Decrease In Tumor Volume Research Articles

Cancer Cells Upregulate Tau to Gain Resistance to DNA Damaging Agents

Recent reports suggested a role for microtubules in double-strand-DNA break repair. We herein investigated the role of the microtubule-associated protein Tau in radio- and chemotherapy. Noticeably, a lowered expression of Tau in breast cancer cell lines resulted in a significant decrease in mouse-xenograft breast tumor volume after doxorubicin or X-ray treatments. Furthermore, the knockdown of Tau impaired the classical nonhomologous end-joining pathway and led to an improved cellular response to both bleomycin and X-rays. Investigating the mechanism of Tau's protective effect, we found that one of the main mediators of response to double-stranded breaks in DNA, the tumor suppressor p53-binding protein 1 (53BP1), is sequestered in the cytoplasm as a consequence of Tau downregulation. We demonstrated that Tau allows 53BP1 to translocate to the nucleus in response to DNA damage by chaperoning microtubule protein trafficking. Moreover, Tau knockdown chemo-sensitized cancer cells to drugs forming DNA adducts, such as cisplatin and oxaliplatin, and further suggested a general role of Tau in regulating the nuclear trafficking of DNA repair proteins. Altogether, these results suggest that Tau expression in cancer cells may be of interest as a molecular marker for response to DNA-damaging anti-cancer agents. Clinically targeting Tau could sensitize tumors to DNA-damaging treatments.

Comprehensive Management of Renal Masses in Solitary Kidneys

BackgroundA renal mass in a solitary kidney (RMSK) has traditionally been managed with partial nephrectomy (PN), although radical nephrectomy (RN) is occasionally required. Most RMSK studies have focused on patients for whom PN was achieved. ObjectiveTo provide a comprehensive analysis of the management strategies/outcomes for an RMSK and address knowledge deficits regarding this challenging disorder. Design, setting, and participantsA total of 1024 patients diagnosed with an RMSK (1975–2022) were retrospectively evaluated. Baseline characteristics and pathologic/functional/survival outcomes were analyzed. InterventionPN/RN/cryoablation (CA)/active surveillance (AS). Outcome measurements and statistical analysisFunctional outcomes, perioperative morbidity/mortality, and 5-yr recurrence-free survival (RFS) were evaluated. Kruskal-Wallis and chi-square tests were used to compare cohorts, and log-rank test and Cox proportional hazard model were used for survival analysis. Results and limitationsOf 1024 patients, 842 underwent PN (82%), 102 CA (10%), 54 RN (5%), and 26 AS (3%). The median tumor size and RENAL([R]adius [tumor size as maximal diameter], [E]xophytic/endophytic properties of tumor, [N]earness of tumor deepest portion to collecting system or sinus, [A]nterior [a]/posterior [p] descriptor, and [L]ocation relative to polar lines) score were 3.7 cm and 8, respectively. The median follow-up was 53 mo. For PN, 95% were clamped, and the median warm and cold ischemia times were 22 and 45 min, respectively. For PN, the median preoperative glomerular filtration rate (GFR) was 57 ml/min/1.73 m2, and the median new baseline and 5-yr GFRs were 47 and 48 ml/min/1.73 m2, respectively. Dialysis-free survival for PN was 97% at 5 yr. Twenty-two (2.1%) patients with clear-cell renal cell carcinoma and RENAL score ≥10 (median = 11) received tyrosine kinase inhibitors (TKIs) to facilitate PN, leading to 57% median decrease of tumor volume; PN was accomplished in 20 (91%). Forty-one patients had planned RN (4.0%), most often due to severe pre-existing chronic kidney disease (CKD), and 13 were converted from PN to RN (1.5%). Clavien III–V perioperative complications were observed in 80 (8%) patients and 90-d mortality was 0.6%. Five-year RFS for PN, CA, and RN were 83%, 80%, and 72%, respectively (p = 0.03 for PN vs RN). ConclusionsNephron-sparing approaches are feasible and successful in most RMSK patients. PN for an RMSK is often challenging but can be facilitated by selective use of TKIs. RN is occasionally required due to severe CKD, over-riding oncologic concerns, or conversion from PN. This is the first large RMSK study to provide a comprehensive analysis of all management strategies/outcomes. Patient summaryKidney cancer in a solitary kidney is a major challenge for achieving cancer-free status and avoiding dialysis. Although partial nephrectomy is the principal treatment for a renal mass in a solitary kidney, other options are occasionally required to optimize outcomes.

Cytotoxic and antitumor properties of methionine γ-lyase conjugate in combination with S-alk(en)yl–L-cysteine sulfoxides

Background. Enzyme prodrug therapy is a promising strategy to treat solid malignancies. The utilization of two-component systems, including an enzyme and a non-toxic prodrug, to generate cytotoxic compounds directly at the surface of the tumor cell can be successful strategy in reducing the overall toxic load on the body.Aim. To determine antitumor activity of the pharmacological pair C115H methionine γ-lyase (C115H MGL) conjugated with daidzein (C115H MGL-Dz) and of S-alk(en)yl-L-cysteine sulfoxides against various types of solid tumors in vitro and in vivo.Materials. MTT-test was used to determine the cytotoxicity of C115H MGL-Dz in the presence of S-alk(en)yl-L-cysteine sulfoxides in vitro against Sw620 (colon cancer), Panc1 (pancreatic cancer), and 22Rv1 (prostate cancer). Apopto- sis induction and cell cycle alteration in 22Rv1, Sw620, and SKBR3 cell lines were studied using the Muse® Caspase-3/7 and Muse® Cell Cycle Assay kits. In vivo anticancer activity was studied on Sw620, Panc1, and 22Rv1 subcutaneous xenografts in Balb/c nude mice.Results. The C115H MGL-Dz had the maximum cytotoxic activity in the presence of S-propyl-L-cysteine sulfoxide (propiin) with IC50 values: 3.88 and 5.4 for Panc1 and 22Rv1, respectively. Dipropyl thiosulfinate formed by the β-eli-mination of propiin catalyzed by C115H MGL-Dz, induces apoptosis through both the activation of caspases and alternative pathways, and also it inhibits cell division, contributing to a decrease in the concentration of cells in the G2/M phase. The anticancer efficacy of the pharmacological pair C115H-Dz/propiin in vivo indicated a significant decrease in Panc1 tumor volume (tumor growth inhibition (TGI) 67.5 %, p = 0.004), Sw620 (TGI 22.07 %, p = 0.12) and 22Rv1 (TGI 70 %, p = 0.043).Conclusion. Pharmacological pair C115H MGL-Dz/propiin was capable of suppressing tumor development in malignant solid tumors and might be considered as a potential anticancer approach in cancer prodrug therapy.

ROS-responsive mechanically and electronically controllable conductive hydrogel sensor with NIR modulated photothermal therapy

This study illustrates the design of a cancer microenvironment-selective detection system via the monitoring of wireless pressure and strain sensing response from a reactive oxygen species (ROS)-responsive carbon dot (CD)-embedded conductive hydrogel. ROS scavenging activity and photothermal therapy (PTT) were employed to eliminate the tumor condition. The ROS-responsive hydrogel (dsCD-Hydrogel) contained diselenide-crosslinked CD, which was dismantled in the cancer microenvironment. After being free from aggregation, the fluorescence intensity, charge carrier density, and hydrogen bonding interactions were increased. As a result, the conductivity, mechanical stretchability, and strain-pressure responses were enhanced by 52%, 122%, and 91%, respectively. The dsCD-Hydrogel produced distinct electronic signals in the presence of cancer cells according to the higher strain–pressure sensitivity in the handwriting experiment compared to normal cells. Ex-situ measurements also revealed an excellent pressure-sensing response in tumor-carrying mice. The ROS scavenging activity of the dsCD-Hydrogel decreased tumor volume. Furthermore, NIR irradiation via PTT abolished the tumor, which was verified by the downregulation of tumor hypoxia by vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) expression. To ease the monitoring procedure and acquire real-time conductivity and pressure profiles on cellphones, a wireless sensor device was deployed. Overall, a theragnostic sensor based on strain–pressure hydrogel that exhibits direct anticancer activity via PTT was successfully constructed.

LW-8 TREATMENT STRATEGY FOR OLIGODENDROGLIOMAS WITH NEOADJUVANT STRATEGY AND STAGED RESECTION UTILIZING THEIR CHEMOTHERAPEUTIC RESPONSIVENESS

Abstract Background In glioma surgery, both of functional preservation and maximal safe resection are critical, however, neoadjuvant strategy has never been used because of difficulty of tissue sampling without craniotomy. Method In Keio University Hospital, oligodendrogliomas, i.e., diffuse gliomas with IDH mutation and 1p/19q codeletion, with incomplete initial resection have been treated by upfront chemotherapy and subsequent resection after tumor volume decrease (second look resection, SLR) since 2006 (J Neurooncol 124:127-35, 2015). At first, initial radiotherapy was prescribed immediately after chemotherapy or SLR only for the cases with aggressive clinical course or subarachnoid infiltration, however, cases with residual FLAIR abnormality after upfront chemotherapy or SLR were also subjected to initial radiotherapy since 2018. Cases 1) with IDH mutation and 1p/19q codeletion, and 2) without history of either chemotherapy or radiotherapy, and 3) treated with upfront chemotherapy and subsequent resection strategy, were included. Results Thirty nine cases of oligodendroglioma have been treated with the above strategy since 2006. Tumor volume decrease following upfront chemotherapy was 30-35% (median), and 19 tumors underwent SLR. Among the total 39 cases, PFS and OS after initiation of upfront chemotherapy were 81 months and not reached, respectively, and were 64 months and not reached, respectively, among the 32 cases with deferred radiotherapy. Importantly, the majority of tumor recurrence occurred at the residual FLAIR abnormality following upfront chemotherapy. Conclusions Treatment of oligodendrogliomas utilizing neoadjuvant strategy enables 1) decrease of resection volume as compared with initial maximal safe resection, 2) more precise resection, 3) confirmation of the necessity of initial radiotherapy based on the observed efficacy of chemotherapy. Moreover, the study also suggested that 4) invasion front of oligodendroglioma likely withdraw by alkylating agents, and 5) cases with residual FLAIR abnormality following chemotherapy may be appropriate subjects for initial radiotherapy.

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial

ObjectiveRobust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role...

Oncogenic RAS Networks Suppression: Reversibly Ionic Oligonucleotide‐Based Nanoparticles Caged microRNA‐143 Inhibit KRAS‐Mutated Colon Cancer Growth in Tumor‐Bearing Mice

AbstractOncogenic RAS has been a particular focus of attention as a pharmacological target over the last four decades. Tumor‐suppressor microRNA‐143 (miR‐143) silences oncogenic KRAS networks, but it requires a nucleic acid delivery vehicle for clinical application. DNA‐ or RNA‐based nucleic acid structures (NASs) are attractive as vehicles that can form unique sequence‐based structures. However, for the biological application of NASs, it is still challenging to create a nanostructure that is stable under physiological conditions by reducing intramolecular repulsion due to negative charges. Here, a novel NAS (named RIONmiR‐143: reversibly ionic oligonucleotide‐based nanoparticles caged miR‐143) is created by self‐assembly involving hybridization and electrostatic interaction via chemically modified oppositely charged ion oligonucleotides. RIONmiR‐143 are nanoparticles of about 70 nm in diameter with improved nuclease resistance under physiological conditions. Moreover, RIONmiR‐143 inhibit the expression of proteins in KRAS networks and cell growth in a dose‐dependent manner in KRAS‐mutated DLD‐1 cells. The anti‐tumor activity of RIONmiR‐143 is demonstrated in a DLD‐1 cell‐bearing mouse model, with a fourfold decrease in tumor volume compared with NakedmiR‐143. This report presents RIONmiR‐143 as a new option for oncogenic KRAS‐targeting medicine, which can be used as a potent nucleic acid delivery platform.

Solitary intraventricular tumors in dogs and cats treated with radiotherapy alone or combined with ventriculoperitoneal shunts: A retrospective descriptive case series.

Intraventricular tumors are rare, optimal treatment is not defined. Symptomatic patients often exhibit life-threatening hydrocephalus. With several months time-to-effect after radiotherapy (RT), increased intracranial pressure is concerning. This increase in pressure can be overcome by ventriculoperitoneal shunting (VPS). Retrospective evaluation of outcome and complications in dogs and cats with intracranial tumors treated with either RT or VPS/RT. Twelve client-owned cats and dogs. Dogs and cats with symptomatic intraventricular tumors treated with definitive-intent RT or VPS/RT were included in a retrospective, descriptive case series. Complications, tumor volume evolution, time-to-progression, and survival time were determined. Twelve animals were included: 1 cat and 5 dogs treated with single-modality RT and 4 cats and 2 dogs treated with VPS/RT. Neurological worsening seen in 4/6 animals during single-modality RT and 2/6 died during RT (suspected brain herniation). All dogs with VPS normalized clinically by the end of RT or earlier. Complications occurred in 4/6 animals, all but 1 were successfully managed surgically. Imaging follow-up in 8 animals surviving RT showed a marked decrease in tumor volume. Median survival time was 162 days (95% confidence interval [CI]: 16; infinity) for animals treated with RT and 1103 days (95%CI: 752; infinity) for animals treated with VPS/RT. Median time-to-progression was 71 days (95%CI: 7; infinity) and 895 days (95%CI: 704; infinity) for each group, respectively. Two dogs died because of intraventricular metastasis 427 and 461 days after single-modality RT. Ventriculoperitoneal shunting led to rapid normalization of neurological signs and RT had a measurable effect on tumor volume. Combination of VPS/RT seems to be beneficial.

Tumor Treating Fields (TTFields) Concomitant with Immune Checkpoint Inhibitors Are Therapeutically Effective in Non-Small Cell Lung Cancer (NSCLC) In Vivo Model.

Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields induce anti-mitotic effects through the disruption of the mitotic spindle and abnormal chromosome segregation, which trigger several forms of cell death, including immunogenic cell death (ICD). The efficacy of TTFields concomitant with anti-programmed death-1 (anti-PD-1) treatment was previously shown in vivo and is currently under clinical investigation. Here, the potential of TTFields concomitant with anti- PD-1/anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-programmed death-ligand 1 (anti-PD-L1) immune checkpoint inhibitors (ICI) to improve therapeutic efficacy was examined in lung tumor-bearing mice. Increased circulating levels of high mobility group box 1 protein (HMGB1) and elevated intratumoral levels of phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α) were found in the TTFields-treated mice, indicative of ICD induction. The concomitant application of TTFields and ICI led to a significant decrease in tumor volume as compared to all other groups. In addition, significant increases in the number of tumor-infiltrating immune cells, specifically cytotoxic T-cells, were observed in the TTFields plus anti-PD-1/anti-CTLA-4 or anti-PD-L1 groups. Correspondingly, cytotoxic T-cells isolated from these tumors showed higher levels of IFN-γ production. Collectively, these results suggest that TTFields have an immunoactivating role that may be leveraged for concomitant treatment with ICI to achieve better tumor control by enhancing antitumor immunity.

CTNI-65. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NEUROFIBROMATOSIS 2 PATIENTS WITH PROGRESSIVE TUMORS: INTERIM RESULTS OF THE BRIGATINIB TREATMENT ARM

Abstract Neurofibromatosis type 2 (NF2) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. We developed an adaptive platform-basket trial to screen multiple drugs against any type of progressive NF2-related tumor. We report the interim analysis of the first treatment arm with brigatinib, an ALK inhibitor that inhibits multiple tyrosine kinases. We conducted a multicenter, phase II, open-label study for subjects ≥12 years old with NF2 and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Up to 5 non-target tumors were followed in each participant. In stage 1, 20 participants (minimum of 2 participants per basket) were treated with brigatinib 180 mg daily. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. Radiographic response (RR) was defined as ≥20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Per protocol, the brigatinib arm would be discontinued if no target tumor achieved a RR at interim analysis. Twenty subjects (median age=25 years, 7 pediatric, 12 females) were treated. Target tumors included 10 VS, 3 NVS, 5 meningiomas, and 2 ependymomas; non-target tumors included 18 VS, 36 NVS, and 14 meningiomas. RR rate for target and non-target tumors was 5% and 22%, respectively. By tumor basket, RR was 28% for meningioma, 26% for non-VS, 4% for VS, and 0% for ependymomas. Annualized tumor growth rates decreased for VS, NVS, and meningioma during treatment. Brigatinib was well tolerated with one dose reduction and one discontinuation due to grade 2 diarrhea. Brigatinib treatment was associated with RR in meningiomas, VS, and NVS. In stage 2, the study will enroll 20 participants in the two most promising baskets (meningioma and NVS). This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.

CoQ10 reduces glioblastoma growth and infiltration through proteome remodeling and inhibition of angiogenesis and inflammation

PurposeMost monotherapies available against glioblastoma multiforme (GBM) target individual hallmarks of this aggressive brain tumor with minimal success. In this article, we propose a therapeutic strategy using coenzyme Q10 (CoQ10) as a pleiotropic factor that crosses the blood–brain barrier and accumulates in cell membranes acting as an antioxidant, and in mitochondrial membranes as a regulator of cell bioenergetics and gene expression.MethodsXenografts of U251 cells in nu/nu mice were used to assay tumor growth, hypoxia, angiogenesis, and inflammation. An orthotopic model was used to explore microglial infiltration, tumor growth, and invasion into the brain parenchyma. Cell proliferation, migration, invasion, proteome remodeling, and secretome were assayed in vitro. Conditioned media were used to assay angiogenesis, monocyte chemoattraction, and differentiation into macrophages in vitro.ResultsCoQ10 treatment decreased tumor volume in xenografts and orthotopic models, although its effect on tumor cell proliferation was not direct. Tumors from mice treated with CoQ10 were less hypoxic and vascularized, having less infiltration from inflammatory cells. Treatment-induced downregulation of HIF-1α and NF-kB led to a complete remodeling of the tumor cells proteome and secretome, impacting angiogenesis, monocyte infiltration, and their differentiation into macrophages. Besides, tumor cell migration and invasion were drastically restricted by mechanisms involving modulation of the actin cytoskeleton and downregulation of matrix metalloproteases (MMPs).ConclusionsCoQ10 has a pleiotropic effect on GBM growth, targeting several hallmarks simultaneously. Thus, its integration into current treatments of this fatal disease should be considered.

MiR-655-3p Regulates the Vascular Endothelial Growth Factor A/AKT Serine Signaling Pathway via ATAD2 to Inhibit the Proliferation, Invasion, and Angiogenesis of Pancreatic Ductal Carcinoma Cells

miR-655-3p has been reported to play crucial roles in the development and progression of tumorigenesis and development. In this study, we investigated the potential biological role of miR-655-3p in pancreatic ductal carcinoma (PDAC). After PDAC cells were transfected with miR-655-3p, cell proliferation, migration and invasion were evaluated. The targeting relationship between miR-655-3p and ATAD2 was verified. A xenograft tumor model was established to evaluate the role of miR-655-3p in tumorigenesis abilities in vivo. Immunohistochemical staining was used to detect the levels of Ki-67, CD31, ATAD2, and VEGFA. We found that miR-655-3p inhibited PDAC cell proliferation, migration, and invasion and decreased the ability of HUVECs to form tubes by decreasing the VEGFA/AKT signaling pathway. Moreover, we predicted and verified that ATAD2, the direct target gene of miR-655-3p, could reverse the inhibitory effect caused by miR-655-3p overexpression. Additionally, we demonstrated that miR-655-3p suppressed PDAC growth and angiogenesis in vivo, characterized by decreased tumor volume, mass, and levels of Ki-67, CD31, ATAD2, and VEGFA. These results show that miR-655-3p might serve as a tumor suppressor in PDAC by targeting ATAD mediated-VEGFA/AKT signaling pathway, which may provide a potential therapeutic candidate for PDAC.

Blocking of The Prostaglandin E2 Receptor as a Therapeutic Strategy for Treatment of Breast Cancer: Promising Findings in a Mouse Model.

The study aimed to investigate the anticancer effect of E-prostanoid receptor 1 (EP1) antagonist, SC19220, alone or in combination with the COX-2 inhibitor Celecoxob(CXB)® in mice bearing solid Ehrlich carcinoma (SEC). The tumors were induced in 40 female mice, which were divided randomly into four equal groups (n= 10 in each group): Tumor control, CXB, EP1 antagonist, and co-treatment. CXB (10mg/kg) and EP1 antagonist (2mg/kg) were given intraperitoneally every three days, six times in total, then tissue was extracted and prepared for histopathology and measurement of weight, PGE2, and gene expression of EP1 and β 1 integrin. Both inhibitors, alone or in combination, showed a significant (p<0.001) antitumorigenic effect by decreasing, significantly (p<0.001), each of the tumor weights, tumor volumes, PGE2 levels, EP1 and β1-integrin gene expression along with increasing, significantly (p<0.001), the P53 tumor suppressor protein. The survival rate was improved from 80% in the control group to reach 100% in the treated groups. The co-treatment by CXB and EP1 antagonist showed a marked decrease in tumor weights and volumes as compared with the single treatment. In parallel, the histopathological findings showed enhanced apoptosis and diminished necrosis in the co-treated group. EP1 antagonist proved an antitumorigenic effect alone or combined with CXB and could play a new therapeutic strategy against breast cancer.

The potential effects and mechanisms of Gegen Qinlian Decoction in oxaliplatin-resistant colorectal cancer based on network pharmacology

BackgroundResistance to chemotherapeutic drugs, such as oxaliplatin (OXA), can lead to unsatisfactory chemotherapy results during the treatment of advanced colorectal cancer (CRC). Therefore, we investigated the potential targets and mechanisms of Gegen Qinlian Decoction (GQD) against OXA-resistant CRC through network pharmacology and performed molecular docking and experimental verification. MethodsWe collected potential compounds, targets, and related disease genes from public databases. The pharmacology model of the compound-target-pathway network and protein-protein interaction (PPI) network were established. The potential active components and mechanisms underlying GQD reversing OXA-resistant CRC were systematically predicted, and the key targets were verified by performing molecular docking and in vitro and in vivo experiments. ResultsA total of 160 active ingredients, 407 potential targets, and 406 CRC drug resistance genes were collected. 16 intersecting genes, which included ABCG2 and belonged to 139 active compounds including baicalin and wogonin. They were enriched in 12 signaling pathways, including ABC transport and metabolism. Along with network topology analysis, ABCB1 and ABCC2 were identified as key targets and proved that various active components of GQD combined well with them. GQD alone and synergized with OXA could inhibit the protein and mRNA of ABC transporters in vivo and in vitro, decrease the IC50 of OXA-resistant CRC to OXA with a good synergistic index at different treatment times and concentrations, improve the sensitivity of OXA-resistant CRC to OXA, inhibit drug efflux, decrease tumor volume, and increase the weight of nude mice at the late stage of treatment. ConclusionsGQD can target ATP-binding proteins, inhibit ABC transporters, reverse OXA resistance, increase the sensitivity of OXA-resistant CRC cells to OXA, decrease tumor volume, alleviate toxic side effects, improve prognosis, and have good synergistic therapeutic effects. These results provide an effective research tool to elucidate ethnomedicine for modernizing refractory diseases.

Evaluation of a Sumoylation Inhibitor as an Intrinsic and Extrinsic Radiosensitizer

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) reduces tumor burden through both intrinsic initiation of tumor cell death and enhancement of anti-tumor immunity. However, radiation treatments are not universally efficacious due to variation in radiosensitivity and anti-tumor immunity. Low proliferative rate, hypoxia, and T cell effector dysfunction can significantly degrade response to RT. Here we evaluate a rational combination therapy pairing radiosensitization and immune activation in conjunction with standard of care RT. Recent studies demonstrated the sumoylation inhibitor, TAK-981, has intrinsic capacity to reduce the proliferation of tumor cells <i>in vitro</i> as a monotherapy and decrease tumor volumes in syngeneic murine colon carcinoma models (CT26 and MC38) in combination with PD-1 or CTLA-4 checkpoint blockade. In these models a dendritic cell dependent type I interferon pathway was implicated to mediate the anti-tumor immune response and enhanced in vivo tumor control in TAK-981 and checkpoint blockade combination therapy, similar to previously elucidated mechanisms of immune activation following hypofractionated radiotherapy. Additionally, multiple intrinsic and extrinsic protein mediators (Myc, IRF3, p21) of tumor cell response to radiation are regulated by the post-translational modification of sumoylation. Consequently, we evaluated whether combining RT with TAK-981 resulted in enhanced tumor radiosensitivity in vitro and improved local tumor control in vivo, consistent with enhanced anti-tumor immune response in murine tumor models. <h3>Materials/Methods</h3> We utilized a longitudinal real time microscopic proliferation assay to evaluate RT response. Titrations of TAK-981 were added to established in vitro tumor cell cultures 4 hours prior to increasing doses of single fraction photon RT. Impacts of RT, TAK-981 or the combination treatment were assessed based upon cell proliferation for 72 hours. We assessed efficacy of this novel combination in vivo using the MC38 colorectal carcinoma model. C57BL6 mice with established tumors (> 50mm2) received TAK981 (15mg/kg) alone three times weekly or in combination with single fraction 8 Gy RT and compared to RT alone to evaluate local tumor control and impacts on overall survival. <h3>Results</h3> Our data demonstrates a synergistic and dose dependent reduction in MC38 colon carcinoma in vitro proliferation in response to combination RT and TAK-981. In vivo MC38 tumor models demonstrate no effect of TAK-981 alone compared to vehicle treated mice while co-administration with a single 8 Gy fraction of radiotherapy synergistically enhanced tumor control and overall survival compared to RT alone. <h3>Conclusion</h3> Our preliminary data support potential dual synergistic roles for the sumoylation inhibitor TAK-981 with radiotherapy, functioning as both an intrinsic radiosensitizer and immunomodulator.

Preclinical Evaluation of Tumor Treating Fields Combined with Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR)

Purpose/Objective(s)The PULSAR paradigm, treats patients using a few large dose “pulses,” delivered at least a week apart. These split treatments represent a radical break from conventional radiation treatments lasting six to nine weeks. The expectation is that therapy will be less toxic and will allow treatments to personalized based upon noted changes in tumor morphology, location and radiation response. Early pre-clinical experiments identified an optimal timing between radiation pulses with the use of immune checkpoint inhibitors (ICI). Other therapeutic combinations are being explored. Tumor Treating Fields (TTFields) is a novel noninvasive physical modality of cancer therapy that disrupts mitosis, causes replication stress, inhibits DNA damage repair, and sets up a conditional vulnerability to DNA damaging agents. This study combined the conditional vulnerabilities caused by TTFields exposure with a preclinical model of PULSAR to determine treatment efficacy for this combination.Materials/MethodsThe Inovivo system was used to generate Tumor Treating Fields across subcutaneously implanted tumors. Three distinct syngeneic mouse tumor models, LLC (Murine Lewis Lung Carcinoma), KPC63 (Pancreatic Cancer) and MC38 (Colon Cancer). Tumor growth delay (TGD) was the endpoint determined.ResultsIn the three mice models tested in vitro, TTFields exposure alone modestly decreased tumor volume. A difference in tumor growth rate between the heat (sham) and TTFields group was not statistically significant. TTFields combined with 8 or 10 Gy radiation pulses, depending on tumor model radiosensitivity, produced a significant TGD effect on the MC38 mouse model after one round. The second round of TTFields and radiation treatment further delayed TGD, in a synergistic manner, confirming that TTFields induces a conditional vulnerability that is particularly suited to the PULSAR concept. The combination of TTFields, PULSAR and an ICI is being tested and will be reported.ConclusionThe addition of TTFields with a pre-clinical model of PULSAR resulted in synergistic delays in tumor growth compared to the PULSAR strategy alone when tested using three different subcutaneous tumor models. This combination is well suited for the addition of an ICI. The PULSAR paradigm, treats patients using a few large dose “pulses,” delivered at least a week apart. These split treatments represent a radical break from conventional radiation treatments lasting six to nine weeks. The expectation is that therapy will be less toxic and will allow treatments to personalized based upon noted changes in tumor morphology, location and radiation response. Early pre-clinical experiments identified an optimal timing between radiation pulses with the use of immune checkpoint inhibitors (ICI). Other therapeutic combinations are being explored. Tumor Treating Fields (TTFields) is a novel noninvasive physical modality of cancer therapy that disrupts mitosis, causes replication stress, inhibits DNA damage repair, and sets up a conditional vulnerability to DNA damaging agents. This study combined the conditional vulnerabilities caused by TTFields exposure with a preclinical model of PULSAR to determine treatment efficacy for this combination. The Inovivo system was used to generate Tumor Treating Fields across subcutaneously implanted tumors. Three distinct syngeneic mouse tumor models, LLC (Murine Lewis Lung Carcinoma), KPC63 (Pancreatic Cancer) and MC38 (Colon Cancer). Tumor growth delay (TGD) was the endpoint determined. In the three mice models tested in vitro, TTFields exposure alone modestly decreased tumor volume. A difference in tumor growth rate between the heat (sham) and TTFields group was not statistically significant. TTFields combined with 8 or 10 Gy radiation pulses, depending on tumor model radiosensitivity, produced a significant TGD effect on the MC38 mouse model after one round. The second round of TTFields and radiation treatment further delayed TGD, in a synergistic manner, confirming that TTFields induces a conditional vulnerability that is particularly suited to the PULSAR concept. The combination of TTFields, PULSAR and an ICI is being tested and will be reported. The addition of TTFields with a pre-clinical model of PULSAR resulted in synergistic delays in tumor growth compared to the PULSAR strategy alone when tested using three different subcutaneous tumor models. This combination is well suited for the addition of an ICI.

The targeting imaging and treatment capacity of gelsolin-targeted and paclitaxel-loaded PLGA nanoparticles in vitro and in vivo.

As a vital sign of carcinomas, lymph node metastasis is closely related to poor prognosis due to a lack of identification and effective treatment in the early stage. Nanoscale contrast agents targeting specific tumor antigens are expected to identify tumor metastasis in the early stage and achieve precise treatment. As a biomarker in the early stage of tumor invasion and metastasis, gelsolin (GSN) might be a promising molecular target to identify and screen tumor metastasis through the lymphatic system. Therefore, GSN-targeted paclitaxel-loaded poly(lactic-co-glycolic acid) nanoparticles (GSN-PTX-PLGA NPs) were prepared, and their physicochemical properties, encapsulation efficiency, drug loading, and dissolution were determined. Besides, uptake experiments and the fluorescent imaging system were used to evaluate their targeting capability. The targeting imaging and treatment capacity were also assessed by experiments in vitro and in vivo. The diameter of the GSN-PTX-PLGA NPs was 328.59 ± 3.82nm. Hca-F cells with GSN-PLGA NPs showed stronger green fluorescence than Hca-P cells. DiI-labeled GSN-PLGA NPs in tumor-bearing mice and isolated organs exhibited more prominent fluorescence aggregation. The imaging of GSN-PLGA NPs was satisfactory in vitro, and the echo intensity gradually increased with increasing concentrations of GSN-PLGA NPs. After treatment with GSN-PTX-PLGA NPs, there was an obvious decrease in tumor volume and lymph node metastasis rate compared to the other groups (p < 0.05). In conclusion, GSN-PTX-PLGA NPs have a remarkable targeting capacity in vivo and in vitro, and they effectively inhibit tumor growth and lymph node metastasis in vivo.

Treatment of NF1-Associated Optic Pathway/Hypothalamic Gliomas in Patients With Diencephalic Syndrome.

Diencephalic syndrome is usually associated with tumors in the hypothalamic region, rarely occurring in patients with neurofibromatosis type 1 (NF1)-associated gliomas. We describe the clinical presentation and response to treatment in 3 patients with NF1 presenting with diencephalic syndrome as first symptom of optic pathway/hypothalamic glioma (OPHG). Because of the rarity of this constellation, knowledge about the clinical course and best treatment options for patients with NF1-associated OPHG and diencephalic syndrome is still limited. All 3 patients showed good response to treatment with normalization of body mass index and decrease in tumor volume within 6 months.

The trends and significance of SSTR PET/CT added to MRI in follow-up imaging of low-grade meningioma treated with fractionated proton therapy.

Overexpression of the somatostatin receptor (SSTR) has led to adoption of SSTR PET/CT for diagnosis and radiotherapy planning in meningioma, but data on SSTR expression during follow-up remain scarce. We investigated PET/CT quantifiers of SSTR tracers in WHO gradeI meningioma following fractionated proton beam therapy (PBT) compared to standard response assessment with MRI. Twenty-two patients diagnosed with low-grade meningioma treated by PBT were included. Follow-up included clinical visits, MRI, and [68Ga]Ga-DOTATOC PET/CT scans. Radiologic tumor response, MRI and PET volume (VMRI and VPET), maximum and mean standardied uptake value (SUVmax/SUVmean), total lesion activity (TLA), and heterogeneity index (HI) were evaluated. Median follow-up was 35.3months (range: 6.4-47.9). Nineteen patients (86.4%, p = 0.0009) showed adecrease of SUVmax between baseline and first follow-up PET/CT (median: -24%, range: -53% to +89%) and in 81.8% of all cases, the SUVmax, SUVmean, and TLA at last follow-up were eventually lower than at baseline (p = 0.0043). Ambiguous trends without significance between the timepoints analyzed were observed for VPET. HI increased between baseline and last follow-up in 75% of cases (p = 0.024). All patients remained radiologically and clinically stable. Median VMRI decreased by -9.3% (range 0-32.5%, p < 0.0001) between baseline and last follow-up. PET/CT in follow-up of irradiated meningioma showed an early trend towards decreased binding of SSTR-specific tracers following radiation and MRI demonstrated consistently stable or decreasing tumor volume. Translational research is needed to clarify the underlying biology of the subsequent increase in SSTR PET quantifiers.

Overexpression of Laminin 5γ2 Chain Correlates with Tumor Cell Proliferation, Invasion, and Poor Prognosis in Laryngeal Squamous Cell Carcinoma.

Objective Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor. Laminin 5γ2 chain (LAMC2) was reported to be associated with tumorigenesis. This study explored the role of LAMC2 on LSCC progression by regulating the integrinβ1/FAK/Src/AKT pathway. Methods The level of LAMC2 in 46 LSCC patients was detected by qRT-PCR and western blot. Then the relationship between LAMC2 expression and LSCC malignancy as well as prognosis was analyzed, and the effect of LAMC2 expression on LSCC patient survival was also analyzed using the Kaplan–Meier survival curves. Afterwards, the LSCC cells were transfected with LAMC2 overexpression and knockdown vectors, the effect of LAMC2 on LSCC cell viability, proliferation ability, cell cycle, cell migration, and invasion were detected by CCK-8, colony formation, flow cytometry, wound healing, and Transwell assays. The expression of EMT-related biomarkers and integrin β1/FAK/Src/AKT signaling-related proteins was detected by western blot. Moreover, the effect of LAMC2 on LSCC tumor growth was evaluated by in vivo xenograft experiments and western blot. Results LAMC2 was expressed at high level in LSCC tissues and associated with poor prognosis. LAMC2 overexpression increased TU177 cell viability, proliferation ability, promoted cell cycle, cell migration, and invasion capacity. The expression of N-cadherin, vimentin, and integrinβ1/FAK/Src/AKT related proteins was increased, while the expression of E-cadherin protein was decreased. When the LAMC2 knockdown in AMC-HN-8 cells had opposite effects. Furthermore, shLAMC2 decreased tumor volume and the expression of LAMC2, Ki-67 and integrinβ1, but increased the expression of E-cadherin in LSCC tumor-bearing mice. Conclusion The findings suggested that LAMC2 was overexpressed in LSCC and correlated with poor prognosis. LAMC2 knockdown inhibited LSCC progression by regulating the integrinβ1/FAK/Src/AKT signaling pathway. Therefore, LAMC2 could be a target for LSCC therapy.