotherapy. In vivo experiments in a mouse model showed tumor reduction and immune response alteration. Combining these inhibitors with gemcitabine, an anticancer drug, synergistically enhanced inhibition of lung cancer cell apoptosis and proliferation. This research offers new insights into PLD inhibitor as potential cancer therapeutics.