Therapeutic Effect Of Radiotherapy Research Articles

Anti irradiation nanoparticles shelter immune organ from radio-damage via preventing the IKK/IκB/NF-κB activation

BackgroundNormal tissue and immune organ protection are critical parts of the tumor radiation therapy process. Radiation-induced immune organ damage (RIOD) causes several side reactions by increasing oxidative stress and inflammatory responses, resulting in unsatisfactory curability in tumor radiation therapy. The aim of this study was to develop a novel and efficient anti irradiation nanoparticle and explore its mechanism of protecting splenic tissue from radiation in mice.MethodsNanoparticles of triphenylphosphine cation NIT radicals (NPs-TPP-NIT) were prepared and used to protect the spleens of mice irradiated with X-rays. Splenic tissue histopathology and hematological parameters were investigated to evaluate the protective effect of NPs-TPP-NIT against X-ray radiation. Proteomics was used to identify differentially expressed proteins related to inflammatory factor regulation. In addition, in vitro and in vivo experiments were performed to assess the impact of NPs-TPP-NIT on radiation therapy.ResultsNPs-TPP-NIT increased superoxide dismutase, catalase, and glutathione peroxidase activity and decreased malondialdehyde levels and reactive oxygen species generation in the spleens of mice after exposure to 6.0 Gy X-ray radiation. Moreover, NPs-TPP-NIT inhibited cell apoptosis, blocked the activation of cleaved cysteine aspartic acid–specific protease/proteinase, upregulated the expression of Bcl-2, and downregulated that of Bax. We confirmed that NPs-TPP-NIT prevented the IKK/IκB/NF-κB activation induced by ionizing radiation, thereby alleviating radiation-induced splenic inflammatory damage. In addition, when used during radiotherapy for tumors in mice, NPs-TPP-NIT exhibited no significant toxicity and conferred no significant tumor protective effects.ConclusionsNPs-TPP-NIT prevented activation of IKK/IκB/NF-κB signaling, reduced secretion of pro-inflammatory factors, and promoted production of anti-inflammatory factors in the spleen, which exhibited radiation-induced damage repair capability without diminishing the therapeutic effect of radiation therapy. It suggests that NPs-TPP-NIT serve as a potential radioprotective drug to shelter immune organs from radiation-induced damage.

A giant solitary fibrous tumor of the abdominal pelvic cavity: A case report and literature review.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor, especially the giant one from the abdominal pelvic cavity. We report on a rare case of a giant SFT of the abdominal pelvic cavity to review the existing literature in detail to improve the diagnosis and treatment of SFT. The patient is a 52-year-old female who presented with 2 weeks of abdominal distension. Abdominal magnetic resonance imaging showed a giant mass (>20 cm) in the abdominal pelvic cavity, considered a mesenchymal tumor. She denies a history of tumor disease. A whole abdomen bulge and a mass of about 18 cm × 10 cm on the right side and middle side were found in the physical examination after admission. Abdominal enhanced computed tomography revealed a giant cystic-solid mass located on the middle and right side of the abdominal pelvic cavity, measuring approximately 20.4 cm × 11.7 cm, with multiple cystic changes and necrosis and compression of adjacent organs and tissues, and marked inhomogeneous enhancement. The patient underwent an open abdominal pelvic cavity giant tumor operation to achieve a radical resection, and did not undergo chemotherapy or radiotherapy. The patient underwent open complete resection of a giant abdominal pelvic tumor with no complications and was diagnosed as SFT according to the pathology, immunohistochemistry showed that the tumor tested positive for CD34(+), STAT-6(+), and Ki-67 (10%). Abdominal computed tomography scans were performed 6 months after resection, and no signs of recurrence or metastasis were found. The clinical symptoms and imaging features of giant abdominal pelvic cavity SFT are not typical. Preoperative diagnosis is difficult and has the potential for malignancy. Based on the results of the current study, there is no standard treatment strategy around the world and the therapeutic effect of radiation therapy and chemotherapy is relatively limited. Thus, complete surgical resection and close clinical follow-up are advocated.

Role of Radiation-related Lung Function Genes in Prognosis and Immune Infiltration of Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common malignant tumor with no obvious clinical symptoms in its early stages. Patients can be divided into radiotherapysensitive groups (RS) and radiotherapy-resistant groups (RR) due to their varying conditions. The therapeutic effect of radiotherapy is quite different between the two groups. Therefore, this paper explores the role of radiation-related lung function genes in LUAD and its immune landscape. Firstly, we divided LUAD samples from the TCGA cohort into RS and RR groups and analyzed differential expression to obtain differentially expressed genes (DEGs). Then, DEGs and patients' grouping information were input into the weighted co-expression network, and the genes in the radiotherapy-related modules were identified. Furthermore, after the intersection of DEGs and lung function-related genes, the prognosis-related genes were obtained through univariate Cox and Lasso-Cox analyses, respectively, and the risk model was constructed. Finally, the differences in prognosis and immunity of the samples in the risk model were explored. Additionally, we also performed a qPCR experiment on lung function-related genes. In this paper, radiation-related genes of LUAD were identified through a series of bioinformatics analyses. By conducting enrichment analysis on these genes, several pathways related to LUAD radiation were identified, and DEGs associated with significant prognosis were determined. Furthermore, a radiation-related risk model of LUAD was developed. All samples were divided into high-risk and low-risk groups based on the risk score, and the differences in immune cell infiltration abundance and immune function between these groups were evaluated. The qPCR experimental results demonstrated a significant difference in the expression of genes related to lung function. The prognosis-related genes identified in this paper and the risk model created can serve as a reference for diagnosing and treating LUAD.

Effect of Therapeutic Radiation on Polycaprolactone/Hydroxyapatite Biomaterials in a Calvarial Model.

Bone defects caused by cancer resection often require postoperative radiotherapy. Although various synthetic polymers have been introduced as graft materials, their biological behavior after radiation exposure remains unclear. Here, we investigated how polycaprolactone/hydroxyapatite (PCL/HA) implants respond to therapeutic radiation exposure (in terms of volume and bone regeneration). Four 8mm diameter calvaria defects were surgically created on the parietal bone of 6 rabbits. PCL/HA implants made of porous, solid, and hybrid polymers were grafted by random placement in each defect. The fourth defect was left untreated. Four weeks after surgery, radiation exposure was conducted weekly for 6 weeks (total: 48Gy). Micro-computed tomography and histologic analysis were performed at 3 and 6 months, and 6 months postradiation, respectively. The total augmented volumes of all implants showed no significant differences between 3- and 6-months postradiation computed tomography images. In histologic analysis, new bone areas were 0.45±0.11mm2, 2.02±0.34mm2, and 3.60±0.77mm2 in solid, hybrid, and porous polymer grafts, respectively. Bone regeneration was limited to the periphery of the defect in the hybrid and porous polymer grafts, whereas new bone formed inside the porous implant. The total augmented volume of the defect was maintained without significant absorption even after radiation exposure. The PCL/HA implant maintained its structure despite radiation exposure. The porous PCL/HA implant demonstrated excellent bone regeneration, followed by the hybrid and solid implants. The PCL/HA implant is a promising candidate for bone defect reconstruction.

The effect of selenium supplementation on sonographic findings of salivary glands in papillary thyroid cancer (PTC) patients treated with radioactive iodine: study protocol for a double-blind, randomized, placebo-controlled clinical trial

BackgroundThyroid cancer is a very damaging disease. The most common treatment for this disease includes thyroidectomy and then using radioactive iodine (RAI). RAI has many side effects, including a decrease in salivary secretions, followed by dry mouth and oral and dental injuries, as well as increased inflammation and oxidative stress. Selenium can be effective in these patients by improving inflammation and oxidative stress and by modulating salivary secretions. So far, only one clinical trial has investigated the effect of selenium on thyroid cancer patients treated with radioiodine therapy (RIT) conducted on 16 patients; considering the importance of this issue, to show the potential efficacy of selenium in these patients, more high-quality trials with a larger sample size are warranted.MethodsThis is a parallel double-blind randomized controlled clinical trial that includes 60 patients aged 20 to 65 years with papillary thyroid cancer (PTC) treated with RAI and will be conducted in Seyyed al-Shohada Center, an academic center for referral of patients to receive iodine, Isfahan, Iran. Thirty patients will receive 200 µg of selenium for 10 days (3 days before to 6 days after RAI treatment) and another 30 patients will receive a placebo for the same period. Sonographic findings of major salivary glands, salivary secretions, and sense of taste will be evaluated before and 6 months after 10-day supplementation.DiscussionDue to its anti-inflammatory and antioxidant effects, as well as improving salivary secretions, selenium may improve the symptoms of thyroid cancer treated with radioactive iodine. In past studies, selenium consumption has not reduced the therapeutic effects of radiation therapy, and at a dose of 300 to 500 μg/day, it has not had any significant side effects in many types of cancer under radiation therapy.Trial registrationIranian Registry of Clinical Trials IRCT20201129049534N6. Registered on 16 September 2021.

Nanoparticle-Mediated Radiotherapy Remodels the Tumor Microenvironment to Enhance Antitumor Efficacy.

Radiotherapy (RT) uses ionizing radiation to eradicate localized tumors and, in rare cases, control tumors outside of the irradiated fields via stimulating an antitumor immune response (abscopal effect). However, the therapeutic effect of RT is often limited by inherent physiological barriers of the tumor microenvironment (TME), such as hypoxia, abnormal vasculature, dense extracellular matrix (ECM), and an immunosuppressive TME. Thus, it is critical to develop new RT strategies that can remodel the TME to overcome radio-resistance and immune suppression. In the past decade, high-Z-element nanoparticles have been developed to increase radiotherapeutic indices of localized tumors by reducing X-ray doses and side effects to normal tissues and enhance abscopal effects by activating the TME to elicit systemic antitumor immunity. In this review, the principles of RT and radiosensitization, the mechanisms of radio-resistance and immune suppression, and the use of various nanoparticles to sensitize RT and remodel TMEs for enhanced antitumor efficacy are discussed. The challenges in clinical translation of multifunctional TME-remodeling nanoradiosensitizers are also highlighted.

Effect of pelvic radiotherapy on patients with stageIB‑IIA cervical cancer after radical hysterectomy: A single‑center retrospective study.

The effects of post-operative adjuvant radiotherapy (RT) on intermediate-risk patients with cervical cancer have not been fully elucidated. Therefore, the present study aimed to investigate the impact of RT on intermediate-risk cervical cancer. The data of 112 patients with stage IB and IIA cervical cancer treated with radical hysterectomy between January 2009 and December 2018 were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and the frequency of adverse events were compared between patients with and without adjuvant RT (RT+ and RT-, respectively). Subgroup analyses of PFS based on tumor size, cervical stromal invasion, lymphovascular space invasion and histology [squamous cell carcinoma (SCC) vs. non-SCC] were performed. Among the 112 patients, 41 received adjuvant RT. Although there were no significant differences in OS or PFS between the RT+ and RT- groups, the frequency of adverse events was much higher in the RT+ group. Patients in the RT+ group also had more recurrent risk factors than those in the RT- group. Based on the subgroup analyses, although no significant differences were observed between any of the groups, RT demonstrated a different impact on PFS between SCC and non-SCC: No difference was observed in the SCC group, whereas patients in the RT+ group tended to have poorer prognoses compared to those in the RT- group of the non-SCC group. These results suggest that the impact of post-operative RT on stage IB and IIA cervical cancer is limited and is accompanied by increased adverse events. The eligibility of patients for post-operative RT should be carefully determined based on the therapeutic effect of RT in each subgroup.

Irradiation-induced exosomal HMGB1 to confer radioresistance via the PI3K/AKT/FOXO3A signaling pathway in ESCC

BackgroundRadioresistance is a major cause of treatment failure in esophageal squamous cell carcinoma (ESCC) radiotherapy, and the underlying mechanisms of radioresistance are still unclear. Irradiation (IR) stimulates changes in tumor-derived exosome contents, which can be taken up by recipient cells, playing an important role in the proliferation, cell cycle and apoptosis of recipient cells. This study investigated the effect of IR-induced exosomal high mobility group box 1 (HMGB1) on radioresistance in ESCC cells.MethodsPlasma exosomes were isolated from 21 ESCC patients and 24 healthy volunteers, and the expression of HMGB1 was examined. Then, the therapeutic effect of radiotherapy was analyzed according to the different expression levels of plasma exosomal HMGB1 in ESCC patients. The uptake of exosomes by recipient cells was verified by immunofluorescence staining, and the localization of exosomes and HMGB1 in cells before and after IR was evaluated. The effects of IR-induced exosomes on cell proliferation, invasion, apoptosis, cell cycle distribution and radioresistance after HMGB1 knockdown were verified. Moreover, western blotting was used to measure changes in the expression of cyclin B1, CDK1, Bax, Bcl2, phosphorylated histone H2AX and the PI3K/AKT/FOXO3A pathway in the HMGB1-knockdown exosome group and the negative control group.ResultsThe expression of HMGB1 in ESCC plasma exosomes was significantly increased compared with that in healthy volunteers, and high expression of HMGB1 in plasma exosomes was associated with radioresistance (P = 0.016). IR-induced the release of exosomal HMGB1 and promoted proliferation and radioresistance in recipient cells, with a sensitization enhancement ratio (SER) of 0.906 and 0.919, respectively. In addition, IR-induced exosomal HMGB1 promotes G2/M phase arrest by regulating the proteins cyclin B1 and CDK1, cooperating with the proteins Bax and Bcl2 to reduce the apoptosis rate through the PI3K/AKT/FOXO3A signaling pathway, and participated in IR-induced DNA damage repair through γH2AX.ConclusionThese findings indicate that high expression of plasma exosomal HMGB1 is associated with an adverse radiotherapy response. IR-induced exosomal HMGB1 enhances the radioresistance of ESCC cells.

TOP2A correlates with poor prognosis and affects radioresistance of medulloblastoma.

Radiotherapy remains the standard treatment for medulloblastoma (MB), and the radioresistance contributes to tumor recurrence and poor clinical outcomes. Nuclear DNA topoisomerase II-alpha (TOP2A) is a key catalytic enzyme that initiates DNA replication, and studies have shown that TOP2A is closely related to the therapeutic effects of radiation. In this study, we found that TOP2A was significantly upregulated in MB, and high expression of TOP2A related to poor prognosis of MB patients. Knockdown of TOP2A inhibited MB cell proliferation, migration, and invasion, whereas overexpression of TOP2A enhanced the proliferative and invasive ability of MB cells. Moreover, si-TOP2A transfection in combination with irradiation (IR) significantly reduced the tumorigenicity of MB cells, compared with those transfected with si-TOP2A alone. Cell survival curve analysis revealed that the survival fraction of MB cells was significantly reduced upon TOP2A downregulation and that si-TOP2A-transfected cells had decreased D0, Dq, and SF2 values, indicating that TOP2A knockdown suppresses the resistance to radiotherapy in MB cells. In addition, western blot analysis demonstrated that the activity of Wnt/β-catenin signaling pathway was inhibited after TOP2A downregulation alone or in combination with IR treatment, whereas overexpression of TOP2A exhibited the opposite effects. Gene set enrichment analysis also revealed that Wnt/β-catenin signaling pathway is enriched in TOP2A high-expression phenotypes. Collectively, these data indicate that high expression of TOP2A leads to poor prognosis of MB, and downregulation of TOP2A inhibits the malignant behaviour as well as the radioresistance of MB cells. The Wnt/β-catenin signaling pathway may be involved in the molecular mechanisms of TOP2A mediated reduced tumorigenicity and radioresistance of MB cells.

Abstract 6216: Intratumoral B0112 in combination with radiotherapy synergizes to achieve CD8 T cell mediated local tumor control

Abstract Background: Radioimmunotherapy combines irradiation of tumor lesions with immunotherapy to achieve local and abscopal control of cancer. Most immunotherapy agents are given systemically, but strategies for delivering immunotherapy locally are under clinical scrutiny to maximize efficacy and avoid toxicity. Local immunotherapy by injecting various patterns of molecules shows efficacy both preclinical and clinically. BO112 is a viral mimetic based on nanoplexed double stranded RNA (poly IC) which exerts immune-mediated antitumor effects in mice and humans upon intratumoral delivery. BO112 and external beam irradiation were used to make the proof-of-concept local immunotherapy plus radiation therapy combinations. Methods: Murine transplantable tumor cells lines (TSA, MC38 and B16 ova) were used to show increased immunogenic features under irradiation as well as bilateral tumor models in which only one of the lesions could be irradiated. Flow cytometry on cell suspensions from tumor draining lymph nodes and multiplex tissue immunofluorescence were used to determine mechanims of antitumor immunity. Depletions of immune cell populations and knock out mice for IFNAAR and BAFT3 genes were used to delineate the immune system requirements for efficacy. Results: In cultures of TSA breast cancer cells the combination of irradiation and BO112 showed more prominent features of immunogenic tumor-cell death including type I interferon reléase. Injection of BO112 in the tumor lesions under radiation achieved excellent control of the treated tumors whilst modest delays in contralateral tumor progression were observed. Local effects were associated with more prominent presence of antitumor CTLs and cDC1 dendritic cells in the tumor and regional lymph nodes. Importantly, local irradiation plus BO112 in a tumor lesion enhanced the therapeutic effect of radiotherapy on distant uninjected tumor lesion. Conclusions: This study demonstrates that local BO112 immunotherapy and external beam radiation therapy can exert synergies to achieve local tumor control. This beneficial effect can be extended to non-injected lesions as long as they are also irradiated, suggesting strategies to treat oligometastatic patients with lesions susceptible to radiotherapy and at least one of them accessible for BO112 repeated intratumoral injections. Citation Format: Maria.E. Rodriguez-Ruiz, Irantzu serrano, Eneko Garate, Inmaculada Rodriguez, maite alvarez, Carmen Molina, Miguel Fernandez de Sanmamed, Leire Arbea, Marta Moreno, Marisol Quintero, Ignacio Melero. Intratumoral B0112 in combination with radiotherapy synergizes to achieve CD8 T cell mediated local tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6216.

X-ray irradiation triggers immune response in human T-lymphocytes via store-operated Ca2+ entry and NFAT activation.

Radiation therapy efficiently eliminates cancer cells and reduces tumor growth. To understand collateral agonistic and antagonistic effects of this treatment on the immune system, we examined the impact of x-ray irradiation on human T cells. We find that, in a major population of leukemic Jurkat T cells and peripheral blood mononuclear cells, clinically relevant radiation doses trigger delayed oscillations of the cytosolic Ca2+ concentration. They are generated by store-operated Ca2+ entry (SOCE) following x-ray-induced clustering of Orai1 and STIM1 and formation of a Ca2+ release-activated Ca2+ (CRAC) channel. A consequence of the x-ray-triggered Ca2+ signaling cascade is translocation of the transcription factor nuclear factor of activated T cells (NFAT) from the cytosol into the nucleus, where it elicits the expression of genes required for immune activation. The data imply activation of blood immune cells by ionizing irradiation, with consequences for toxicity and therapeutic effects of radiation therapy.

Long-term Survival After Diverse Therapeutic Modalities in Malignant Phyllodes Tumors of the Breast.

Background and Objects: Malignant phyllodes tumor of the breast (MPTB) is a rare tumor for which surgery or surgery combined with radiotherapy (RT) is the primary treatment method. However, recently, the therapeutic effect of RT on MPTB has been controversial. We aimed to explore the role of RT, chemotherapy (CT), and surgical modalities in patients with MPTB. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to select patients with MPTB who met the criteria between 2010 and 2018. Kaplan–Meier curves and Cox proportional risk regression models were used to analyze the effects of RT on MPTB patients. Based on this, we compared the effects of breast-conserving surgery (BSC) and mastectomy on the postoperative survival of MPTB. Results: A total of 298 patients with MPTB were included in this study. RT was received by 22.1% (n = 66) of the patients while 77.9% (n = 232) did not receive RT. CT was received by 4.7% (n = 14) patients while 95.3% (n = 284) did not receive CT. According to Kaplan–Meier curves, RT and CT combined resulted in a decrease in breast cancer-specific survival (BCSS) and overall survival (OS) compared to patients who did not receive RT. Mastectomy improved the OS and BCSS of the patients more than BCS). The findings of univariate and multivariate Cox regression analyses suggested that “distant metastasis”, “tumor grade” and “number of positive lymph node biopsies” affected OS of breast cancer, while “distant metastasis”, “tumor grade”, “surgery combined with radiotherapy/surgery”, and “radiotherapy/chemotherapy or not”, had a significant effect on BCSS. Conclusion: RT and CT did not significantly improve the long-term survival of MPTB patients. Mastectomy improved OS and BCSS of the patient more than BCS. RT in an early stage improved early prognosis moderately in MPTB patients with tumor diameter less than 50 mm.

Spacers with boluses applied to various sites of oral squamous cell carcinoma: Technical note and retrospective case series.

The present report describes a case series in which spacers with boluses were used at various sites in the oral cavity to enhance the therapeutic effect of radiation therapy in oral squamous cell carcinoma. In radiotherapy, the surface dose is reduced due to the build-up region of X-rays. In the present study, a bolus was used to complement the build-up region and increase the surface dose effect. A total of 7 patients with oral cancer from a primary care hospital underwent radiation therapy using spacers and added boluses to improve the surface dose effect. The spacer was made from a plastic splint and the bolus was connected to the splint with a quick self-curing resin. There were no complaints of pain or adverse events from the patients while wearing the intraoral splint. A total of 2 of the 7 patients were subsequently confirmed as having progressed disease, and the remaining 5 are currently being managed following a complete response to treatment. The spacers used at various sites of oral squamous cell carcinoma were safe and effective and did not cause any severe adverse effects.

Abstract CT258: EF-32 (TRIDENT): A pivotal randomized trial of radiation therapy concomitant with temozolomide +/- Tumor Treating Fields (TTFields) in newly diagnosed glioblastoma

Abstract Purpose: Tumor treating fields (TTFields) is a non-invasive, loco-regional antimitotic treatment approved as a standard-of-care for newly diagnosed glioblastoma (ndGBM). In the Phase 3 EF-14 trial, TTFields (200 kHz) plus temozolomide (TMZ) post-surgery and chemoradiation significantly increased survival of ndGBM patients compared to TMZ alone. The addition of TTFields was not associated with any increases in systemic toxicity. TTFields-related adverse events (AEs) were mainly dermatological. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of TTFields concomitant with RT and TMZ will be investigated in the TRIDENT trial. Methodology: TRIDENT (NCT04471844) is an international, pivotal randomized trial comparing standard RT with concomitant TMZ vs the triple combination of RT with concomitant TMZ and TTFields. RT is delivered through the TTFields transducer arrays. Patients in both arms will receive maintenance TTFields and TMZ. TTFields (200 KHz) will be delivered >18 hours/day using the Optune device. TTFields treatment will be continued until the second disease recurrence. Patients with pathologically confirmed ndGBM, ≥ 18 years (≥ 22 years in the US), KPS ≥ 70, either sex, post-surgery or biopsy, and candidates for RT/TMZ therapy will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points include progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), PFS (PFS6M, PF12M, PFS2Y); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields/RT/TMZ will significantly improve OS versus RT/TMZ. Sample size (N=950; 475/arm) will detect a HR< 0.8 with 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive. The TRIDENT trial is currently enrolling patients. Citation Format: Wenyin Shi, Lawrence Kleinberg, Suriya A. Jeyapalan, Samuel A. Goldlust, Seema Nagpal, Stephanie E. Combs, David Roberge, Ryo Nishigawa, Rachel Grossman, Martin Glas. EF-32 (TRIDENT): A pivotal randomized trial of radiation therapy concomitant with temozolomide +/- Tumor Treating Fields (TTFields) in newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT258.

Impact of metformin on the therapeutic effect of radiotherapy

ObjectiveTo explore the effect of metformin on therapeutic outcomes in cancer patients undergoing radiotherapy. MethodsA literature search of the electronic databases was conducted to retrieve articles that investigated the effect of metformin on radiotherapy. Timeframe of electronic search ranged from the inception of each database to May 2020. These databases include PubMed, Embase and Scopus. ResultsFrom an initial search of 142 articles, and after the removal of duplicates as well as applying the inclusion and the exclusion criteria, 20 articles were finally included in this systematic review. Results from the reviewed clinical studies showed promising therapeutic effect of the combination of metformin with radiotherapy. Metformin has promising therapeutic effects as an adjuvant with radiotherapy. ConclusionsThe use of metformin as an adjuvant with radiotherapy should be treated with caution, as further studies investigating its optimal dose as well as molecular mechanisms are still needed.

ES-2 Phase 3 TRIDENT Trial: Radiation and Temozolomide with or without Tumor Treating Fields in newly diagnosed glioblastoma

Background: Tumor treating fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard-of-care for glioblastoma. In the EF-14 Phase 3 trial, TTFields (200 kHz) plus temozolomide (TMZ) significantly increased survival of patients with newly diagnosed GBM(ndGBM) without increasing systemic toxicity. TTFields-related AEs were mainly skin AEs. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of concomitant TTFields with RT and TMZ will be tested in the TRIDENT trial. Methods: TRIDENT is an international phase III randomized trial comparing standard RT/TMZ vs the triple combination of RT/TMZ with concomitant TTFields. RT is delivered through the TTFields arrays. Patients in both arms will receive maintenance TTFields/TMZ. TTFields (200 kHz) will be delivered over18 hours/day using Optune. Patients will continue TTFields treatment until second recurrence. Patients with pathologically confirmed ndGBM, over 18 years old, KPS over 70, either sex, post-surgery or biopsy, and amenable for RT/TMZ therapy will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points: progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), progression-free survival (PFS2, PFS6, PFS12); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields/RT/TMZ will significantly improve OS versus RT/TMZ. Sample size (N=950; 475/arm) will detect a HR lower than 0.8 with 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive.

CTNI-74. PHASE 3 TRIDENT TRIAL: CONCOMITANT RADIATION THERAPY (RT) AND TEMOZOLOMIDE +/- TUMOR TREATING FIELDS (TTFIELDS) IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Tumor treating fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard-of-care for newly diagnosed glioblastoma (ndGBM). In the EF-14 Phase 3 trial, TTFields (200 kHz) plus temozolomide (TMZ) significantly increased survival of ndGBM patients without increasing systemic toxicity. TTFields-related AEs were mainly skin AEs. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of concomitant TTFields with RT and TMZ will be tested in the TRIDENT trial. METHODS TRIDENT is an international phase III randomized trial comparing standard RT with TMZ vs the triple combination of RT/TMZ with concomitant TTFields. RT is delivered through the TTFields arrays. Patients in both arms will receive maintenance TTFields/TMZ. TTFields (200 KHz) will be delivered >18 hours/day using Optune. Patients will continue TTFields treatment until second recurrence. Patients with pathologically confirmed ndGBM, ≥ 18 years, KPS ≥ 70, either sex, post-surgery or biopsy, and amenable for RT/TMZ therapy will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points: progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), progression-free survival (PFS6M, PF12M, PFS2Y); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields/RT/TMZ will significantly improve OS versus RT/TMZ. Sample size (N=950; 475/arm) will detect a HR< 0.8 with 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive.

PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation

The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; however, resistant cells rapidly initiate mechanisms to repair such damage. While DNA repair mechanisms responsible for cancer cell survival following DNA damage are understood, less is known about the epigenetic mechanisms resulting in resistance to radiotherapy. Although changes in DNA methylation are related to mechanisms of long-term resistance, it is more likely that the methylation state of a series of proteins could be responsible for the first-line of defense of cancer cells against irradiation. In this study, we observed that irradiation of breast cancer cells was accompanied by an overproduction in S-adenosylmethionine, which increases the activity of cellular methylases. We found that by activating PRMT1, irradiation triggers a BRCA1-dependent program that results in efficient DNA repair and inhibition of apoptosis. Depletion of PRMT1 in irradiated cells resulted in a switch of BRCA1 functions from repair and survival in the nucleus to activation of cell death signals in the cytoplasm. We conclude that by modulating the cellular localization of BRCA1, PRMT1 is an important regulator of the oncogenic functions of BRCA1, contributing to the epigenetic defense of breast cancer cells against ionizing radiation.

Phase III TRIDENT trial: Radiation and temozolomide +/- tumor treating fields in newly diagnosed glioblastoma.

TPS2580 Background: Tumor treating fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard of care for glioblastoma (GBM). In the EF-14 phase III trial, TTFields (200 kHz) plus temozolomide (TMZ) significantly increased the survival of patients with newly diagnosed GBM (ndGBM) without increase in systemic toxicity. TTFields-related AEs were mainly skin AEs. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of concomitant TTFields with RT and TMZ will be tested in this phase III TRIDENT randomized trial. Methods: TRIDENT is an international phase III randomized trial comparing standard RT with TMZ vs the triple combination of RT plus TMZ with concomitant TTFields. RT is delivered through the TTFields arrays. Patients in both arms will receive maintenance TTFields with TMZ. TTFields (200 KHz) will be delivered >18 hours/day using Optune. Patients will continue TTFields treatment until second recurrence. Patients with pathologically confirmed newly ndGBM, ≥ 18 years, KPS ≥ 70, either sex, post-surgery or biopsy, who are amenable for RT/TMZ therapy will be enrolled. Patients will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points include: progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), progression-free survival (PFS2, PFS6, PFS12); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields with radiation and TMZ will significantly improve OS as compared to radiation and TMZ alone. The sample size is 950, with 475 in each arm to detect a HR <0.8 with a 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients who are lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive.

The emerging role of myeloid-derived suppressor cells in radiotherapy.

Radiotherapy (RT) has been used for decades as one of the main treatment modalities for cancer patients. The therapeutic effect of RT has been primarily ascribed to DNA damage leading to tumor cell death. Besides direct tumoricidal effect, RT affects antitumor responses through immune-mediated mechanism, which provides a rationale for combining RT and immunotherapy for cancer treatment. Thus far, for the combined treatment with RT, numerous studies have focused on the immune checkpoint inhibitors and have shown promising results. However, treatment resistance is still common, and one of the main resistance mechanisms is thought to be due to the immunosuppressive tumor microenvironment where myeloid-derived suppressor cells (MDSCs) play a crucial role. MDSCs are immature myeloid cells with a strong immunosuppressive activity. MDSC frequency is correlated with tumor progression, recurrence, negative clinical outcome, and reduced efficacy of immunotherapy. Therefore, increasing efforts to target MDSCs have been made to overcome the resistance in cancer treatments. In this review, we focus on the role of MDSCs in RT and highlight growing evidence for targeting MDSCs in combination with RT to improve cancer treatment.