Effective Tumor Treatment Research Articles

Pathological and Molecular Diagnosis of Uveal Melanoma.

(1) Background: Uveal melanoma (UM) is a common malignant intraocular tumor that presents with significant genetic differences to cutaneous melanoma and has a high genetic burden in terms of prognosis. (2) Methods: A systematic literature search of several repositories on uveal melanoma diagnosis, prognosis, molecular analysis, and treatment was conducted. (3) Results: Recent genetic understanding of oncogene-initiation mutations in GNAQ, GNA11, PLCB4, and CYSLTR2 and secondary progression drivers of BAP1 inactivation and SF3B1 and EIF1AX mutations offers an appealing explanation to the high prognostic impact of adding genetic profiling to clinical UM classification. Genetic information could help better explain peculiarities in uveal melanoma, such as the low long-term survival despite effective primary tumor treatment, the overwhelming propensity to metastasize to the liver, and possibly therapeutic behaviors. (4) Conclusions: Understanding of uveal melanoma has improved step-by-step from histopathology to clinical classification to more recent genetic understanding of oncogenic initiation and progression.

Recurrence rate and management after endoscopic papillectomy in a tertiary referral center

Background and study aimsEndoscopic papillectomy (EP) is considered a safe procedure for ampullary lesions. Few data are available on management of residual and recurrent adenomas. The aims of the present study were to evaluate long-term recurrence rate, median time-to-recurrence after EP and treatment of both residual and recurrent adenomas. Patients and methodsConsecutive patients who underwent EP of major and minor papilla at our endoscopy center between 2011 and 2022 were enrolled. Residual adenoma was defined as the endoscopic evidence of adenomatous tissue after EP. Recurrent adenoma was defined as the presence of adenomatous tissue after the first endoscopic follow-up and complete adenoma resection. Results95 patients satisfied the inclusion criteria. Pathology after resection showed adenoma with low-grade dysplasia (LGD) in 52 patients, high-grade dysplasia (HGD) in 25 patients, adenocarcinoma in 6 patients, NET in 4 patients and not-neoplastic duodenal mucosa in 8 patients. Adverse events occurred in 25 % of patients. The median follow-up after EP was 22.5 months. Local residual was observed in 27 patients (28,4 %) and recurrence after the endoscopic retreatments occurred in 11 patients (11,6 %). Furthermore, recurrence occurred in 16 of 68 patients with adenoma-free after a first endoscopic follow-up and 9 patients developed at least a second recurrence. All the recurrences but one were endoscopically treated. ConclusionsEP and its ancillary treatments for residual and recurrent adenomas is an effective treatment for ampullary tumors. Long-term surveillance demonstrates that recurrences can be mainly treated endoscopically.

CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition

Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces significant hurdles, including T-cell inhibition mediated by the PD-1/PD-L1 axis. The effects of disrupting this pathway on T-cells are being actively explored and controversial outcomes have been reported. Here, we hypothesize that CAR-antigen affinity may be a key factor modulating T-cell susceptibility towards the PD-1/PD-L1 axis. We systematically interrogate CAR-T cells targeting HER2 with either low (LA) or high affinity (HA) in various preclinical models. Our results reveal an increased sensitivity of LA CAR-T cells to PD-L1-mediated inhibition when compared to their HA counterparts by using in vitro models of tumor cell lines and supported lipid bilayers modified to display varying PD-L1 densities. CRISPR/Cas9-mediated knockout (KO) of PD-1 enhances LA CAR-T cell cytokine secretion and polyfunctionality in vitro and antitumor effect in vivo and results in the downregulation of gene signatures related to T-cell exhaustion. By contrast, HA CAR-T cell features remain unaffected following PD-1 KO. This behavior holds true for CD28 and ICOS but not 4-1BB co-stimulated CAR-T cells, which are less sensitive to PD-L1 inhibition albeit targeting the antigen with LA. Our findings may inform CAR-T therapies involving disruption of PD-1/PD-L1 pathway tailored in particular for effective treatment of solid tumors.

Open versus robot-assisted retroperitoneal tumors resection involving inferior vena cava, abdominal aorta, and renal hilum: a comparative study

IntroductionSurgery is currently the only effective treatment for retroperitoneal tumors that do not involve any specific organ. The use of robots for removing both benign and malignant retroperitoneal tumors is considered safe and feasible. However, there is insufficient evidence to determine whether robotic retroperitoneal tumor resection (RMBRs) is superior to open retroperitoneal malignant resection (OMBRs). This study compares the short-term outcomes of robotic excision of benign and malignant retroperitoneal tumors with open excision of the same-sized tumors.MethodsThe study compared demographics and outcomes of patients who underwent robotic resection (n = 54) vs open resection (n = 54) of retroperitoneal tumors between March 2018 and December 2022. A 1:1 matching analysis was conducted to ensure a fair comparison.ResultsThe study found that RBMRs resulted in reduced operative time (OT), estimated blood loss (EBM), and postoperative hospital stay (PSH) when compared to OBMRs. Additionally, RBMRs reduced EBL, PHS, and OT for patients with malignant tumor involvement in major vessels. No significant differences were found in tumor size, blood transfusion rate, and morbidity rate between the RBMRs and OBMRs groups.ConclusionWhen comparing RMBRs to OMBRs, it was observed that RMBR was associated with lower (EBL), shorter postoperative hospital stays (PHS), and reduced operative time (OT) in a specific group of patients with both benign and malignant tumors.

FeNC with atomically dispersed iron atoms as a photosensitizer for combined photodynamic and photothermal therapy

This research explores the efficacy of photodynamic therapy (PDT) and photothermal therapy (PTT) in combating chemotherapy-resistant diseases. This study focuses on enhancing tumor treatment effectiveness by leveraging the synergetic effects of combining PDT and PTT through the development of Fe-nitrogen-carbon (FeNC) nanoparticles with superior photostability. These nanoparticles, functioning as photosensitizers for the combined PDT/PTT treatment, can generate both type I and type II ROS and heat upon 808 nm irradiation. Notably, the FeNC nanoparticles demonstrate an exceptional photothermal conversion efficiency (34 %), surpassing commonly used PTT photosensitizers. In vitro and in vivo experiments corroborate the efficiency of FeNC as a photosensitizer in achieving significant tumor inhibition. In conclusion, the FeNC nanoparticles present promising applicability in the synergistic PTT/PDT treatment of tumors.

Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11

BackgroundThe dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood.MethodsEndoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT–PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT–PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models.ResultsERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors.ConclusionsThe ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.

Modified technique of Hepatojejunostomy for biliary tract reconstruction after resection of tumors affecting the perihilar region: a case series

BackgroundsRadical resection is the most effective treatment for perihilar tumors. Biliary tract reconstruction after resection is one of the key steps in this surgery. Mucosa-to-mucosa cholangiojejunostomy is traditionally performed, in which the bile ducts at the resection margin are separately anastomosed to the jejunum. However, this approach is associated with long operative time and high risk of postoperative complications. The present study presents a modified technique of hepatojejunostomy and its outcomes.MethodsThe data of patients who underwent hepatojejunostomy using the modified technique at the Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China, from January 2016 to December 2021, were retrospectively analyzed.ResultsA total of 13 patients with perihilar tumors underwent R0 resection and bilioenteric reconstruction using the modified hepatojejunostomy technique during the study period. During the operation, the alignment of the bile duct stumps was improved, the posterior wall of the anastomosis was reinforced, internal stents were placed in the smaller bile ducts, external stents were placed in the larger bile ducts, and hepatojejunostomy was performed using 4 − 0 prolene. No serious postoperative complications, such as death or bile leakage, occurred during the hospitalization. Furthermore, there were no cases of biliary stricture or cholangitis after the six-month follow-up period.ConclusionThe modified hepatojejunostomy technique is a safe and effective technique of biliary reconstruction after the resection of perihilar tumors. This can be easily performed for difficult cases with multiple bile ducts that require reconstruction after resection.

Sustainable gambogic acid release via pH/Redox Dual-Responsive C60-Modified magnetic mesoporous nanospheres for antitumor therapy

Traditional cancer treatment modalities such as surgery, chemotherapy, and radiation therapy have seen significant advancements in the past. However, inherent drawbacks, including systemic toxicity and high recurrence rates. Consequently, The nanoparticles, with their targeting and multifunctionality, have captured significant attention. This work synthesizes HMNPs-C60-N-GQDs-SS-PEI (HMNPs:Fe3O4@SiO2@mSiO2-C18) nanoparticles, integrating diverse functionalities for enhanced cancer therapy. The inclusion of SiO2 and C60 significantly improves the loading efficiency of gallic acid (GA). The magnetic properties of HMNPs enable efficient targeting to cancer sites under external magnetic fields. The -SS- linkage ensures drug release exclusively in tumor cells over-expressing glutathione (GSH), minimizing adverse effects on normal tissues. Introduction of Polyethyleneimine (PEI) imparts positive charge to facilitate accumulation on negatively charged tumor surfaces and enhances biocompatibility. Additionally, the fluorescence properties of N-doped graphene quantum dots (N-GQDs) facilitate real-time monitoring of material distribution in vivo during mouse and clinical therapy. Furthermore, the nano-magnetic targeting material demonstrates efficient drug loading and precise control over drug release, addressing issues such as the poor biocompatibility and high biotoxicity associated with traditional materials. This study not only achieves effective tumor treatment but also offers a promising direction for developing efficient multifunctional nano-targeting materials.

Application of the Left Lateral Decubitus Position in Laparoscopic Right Posterior Lobectomy.

To investigate the value of the left lateral decubitus position in laparoscopic right posterior lobe tumor resection. The clinical data of patients who underwent laparoscopic right posterior lobectomy from January 2020 to March 2023 were retrospectively collected and divided into group A (left lateral decubitus position group, n=30) and group B (conventional position group, n=35) according to different body positions. Intraoperative and postoperative data were collected and compared between the 2 groups. The operation time (210.43±57.56 vs. 281.97±65.89, t =5.887, P <0.05), hilar occlusion time (23.97±14.25 vs. 35.79±12.62, t =4.791, P <0.05), intraoperative blood loss (162.14±72.61 vs. 239.65±113.56, t =5.713, P <0.05), postoperative feeding time (1.13±0.36 vs. 1.57±0.67, t =3.681, P <0.05), postoperative visual analog scale score (5.16±0.89 vs. 7.42±1.31, t =3.721, P <0.05), postoperative abdominal drainage tube indwelling time (4.58±1.34 vs. 5.42±1.52, t =4.553, P <0.05), incidence rate of complications (43.33% vs. 82.86%, χ 2 =11.075, P <0.05) in group A were lower than those in group B ( P <0.05). Symptoms/side effects (32.42±3.42 vs. 27.44±3.31, t =4.331, P <0.05), and there were significant differences in social function (33.55±2.56 vs. 29.31±3.32, t =4.863, P <0.05). For right posterior lobe tumors of the liver, the left lateral decubitus position has many advantages in laparoscopic right posterior lobectomy, such as a wide field of view, simple steps, a short operation time, less bleeding, and a high postoperative quality of life. It is an effective treatment for right posterior lobe tumors of the liver and is worthy of being widely popularized.

DECIDE: A decoupled semantic and boundary learning network for precise osteosarcoma segmentation by integrating multi-modality MRI

Automated Osteosarcoma Segmentation in Multi-modality MRI (AOSMM) holds clinical significance for effective tumor evaluation and treatment planning. However, the precision of AOSMM is challenged by the diverse characteristics of multi-modality MRI and the inherent heterogeneity and boundary ambiguity of osteosarcoma. While numerous methods have made significant strides in automated osteosarcoma segmentation, they primarily focused on the use of a single MRI modality and overlooked the potential benefits of integrating complementary information from other MRI modalities. Furthermore, they did not adequately model the long-range dependencies of complex tumor features, which may lead to insufficiently discriminative feature representations. To this end, we propose a decoupled semantic and boundary learning network (DECIDE) to achieve precise AOSMM with three functional modules. The Multi-modality Feature Fusion and Recalibration (MFR) module adaptively fuses and recalibrates multi-modality features by exploiting their channel-wise dependencies to compute low-rank attention weights for effectively aggregating useful information from different MRI modalities, which promotes complementary learning between multi-modality MRI and enables a more comprehensive tumor characterization. The Lesion Attention Enhancement (LAE) module employs spatial and channel attention mechanisms to capture global contextual dependencies over local features, significantly enhancing the discriminability and representational capacity of intricate tumor features. The Boundary Context Aggregation (BCA) module further enhances semantic representations by utilizing boundary information for effective context aggregation while also ensuring intra-class consistency in cases of boundary ambiguity. Substantial experiments demonstrate that DECIDE achieves exceptional performance in osteosarcoma segmentation, surpassing state-of-the-art methods in terms of accuracy and stability.

Carbon-based Nanomaterials in Photothermal Therapy Guided by Photoacoustic Imaging: State of Knowledge and Recent Advances.

Carbon-based nanomaterials (CBNM)have been widely used in various fields due to their excellent physicochemical properties. In particular, in the area of tumor diagnosis and treatment, researchers have frequently reported them for their potential fluorescence, photoacoustic (PA), and ultrasound imaging performance, as well as their photothermal, photodynamic, sonodynamic, and other therapeutic properties. As the functions of CBNM are increasingly developed, their excellent imaging properties and superior tumor treatment effects make them extremely promising theranostic agents. This review aims to integrate the considered and researched information in a specific field of this research topic and systematically present, summarize, and comment on the efforts made by authoritative scholars. In this review, we summarized the work exploring carbon-based materials in the field of tumor imaging and therapy, focusing on PA imaging-guided photothermal therapy (PTT) and discussing their imaging and therapeutic mechanisms and developments. Finally, the current challenges and potential opportunities of carbon-based materials for PA imaging-guided PTT are presented, and issues that researchers should be aware of when studying CBNM are provided.

Tumor microenvironment-responsive intelligent nanoplatform with oxygen self-supply for synergistic chemotherapy/photodynamic therapy/photothermal therapy against hypoxic tumors

Nanomaterial-based multi-modal synergistic therapies are emerging as highly promising strategies for the treatment of malignant tumors. Herein, a novel nanoplatform modified with the peptide of cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) was designed for synergistic treatment of hypoxic tumors by the combination of chemotherapy (CT)/photodynamic therapy (PDT)/photothermal therapy (PTT). Firstly, Mn@APDA nanoparticles were synthesized for PTT and oxygen (O2) supply, consisting of an L-arginine-doped polydopamine (APDA) core and a manganese dioxide (MnO2) shell. Subsequently, the liposome nanoplatform (cRGD-Lipo-MART), loaded with Mn@APDA (MA), chemotherapy drug of deoxybouvardin dodecyl ester (RA, “R” for short), and mitochondrial targeted photosensitizer of triphenylphosphine-grafted protoporphyrin IX (TPPP, “T” for short), was developed using a film dispersion method. Upon targeted delivery to tumors, the nanoplatform disintegrated in response to the acidic and hydrogen peroxide (H2O2)-rich tumor microenvironment (TME) and near-infrared (NIR) laser irradiation, thereby facilitating controlled drug release and O2 supply to overcome hypoxia. The released RA could cause DNA damage and suppress the HIF-1α expression to sensitize PDT. Simultaneously, TPPP could generate singlet oxygen (1O2) and convert L-arginine (L-Arg) into nitric oxide (NO) for PDT, while APDA could induce hyperthermia for PTT. The combination of PDT and PTT resulted in significant mitochondrial dysfunction and lysosomal damage, ultimately leading to apoptosis. Furthermore, the chemotherapeutic effect of RA could be potentiated by the enhancement of cytoplasmic delivery caused by lysosomal disruption and the blocking of DNA damage repair pathway caused by mitochondrial dysfunction. Overall, cRGD-Lipo-MART, designed with a synergistic CT/PDT/PTT strategy, showed minimal systemic toxicity and could be used as an effective treatment for hypoxic tumors.

Abstract 5703: Development of RVL-101, a CDK4/6-selective, small molecule inhibitor with superior CNS penetration and combinability potential for the effective treatment of primary and metastatic brain tumors

Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle that are frequently dysregulated in cancer, leading to unchecked cell growth. CDK4/6 inhibitors have emerged as a promising class of anticancer agents that selectively target this pathway. The primary mode of action of CDK4/6 inhibitors relies on the disruption of retinoblastoma (Rb) protein phosphorylation, which thereby blocks cell cycle progression from G1 to S phase and reduces proliferation of cancer cells by a cytostatic mechanism. However, despite their efficacy, approved and clinical-stage CDK4/6 inhibitors have modest penetration of unbound drug into the brain, limiting their utility in the treatment of brain metastases and primary brain tumors. Additionally, despite the potential benefits of CDK4/6 inhibitors as combination therapies with cytotoxic agents, adjunctive treatment options remain underexplored due to the poor safety profiles of existing therapies. RVL-101 is a preclinical, investigational drug with a novel pharmacophore that has a low nanomolar activity against CDK4, is CDK2,6,7,9-sparing, and maintains &amp;gt;500-fold selectivity over CDK1. To maximize the potential of RVL-101 as a preferred combination partner, this novel agent has been engineered to have exquisite kinome- and safety-panel selectivity with no measured CYP inhibition or induction liabilities. RVL-101 is differentiated from approved and clinical stage CDK4/6 inhibitors having both high partitioning into the brain (Kp) and high free-brain (Kpu,u = 0.7) levels resulting in equal levels of unbound drug in all relevant compartments at steady state. Like other CDK4/6 agents, RVL-101 is broadly efficacious in vivo in ER+/HER2- xenograft models at well-tolerated doses. However, RVL-101 has also demonstrated robust activity in HR-/HER2+ xenograft models as a single-agent and has uniquely shown improved tumor inhibition effect in combination with approved HER2 cytotoxic therapeutics tucatinib and fam-trastuzumab-deruxtecan. RVL-101 was also tested in a GBM model as a monotherapy and in conjunction with the cytotoxic agent temozolomide (TMZ). Remarkably, QD dosing of the cytostatic agent, RVL-101, after pulsatile pretreatment with TMZ led to dramatic synergistic efficacy compared to either agent alone, leading to 100% survival of all animals on the dual therapy arm for more than 3 weeks post discontinuation of dosing. RVL-101 offers the combination of substantial therapeutic benefit and consistent free-drug levels in plasma and CNS that could lead to safe and effective treatment for a broader patient population. Citation Format: John E. Campbell, Bo-Sheng Pan, Michael Bower, Peter Bertinato, Nisha Perez, Victoria Gras Andreu, Neha Rana, Sophia Tabchouri, Ankit Gupta, Jonah Kallenbach. Development of RVL-101, a CDK4/6-selective, small molecule inhibitor with superior CNS penetration and combinability potential for the effective treatment of primary and metastatic brain tumors [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 5703.

Abstract 7614: Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy

Abstract Background: Peptide Receptor Radionuclide Therapy (PRRT) using 177Lu-DOTATATE is an effective treatment for metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs). However, it remains unknown why some patients (pts) respond more favorably than others. Pre-clinical data suggests that mutations in the MEN1, DAXX, and/or ATRX genes influence DNA repair capabilities and increase radiation effect in cancer cells. We therefore thought to evaluate the association between response to PRRT and the presence of MEN1, DAXX, and/or ATRX mutations in patients with GEP-NETs. Methods: We retrospectively analyzed CLIA certified tissue-based Next Generation Sequencing (NGS) assay results and clinicopathological data from 28 pts with GEP-NETs treated with PRRT at our center from 2017 to 2023. Genetic findings were correlated with progression-free survival (PFS) using Kaplan-Meier estimators and Cox proportional hazards regression modeling. Objective response was assessed per RECIST v1.1 by investigator review. Results: Pts with mutations in MEN1, DAXX, or ATRX (n = 13, 46.42%) had a longer PFS [mPFS, 26.47 months (95% CI, 17.97 - NA) vs. 12.13 months (95% CI, 9.17 - NA); HR, 0.19; 95% CI, 0.06 - 0.68; p = 0.01] than wildtype (n = 15, 53.58%) pts, when adjusted for surgery prior to PRRT and tumor grade. Pts with mutations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended towards better PFS compared to patients without concurrent mutations [only MEN1mt or DAXXmt/ATRXmt, but not both; mPFS, 31.53 months (95% CI, 28.43 - NA) vs. 17.97 months (95% CI, 11.17 - NA); HR, 0.25; 95% CI, 0.05 - 1.29; p = 0.09]. Among evaluable pts, objective response rate was higher in pts with a mt in MEN1, DAXX, or ATRX compared to wild-type pts (41.67% vs. 15.38%; p = 0.09). In the pancreatic NET (PNET) subset, mutations in either MEN1, DAXX, or ATRX were found in 11/16 pts (68.75%) and were also associated with a better PFS compared to wild type patients [mPFS, 28.43 months (95% CI, 11.50 - NA) vs. 9.83 months (95% CI, 7.83 - NA); HR, 0.21; 95% CI, 0.05 - 0.95; p = 0.04). Conclusions: Mutations in MEN1/DAXX/ATRX correlate with improved PFS in patients with GEP-NETs receiving PRRT. Concurrent mutations in MEN1 and DAXX/ATRX may have additive effects on response to PRRT. If validated in larger studies, these findings may represent a novel biomarker to predict PRRT response. Limitations: Limited sample size precludes generalization of results and might overestimate effect sizes. Citation Format: Rushabh Gujarathi, Sara Abou Azar, Joseph Tobias, Xavier Keutgen, Chih-Yi Liao. Mutations in MEN1/DAXX/ATRX are associated with improved progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy [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 7614.

Abstract 690: Investigation of BH-3 mimetics as radiosensitizing agents in glioblastoma

Abstract Glioblastoma (GBM) is a highly aggressive primary brain tumor. Treatment consists of maximal safe tumor resection, chemotherapy (temozolomide) and radiotherapy; however, this aggressive treatment offers only a modest improvement in outcomes, with average life expectancy of approximately 12 months. Consequently, novel, effective and easily translatable therapies are urgently required. While radiotherapy is an effective treatment for many solid tumors, GBM displays an innate radio-resistance that contributes to treatment failure. Therefore, there is a need to identify chemotherapeutics that can be used as radiosensitizers to increase efficacy. Notably, a key pathway involved in therapeutic resistance is apoptotic evasion, which is driven by upregulation of pro-survival BCL-2 proteins that inhibit the pro-apoptotic proteins necessary for the apoptotic response. Recent advances in drug development have produced a range of BH3 mimetics - novel chemotherapeutics with potential to reinstate apoptosis by targeting specific pro-survival molecules. We hypothesized that the radiation sensitivity of GBM cells would be enhanced by using BH3 mimetics to inhibit pro-survival molecules and release the apoptotic block. A panel of BH3 mimetics was tested in combination with radiotherapy across three patient-derived GBM cell lines (G7, E2 and R15), using a 3D clonogenic culture system that recapitulates in vivo growth patterns and responses. We found that the BCL-XL inhibitor, A1331852, significantly radiosensitized all 3 GBM lines. In addition, Western blot analysis revealed A1331852 to induce PARP1 cleavage in G7 cells when used as a single agent. Subsequent in vivo studies were conducted in our well characterized orthotopic G7 xenograft murine model of GBM. Immunohistochemical studies showed that the pro-survival proteins MCL-1 and BCL-XL were upregulated in irradiated tumors. Furthermore, a pharmacokinetic study in the same orthotopic murine model, allowing for drug delivery evaluation, and optimized treatment scheduling. Importantly, A1331852 was found to be blood brain barrier penetrant at 25 mg/kg, with increased drug detected in tumor vs normal brain tissue. From these data, a survival study investigating A1331852 as a radiosensitizing agent was carried out in the same G7 GBM orthotopic xenograft model. Kaplan-Meier analysis showed an increase in survival of mice treated with A133852 plus radiotherapy compared with the radiotherapy only group (p = 0.0309). Overall, we have demonstrated that dependence on BCL-2 family proteins is a vulnerability that can be targeted to improve radiotherapy response in GBM. Furthermore, we have identified a promising BH3 mimetic, A1331852, to use in combination with RT and have completed a proof-of-concept in vivo study that confirms the potential of BH3 mimetics to improve outcomes for patients with GBM. Citation Format: Louise R. Dutton, Clara Mullen, Anna L. Koessinger, Mark Jackson, Katrina Stevenson, Anthony J. Chalmers, Stephen Tait, Kirsteen J. Campbell, Joanna L. Birch. Investigation of BH-3 mimetics as radiosensitizing agents in glioblastoma [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 690.

CA IX-targeted Ag2S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

Hypoxia is the common characteristic of almost all solid tumors, which prevents therapeutic drugs from reaching the tumors. Therefore, the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned. As carbonic anhydrase IX (CA IX) is abundantly distributed on the hypoxia tumor cells, it is considered as a potential tumor biomarker. 4-(2-Aminoethyl)benzenesulfonamide (ABS) as a CA IX inhibitor has inherent inhibitory activity and good targeting effect. In this study, Ag2S quantum dots (QDs) were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe (Ag2S@polyethylene glycol (PEG)-ABS) through ligand exchange and amide condensation reaction. Ag2S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II (NIR-II) fluorescence characteristics of Ag2S QDs. PEG modification of Ag2S QDs greatly improves its water solubility and stability, and therefore achieves high photothermal stability and high photothermal conversion efficiency (PCE) of 45.17%. Under laser irradiation, Ag2S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells (CT-26) in vitro. It also has been proved that Ag2S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility. Therefore, it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

Abstract 6708: MAIT engagers: Bispecific antibody-mediated redirection of mucosal associated invariant T cells to treat solid tumors

Abstract Background. Using bispecific antibodies (BiXAb) to redirect T cells to engage and kill cancer cells is an efficacious modality in the treatment of haematological cancers but has had limited success in the treatment of solid tumors. Mucosal-Associated Invariant T cells (MAITs) are an abundant subset of non-conventional T-cells with potent cytotoxic capacity (up to 20% of circulating T-cells) that are naturally resident in many tissues and solid tumors. MAIT cells utilize a semi-invariant TCR and recognize bacterial metabolites presented in the context of the MR1 protein. Biomunex has generated bispecific antibodies that bind the MAIT semi-invariant TCR (iTCR) and the HER2 receptor tyrosine kinase expressed on tumor cells. At difference to classical T-cell engagers that activate all T-cell subsets, MAIT engagers only modulate the activity of the cytotoxic MAIT cells leading to efficient tumor control and greater safety profile. Methods. Using the Biomunex proprietary BiXAb platform, bispecific, tetravalent antibodies were generated that target the MAIT iTCR and the HER2. MAIT-cell activation, proliferation and degranulation were followed by gating on MAIT cells within a purified CD8 cell population. Tumor cell lines (varying in [HER2] expression) were co-cultured with MAIT cells and the BiXAbs in several cytotoxic assays (evaluated by Chromium release). Cytokine release was assessed by Legend Plex assays or ELISA. Cytotoxicity of tumor-resident MAITs, from fresh patient samples, was determined by impedence measurements and in patient-derived 3D organoids by The Hub organoids (imaging). For in vivo analysis, sub-cutaneous tumor growth was measured with callipers. Results. MAIT engagers induce the rapid activation, proliferation and degranulation of MAIT cells leading to efficient killing of engaged HER2+ cancer cells with a potency similar to that of a classical HER2-directed TCE (in clinical development). The MAIT engager did not activate the regulatory T cells or other CD4/CD8 subsets. In addition, using PBMCs, total cytokine release was 1000-fold less with the MAIT engager compared to a classical TCE, opening up a large therapeutic window, which should permit effective treatment of solid tumors. Ex vivo cytotoxicity of tumor-resident MAIT cells using dissociated ovarian cancer samples at “real E:T ratios”, MAIT engager-mediated cytotoxicity of patient-derived organoids (CRC) and in vivo evaluation of tumor control will be shown. Conclusions. MAIT cell redirection is a promising approach for the treatment of solid tumors that has the potency and efficacy of a classical TCE but with a significantly improved cytokine safety profile leading to a larger therapeutic window. Citation Format: Simon Edward Plyte, Marie Fraudeau, Dorothee Winterberg, Claire Germain, Camille Rousseau, Gaetano Sodaro, Lise Fenou, Maxime Audin, Alexandre Ivagnes, Han-Heinrich Oberg, Pierre Emmanuel Gerard, Isabelle Navarro-Teulon, Daniela Wesch, Matthias Peipp, Julie Prigent. MAIT engagers: Bispecific antibody-mediated redirection of mucosal associated invariant T cells to treat solid tumors [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 6708.

Abstract 4031: P-selectin as an emerging target for the treatment of primary and secondary brain tumors

Abstract Glioblastoma (GB) is an aggressive type of brain cancer with a high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells that have been shown to facilitate GB cell invasion and immune suppression. The mechanism by which GB cells alter microglia behavior is yet to be fully understood. One proposed mechanism involves adhesion molecules such as the Selectins family of proteins which are expressed on the surface of endothelial and immune cells and are involved in immune modulation and cancer immunity. We have previously shown that one member of the Selectin family, P-Selectin (SELP), is expressed by GB cells. Here, we investigated the functional role of SELP in GB-microglia interactions. First, we found that microglia cells facilitate the expression and secretion of SELP by GB cells, and that GB cells facilitate the expression of P-Selectin ligand-1 (PSGL-1) by Glioma-associated microglia/macrophages (GAMs). We then showed that SELP mediates GAMs-enhanced GB invasion and proliferation in our unique 3D-bioprinted ex vitro models and has a role in GAMs activation state. These findings were validated in vivo, showing that inhibition or downregulation of SELP leads to reduced tumor growth, increased overall survival, and improved immune response. Single-cell RNA-seq analysis of the tumors revealed an increase in pro-inflammatory GAMs signature, reduction in cancer cell tumorigenesis potential, and improved T cell activation. Thus, combining SELP inhibition with other immune checkpoint inhibitors, such as anti-PD-1, may have a synergistic effect by harnessing both the innate and the adaptive immune systems against the tumor. Furthermore, we found SELP/PSGL-1 axis to be involved in the progression of brain metastasis originating from melanoma, and breast, and lung cancer. Thus, we have begun an investigator-initiated clinical trial, testing the efficacy of the anti-SELP antibody, Crizanlizumab, alone or in combination with anti-PD-1 antibody, Nivolumab, for GB and melanoma brain metastasis patients (NCT05909618). Crizanlizumab, approved by the FDA and EMA for sickle cell pain crisis (VOC, Vaso-Occlusive Crisis) of sickle-cell anemia patients, was proven to be safe for human use, and efficient in inhibiting SELP function. As such, it has the potential to reduce tumor burden and improve patient outcomes. This work can improve our understanding of GAMs function, which may pave the way for new and effective treatments for primary and secondary brain tumors. Citation Format: Eilam Yeini, Ronnie Frommer-Shapira, Alisa Talianski, Paula Ofek, Sabina Pozzi, Nitzan Albeck, Dikla Ben-Shushan, Galia Tiram, Sapir Golan, Ron Kleiner, Ron Sheinin, Shlomit Reich-Zeliger, Rachel Grossman, Zvi Ram, Henry Brem, Thomas M. Hyde, Prerna Magod, Dinorah Friedmann-Morvinski, Asaf Madi, Ronit Satchi-Fainaro. P-selectin as an emerging target for the treatment of primary and secondary brain tumors [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 4031.

Intelligent gold nanocluster for effective treatment of malignant tumor via tumor-specific photothermal-chemodynamic therapy with AIE guidance.

Precise and efficient therapy of malignant tumors is always a challenge. Herein, gold nanoclusters co-modified by aggregation-induced-emission (AIE) molecules, copper ion chelator (acylthiourea) and tumor-targeting agent (folic acid) were fabricated to perform AIE-guided and tumor-specific synergistic therapy with great spatio-temporal controllability for the targeted elimination and metastasis inhibition of malignant tumors. During therapy, the functional gold nanoclusters (AuNTF) would rapidly accumulate in the tumor tissue due to the enhanced permeability and retention effect as well as folic acid-mediated tumor targeting, which was followed by endocytosis by tumor cells. After that, the overexpressed copper ions in the tumor cells would trigger the aggregation of these intracellular AuNTF via a chelation process that not only generated the photothermal agent in situ to perform the tumor-specific photothermal therapy damaging the primary tumor, but also led to the copper deficiency of tumor cells to inhibit its metastasis. Moreover, the copper ions were reduced to cuprous ions along with the chelation, which further catalysed the excess H2O2 in the tumor cells to produce cytotoxic reactive oxygen species, resulting in additional chemodynamic therapy for enhanced antitumor efficiency. The aggregation of AuNTF also activated the AIE molecules to present fluorescence, which not only imaged the therapeutic area for real-time monitoring of this tumor-specific synergistic therapy, but also allowed us to perform near-infrared radiation at the correct time point and location to achieve optimal photothermal therapy. Both in vitro and in vivo results revealed the strong tumor elimination, effective metastasis inhibition and high survival rate of tumor-bearing mice after treatment using the AuNTF nanoclusters, indicating that this AIE-guided and tumor-specific synergistic strategy could offer a promising approach for tumor therapy.

Abstract 7014: Integrative DNA methylation cancer profiling reveals patterns associated with tumor progression and treatment response

Abstract DNA methylation plays a critical role in tumor progression and response to chemotherapy. Frequently dysregulated during tumor development, it is closely intertwined with mixed effects from patient epigenetic background, tissue context, and treatment pressure. Here, we leveraged methylomic and transcriptomic profiling of 400 whole-genome sequencing samples from 125 patients with ovarian high-grade serous carcinoma (HGSC), belonging to the prospective, longitudinal, multi-region DECIDER trial (NCT04846933). This cohort included 120 samples from tubo-ovarian tumors, 209 samples from intra-abdominal metastases, and 71 ascites, representing all major sites of HGSC metastases. We profiled cancer methylome across tissues, patient groups, and various anticancer treatments using decomposition method, which allows separating the effects of tumor microenvironment and treatment, tissue, and patient specific changes, thus, facilitating integration of the heterogeneous collection of samples. First, we systematically examined the tissue-specific carcinogenesis and characterized methylomes of all types of metastases and excess fluid accumulations in the abdominal cavity. In our analyses, the cancer spread from tubo-ovarian sites to metastatic deposits involved gradual loss of DNA methylation and increase in transcriptomic levels, possibly indicating stemness. Specifically, several members of the ATP-binding-cassette (ABC) family of transporters, as well as receptor tyrosine kinases were frequently hypomethylated in bowel and omentum. The methylome of ascites showed most commonality to the tubo-ovarian tumors and peritoneum. Our results confirmed that several well-known tumor-associated genes, such as PTEN, GSK3B, ESR1, FGFR2, TNC, BCL6, HIF1A, NOTCH2 are regulated epigenetically, and this dysregulation stems early from the sites of origin. Next, we built methylomic profiles of patients with various treatment responses. Direct comparisons between good and poor responders revealed pronounced methylation differences, with refractory disease being associated with severely aberrated methylome prior to chemotherapy treatment. Neoadujuvant chemotherapy resulted in very few changes to these epigenetic aberrations and no acquired mechanisms, suggesting that intrinsic methylomes of poor responders accommodate multiple drivers for EMT, hypoxia, and chronic inflammation to resist chemotherapy-induced cell death already prior to treatment. In conclusion, using a large whole-genome sequencing DNA methylation dataset we elucidated the major underlying epigenetic mechanisms of tumorigenesis and platinum resistance, which provide possible drug targets for improving platinum sensitivity. Our multi-omics analyses enabled the identification of aberrated patterns that drive transcriptional changes, shedding light on epigenetic landscape of HGSC. Citation Format: Alexandra Lahtinen, Giovanni Marchi, Daria Afenteva, Kari Lavikka, Susanna Holmström, Elsi Pöllänen, Giulia Micoli, Ilari Maarala, Yilin Li, Taru A. Muranen, Jaana Oikkonen, Sakari Hietanen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi. Integrative DNA methylation cancer profiling reveals patterns associated with tumor progression and treatment response [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 7014.