Improve Radiotherapy Outcomes Research Articles

Open-Face Masks in Radiotherapy: Enhancing Therapeutic Strategies for Head and Neck and Brain Cancer Patients-A Comprehensive Scoping Review.

Introduction: The main goal of radiotherapy (RT) is to deliver a precise dose to the target while sparing the surrounding normal tissue and minimizing side effects. Appropriate patient immobilization is crucial, especially for head and neck cancer (HNC) and Brain Cancer (BC). Conventional closed-face masks (CFMs), while effective in minimizing head motion, can cause significant discomfort, anxiety, and claustrophobia. Open-face masks (OFMs) have been developed to increase patient comfort while providing precise immobilization. Methods: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) extension for scoping reviews and the Arskey and O'Malley framework, an electronic search of EMBASE, PubMed, SCOPUS, and Web of Science was conducted to identify original studies reporting the use and description of OFMs in clinical practice up to April 2024. The inclusion criteria were English-language articles focusing on OFMs for HNC and BC patients undergoing RT. Results: Of 618 titles, 19 articles fulfilled the selection criteria. Most studies were comparative (n = 13) or observational (n = 6). The articles were categorized by treatment site, resulting in three groups: BC (n = 14, 68.4%), HNC (n = 4, 21.4%), and mixed (n = 2, 10.5%), which includes both BC and HNC. Of note, 82.4% (n = 16) of the included studies were published from 2020 onwards, emphasizing the recent adoption of OFM in clinical practice. Conclusions: The reviewed studies show that OFMs, in combination with SGRT, offer significant advantages in terms of patient comfort and positioning accuracy in HNC and BC treatments. Reproducibility in the sub-millimeter and sub-degree range can be achieved, which supports the use of OFMs in clinical practice. Future research should explore innovative combinations of immobilization and monitoring to further improve RT outcomes and ensure precise treatment while increasing patient comfort.

Abstract 1282: Gavage with Candida albicans leads to fungal colonization of colorectal tumors and decreased response to radiotherapy

Abstract The host microbiome in the gut and tumors have been shown to affect tumor growth and therapeutic response in cancer. Furthermore, the presence of specific fungal taxa are associated with tumor hypoxia, tumor progression, therapeutic response, and clinical outcomes in colorectal cancer (CRC). Preliminary data from our group found that the presence of Candida species increased tumor hypoxia and decreased overall survival in CRC. However, whether intratumoral Candida drive, support, or simply inhabit tumors with poor prognoses remains unclear. Here, we investigate a casual role for Candida albicans in tumor progression and therapy response using a syngeneic mouse model of microsatellite-instability high (MSI-H) colorectal cancer. We subcutaneously implanted MC38 colorectal cancer cells into C57BL/6 mice and then orally gavaged these mice with C. albicans, Saccharomyces cerevisiae, or PBS. The site of tumor formation was locally irradiated once (7.5 Gy), and growth of the tumor was measured over time. Differences in tumor volume were assessed by longitudinal mixed-effect models. Tumor sections were stained for fungi using calcofluor white (CFW) and underwent bulk RNA sequencing to detect differential gene expression, which were interpreted using gene set enrichment analysis (GSEA). Mice gavaged with C. albicans showed decreased response to radiation compared to mice gavaged with either S. cerevisiae (p<0.05) or PBS (p<0.001). Additionally, hyphae were observed in murine tumors gavaged with C. albicans, suggesting translocation of gavaged C. albicans from the gut to tumors. Further, tumors from mice gavaged with C. albicans displayed unique gene expression profiles, including decreased interferon alpha and IL-6 and STAT3 signaling, decreased oxidative phosphorylation, and decreased apoptosis-related gene expression. Here, we show that C. albicans may confer resistance to radiation therapy and affects immune and cancer cell activity in the MC38 (MSI-H) syngeneic in vivo model of colorectal cancer. Further, we show that hyphal fungi can be visualized in heterotopic murine tumors from our C. albicans gavage condition. These data establish that fungi can translocate from the gut to distal tumor sites, and that upon translocation, changes in gene expression and therapy response are observed. Future directions will explore the mechanism by which these effects occur and whether these findings can be leveraged to improve radiotherapy outcomes. Citation Format: Dennis J. Grencewicz, Alexander Loncar, Rebecca Hoyd, Aaditya Pallerla, Nyelia Williams, Martin Benej, McKenzie Kreamer, Yogita Mehra, Shiva Jahanbakhshi, Matthew Anderson, Nicholas Denko, Daniel Spakowicz. Gavage with Candida albicans leads to fungal colonization of colorectal tumors and decreased response to radiotherapy [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 1282.

Genomic-driven nutritional interventions for radiotherapy-resistant rectal cancer patient

Radiotherapy response of rectal cancer patients is dependent on a myriad of molecular mechanisms including response to stress, cell death, and cell metabolism. Modulation of lipid metabolism emerges as a unique strategy to improve radiotherapy outcomes due to its accessibility by bioactive molecules within foods. Even though a few radioresponse modulators have been identified using experimental techniques, trying to experimentally identify all potential modulators is intractable. Here we introduce a machine learning (ML) approach to interrogate the space of bioactive molecules within food for potential modulators of radiotherapy response and provide phytochemically-enriched recipes that encapsulate the benefits of discovered radiotherapy modulators. Potential radioresponse modulators were identified using a genomic-driven network ML approach, metric learning and domain knowledge. Then, recipes from the Recipe1M database were optimized to provide ingredient substitutions maximizing the number of predicted modulators whilst preserving the recipe’s culinary attributes. This work provides a pipeline for the design of genomic-driven nutritional interventions to improve outcomes of rectal cancer patients undergoing radiotherapy.

7-Geranyloxcycoumarin enhances radio sensitivity in human prostate cancer cells.

Prostate cancer is the second most prevalent and the fifth deadliest cancer among men worldwide. To improve radiotherapy outcome, we investigated the effects of 7-geranyloxycoumarin, also known as auraptene (AUR), on radiation response of prostate cancer cells. PC3 cells were pretreated with 20 and 40 µM AUR for 24, 48 and 72h, followed by X-ray exposure (2, 4 and 6Gy). After 72h recovery, cell viability was determined by alamar Blue assay. Flow cytometric analysis was performed to assess apoptosis induction, clonogenic assay was carried out to investigate clonogenic survival, and the expression of P53, BAX, BCL2, CCND1 and GATA6 was analyzed by quantitative polymerase chain reaction (qPCR). Cell viability assay indicated that toxic effects of radiation was enhanced by AUR, which was also confirmed by increased numbers of apoptotic cells and reduced amount of survival fraction. The qPCR results demonstrated significant induction of P53 and BAX, while the expression of BCL2, GATA6, and CCND1 was significantly downregulated. The findings of the present study indicated, for the first time, that AUR improved radio sensitivity in prostate cancer cells, and thus, has the potential to be used in future clinical trials.

A competing risk analysis of the patterns and risk factors of recurrence in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy

IntroductionTo assess patterns of recurrence after stereotactic ablative radiotherapy (SABR) in patient ineligible to surgery with early-stage non-small cell lung cancer (ES-NSCLC), report survival and treatment after first recurrence. MethodsWe performed a retrospective analysis on 1068 patients with ES-NSCLC and 1143 lesions. Between group differences were estimated using competing risk analysis and cause-specific hazard ratios were calculated. Overall survival (OS) after first recurrence was calculated. ResultsMedian follow-up was 37.6 months. Univariate analysis demonstrated that ultra-central location was associated with higher risk of regional recurrence (RR) and distant metastasis (DM) (p = 0.004 and 0.01). Central lesions were associated with higher risk of local recurrence (LR) and RR (p < 0.001). Ultra-central lesions were associated with shorter OS (p = 0.002) compared to peripheral lesions. In multivariate analysis, central location was the only factor associated with increased LR and RR risks (p = 0.016 and 0.005). Median OS after first recurrence was 14.8 months. There was no difference in OS after first recurrence between ultra-central, central, and peripheral lesions (p = 0.83). Patients who received a second SABR course had an OS of 51.3 months, compared to 19.5 months with systemic therapy and 8.1 months with supportive care (p < 0.0001). DiscussionThe main prognostic factor for LR and RR risks was central location. Ultra-central and central tumors might benefit from treatment intensification strategies such as dose escalation and/or addition of systemic therapy to improve radiotherapy outcomes. After a first recurrence post SABR, patients with contralateral lung recurrences and those who were eligible to receive a second course of SABR had improved OS.

Phase 2, multicenter, randomized study of salvage radiation therapy +/- metformin for recurrent prostate cancer after radical prostatectomy (SAKK 08/15 – GETUG-AFU 34 PROMET trial).

353 Background: Pre-clinical and retrospective clinical data support an interaction of metformin (MET) and radiotherapy. Thus, MET may represent a cost-effective means to improve radiotherapy outcomes. We sought to investigate whether MET increases time to progression (TTP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). Methods: Non-diabetic men with biochemical recurrence after RP were enrolled into an open label, randomized, phase 2 study in 17 hospitals in Switzerland, France, and Germany. The randomization (1:1) was stratified by Gleason score (&lt;8 vs ≥8), surgical margin status (R0 vs R1), PSA at randomization (PSA &gt; 0.5 vs ≤ 0.5 ng/mL), ADT use, and evidence of local recurrence. Following randomization, patients received either prostate bed SRT (70Gy) or prostate bed SRT (70Gy) + MET. MET 850mg PO QD was given for 4 weeks before SRT, then 850mg PO QD for 48 weeks. The primary endpoint was TTP. Secondary endpoints were progression-free survival, undetectable PSA under normal testosterone levels, 50% PSA response, clinical progression-free survival, time to further systemic therapy, prostate cancer-specific survival, overall survival, and adverse events (AE). The trial design was powered for a HR 0.65 with planned enrollment of 170 patients. The trial was prematurely closed by the sponsor due to financial reasons. Data is reported after patients reached a minimum follow-up of 12 months after SRT and corresponds to the final analysis. Results: A total of 111 patients were randomized (106 evaluable) between 10/2017 and 11/2020. The median PSA at randomization was 0.3 ng/mL (range, 0.03-1.5 ng/mL), 19 patients (17.9%) had Gleason ≥8, 54 (50.9%) pT3 disease, and 50 (47.2%) positive surgical margins. Twenty-four patients (22.6%) used short-term ADT. Trial arms were well balanced. At a median follow-up of 27.1 months (95% CI: 26.7-27.8), a total of 16 progression events occurred. The median TTP was not reached in either treatment arm. The hazard ratio adjusted by stratification factors was 1.25 (95% CI: 0.40-3.94; one-sided 80% CI: 2.05; log-rank p=0.62). Two-year TTP was 89% (95% CI: 76%-96%) in the SRT arm vs 82% (95% CI: 67%-91%) in the SRT + MET arm. No statistically significant differences were found for the secondary endpoints. Most common AE during treatment was grade 1-2 diarrhea (24.1% SRT vs 54.6% SRT + MET). Grade 2 and 3 AE (gastrointestinal and/or urinary) were 25.9% and 3.7% with SRT vs 34.5% and 7.3% with SRT + MET (p=0.41 and p=0.68), respectively. Conclusions: Adding MET to SRT did not result in a significant improvement in TTP in non-diabetic men with recurrent prostate cancer post-RP. Because of early trial closure and fewer than expected events, the trial may have been underpowered for this endpoint. Additional correlative studies will be pursued. Clinical trial information: NCT02945813 .

PARP-1 genetic polymorphism associated with radiation sensitivity of non-small cell lung cancer.

About 70% of non-small cell lung cancer (NSCLC) patients require radiotherapy. However, due to the difference in radiation sensitivity, the treatment outcome may differ for the same pathology and choice of treatment. Poly (ADP-ribose) polymerase 1 (PARP-1) is a key gene responsible for DNA repair and is involved in base excision repair as well as repair of single strand break induced by ionizing radiation and oxidative damage. In order to investigate the relationship between PARP-1 gene polymorphism and radiation sensitivity in NSCLC, we collected 141 primary NSCLC patients undergoing three-dimensional conformal radiotherapy. For each case, the gross tumor volumes (GTV) before radiation and that after 40Gy radiation were measured to calculate the tumor regression rate. TaqMan real-time polymerase chain reaction was performed to genotype the single-nucleotide polymorphisms (SNPs). Genotype frequencies for PARP-1 genotypes were 14.2% for C/C, 44.7% for C/G and 41.1% for G/G. The average tumor regression rate after 40Gy radiation therapy was 35.1% ± 0.192. Tumor regression rate of mid-term RT of C/C genotype was 44.6% ± 0.170, which was higher than that of genotype C/G and G/G (32.4% ± 0.196 and 34.8% ± 0.188, respectively) with statistical significance (F = 3.169 p = 0.045). The higher tumor regression rate in patients with C/C genotype suggested that G allele was a protective factor against radiation therapy. Using the median tumor regression rate of 34%, we divided the entire cohort into two groups, and found that the frequency distribution of PARP-1 gene rs3219073 had significant difference between these two groups (p < 0.05). These results showed that PARP-1 gene polymorphism may affect patient radiation sensitivity and predict the efficacy of radiotherapy. It therefore presents an opportunity for developing new therapeutic targets to improve radiotherapy outcome.

Review of recent impacts of artificial intelligence for radiation therapy procedures

Artificial intelligence (AI) is a discipline of computing science whose goal is to develop intelligent computer-based systems replicating humans' decision-making and problem-solving abilities. Globally, 26 million new cancer cases are expected to be diagnosed in 2030, with cancer death accounting for nearly half of the incidence. The challenge in radiation therapy is increasing tumor control probability while minimizing damage to surrounding normal tissue. The objective of this review study is to review the recent developments in the use of AI for radiation therapy and dose optimization. The current study examines recent research publications published in the last ten years on the Web of Science, Scopus, and PubMed databases related to AI. The study revealed that AI is valuable, helps improve radiotherapy outcomes, and allows for the processing and analysis of enormous datasets. AI enables the iterative implementation of complicated functions in massive data files (e.g., defining healthy tissue or determining ideal treatment planning) for image segmentation and outcome prediction, benefiting the entire radiation therapy community.

Prediction of treatment response from the microenvironment of tumor immunity in cervical cancer patients treated with chemoradiotherapy.

To supplement clinical decision-making in the management of cervical cancer, various prognostic factors, including tumor immune microenvironments, were examined in patients with cervical cancer treated with definitive chemoradiotherapy. We retrospectively analyzed the expression of CD8, FoxP3, HLA-1, PD-L1, and XRCC4 in 100 cases of cervical cancer. The observed tumor immune microenvironments were also classified into three types: inflamed, excluded, and cold type. Less FoxP3+ T cells and cold-type tumor were found to be poor prognostic factors in addition to non-SCC, large pre-treatment tumor volume, and three or less cycles of concurrent chemotherapy based on multivariate analysis. Cold-type tumors had significantly worse prognoses than the other two types, whereas inflamed- and excluded-type tumors showed similar 5-year disease-specific survival (P < 0.001; 0% vs. 60.3% vs. 72.3%). Radiotherapy could overcome the inhibitory immune microenvironment that occurs in excluded type. Individualized combination therapy adapted to pre-treatment tumor immunity may be necessary to improve radiotherapy outcomes in cervical cancer.

Abstract PO-014: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP): A promising radiochemotherapy for gastroenteropancreatic neuroendocrine tumors

Abstract Background: Peptide receptor radionuclide therapy (PRRT) is a novel radiotherapy approved for gastroenteropancreatic neuroendocrine tumors (GEP-NETs); however, PRRT has a relatively low treatment response rate of 20-30%. We hypothesize that addition of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a ribonucleotide reductase (RnR) inhibitor that inhibits the rate-limiting enzyme of DNA synthesis and repair, can improve radiotherapy outcomes. The purpose of this study is to determine the therapeutic rationale of RnR-targeted therapy and evaluate 3-AP as a radiosensitizer in treating GEP-NET in vitro and in vivo. Methods: We utilized two human GEP-NET cell lines: BON, a pancreatic carcinoid tumor, and QGP-1, a somatostatinoma. (i) Cells were treated with 3-AP for 96h and cell proliferation assays were performed using a sulforhodamine B (SRB) kit. Next, cells were treated with 3-AP for 24, 48, 72, 96h and cell cycle analyses were performed with Beckman Coulter cell cycle kit and quantified by flow cytometry. Expression of cell cycle arrest markers (i.e., pCdk-1, cyclin D1) was assessed by immunoblotting. (ii) To determine radiosensitivity in vitro, cells were treated with 3-AP for 16h, followed by X-ray radiotherapy (XRT), and incubation in drug-free medium. Cell survival was assessed by colony formation assay and quantified by SRB kit at 14d post-XRT. Apoptosis was measured at 72 and 96h post-XRT, and expression of apoptotic proteins (i.e., cleaved PARP and cleaved CASPASE 3) was examined by immunoblotting. (iii) To determine radiosensitivity in vivo, we randomized 20 nude mice bearing QGP-1 xenografts into four groups: control; 3-AP (10mg/Kg); XRT (2 Gy); and combination (XRT immediately followed by 3-AP); each mouse received 5 consecutive treatments. Results: (i) A dose of 2500nM 3-AP arrested cells before entering G2/M phase, significantly reducing percentage of G2/M cells from 8.4% to 0.5% at 72h. Concurrently, we observed increased expression of checkpoint proteins (pRb, pCdk1, pCdk2, pCdc2) and decreased expression of cell cycle inhibitory proteins (cyclin D1, p21, p27 Kip). (ii) Exposure of QGP-1 and BON cells to 3-AP prior to XRT resulted in a synergistic decrease (i.e., 85% and 90%, respectively) in clonogenicity. Furthermore, the combination of 3-AP and XRT increased apoptosis 5-fold and cleaved PARP expression in BON cells. (iii) A significant decrease in tumor size was noted in mice with XRT alone compared to control (146mm2 vs. 280 mm2, respectively); combination treatment (3-AP + XRT) demonstrated a further 48% decrease in tumor size compared to XRT alone. There was no significant decrease in tumor size with 3-AP treatment alone. Conclusion: 3-AP treatment prior to XRT therapy resulted in significant increase in apoptosis in vitro and decrease in tumor size in vivo, suggesting synergistic cytotoxicity and radiosensitivity. Selective RNR inhibition by 3-AP provides a potent therapeutic strategy as a radiosensitizer and offers a novel approach in treating advanced GEP-NETs. Citation Format: Zeta Chow, Jeremy Johnson, Aman Chauhan, Tadahide Isumi, Lowell Anthony, Courtney M. Townsend, B. Mark Evers, Piotr Rychahou. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP): A promising radiochemotherapy for gastroenteropancreatic neuroendocrine tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-014.

MiRNA as promising theragnostic biomarkers for predicting radioresistance in cancer: A systematic review and meta-analysis.

Radioresistance remains as an obstacle in cancer treatment. This systematic review and meta-analysis aimed to evaluate the association between the expression of miRNAs and responses to radiotherapy and the prognosis of different tumors. In total, 77 miRNAs in 19 cancer types were studied, in which 24 miRNAs were upregulated and 58 miRNAs were downregulated in cancer patients. Five miRNAs were differentially expressed. Moreover, 75 miRNAs were found to be related to radioresistance, while 5 were observed to be related to radiosensitivity. The pooled HR and 95 % confidence interval for the combined studies was 1.135 (0.819-1.574; P-value = 0.4). The HR values of the subgroup analysis for miR-21 (HR = 2.344; 95 % CI: 1.927-2.850; P-value = 0.000), nasopharyngeal carcinoma (HR = 0.448; 95 % CI: 0.265-0.760; P = 0.003) and breast cancer (HR = 1.131; 95 % CI: 0.311-4.109; P = .85) were obtained. Our results highlighted that across the published literature, miRNAs can modulate tumor radioresistance or sensitivity by affecting radiation-related signaling pathways. It seems that miRNAs could be considered as a theragnostic biomarker to predict and monitor clinical response to radiotherapy. Thus, the prediction of radioresistance in malignant patients will improve radiotherapy outcomes and radiotherapeutic resistance.

Virtual Spacer Implantation Platform Based on Finite Element Method for Simulation and Planning Patient-Specific Spacer Placement

In recent years, due to major advances in radiotherapy (RT) delivery systems, more attention is paid to integrating RT into cancer management. Efficacy of advanced RT techniques like stereotactic body radiation therapy is shown for lung, liver, prostate and pancreas cancer. Use of RT, however, can be limited due to proximity of organs at risk (OARs). Previous studies show dosimetric benefits of spacers, namely dose escalation and increasing OAR sparing, to make separation between target and OARs for prostate and recent studies for pancreas. Yet, dosimetric benefits of placement of spacer highly depend on location and shape of spacer implanted. Accordingly, purpose of our study is to reduce geometric uncertainties of spacer placement by presenting a simulation platform that generates an optimized plan for spacer implantation. Pre- and post-spacer paired computed tomography (CT) are acquired. Gross target volume (GTV) and OARs are delineated by physician, as well as, spacer in the post-injection CT. Data is anonymized and fed into our simulation platform to create finite element model (FEM) of spacer placement process and simulate using finite element analysis (FEA). In this study, location of spacer is determined by post-injection CT for validation. To do so, pre- and post-injection CTs are registered by a rigid registration method while bones and later head of pancreas and prostate are used as landmark. To ensure the accuracy and convergence of FEA, anatomical and physical properties of organs are considered as a set of patient-specific boundary conditions. Finally, result of FEA is interpreted as deformations of 3D CT images and structures. To evaluate performance of simulation, we utilized overlap volume histogram (OVH) thresholds, L3cc and L9cc defined as overlapping tumor and OAR volume at 3mm and 9mm expansion of GTV, while introducing Distance Angular Histogram (DAH) to assess spatial performance of our method. 4 cases of hydrogel spacer are included in this study: 2 prostate and 2 pancreas cases. Applicable to any type of spacer, we used hydrogel cases for validation due to considerably higher level of biomechanical complexity. OVH thresholds (L3cc and L9cc) are similar for virtual and post injection cases, and considerably lower compared to pre-injection (table_1). Further, DAH shows that distribution of distance between tumor and OAR is more than a simple shift, and thus, closer to reality. Although spacer can improve RT outcome, its use is impeded by uncertainties associated with placement procedure. Our virtual spacer platform is aimed to help planning placement of spacer and obviate uncertainties of using it. Future studies will focus on improving performance and integration to real-time ultrasound guided procedure.Tabled 1Abstract 2678; TableOVH MetricL3mmL9mmSitesPancreasProstatePancreasProstateCasesABCDABCDPre-Injection0.0050.015000.0700.1600.0200.126Post-Injection00000.0140.0140.0050.004Virtual Spacer00000.0190.0120.0010.005 Open table in a new tab

INOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to radiotherapy, chemotherapy, or a combination of these modalities, and surgery remains the only curative intervention for localized disease. Although cancer-associated fibroblasts (CAF) are abundant in PDAC tumors, the effects of radiotherapy on CAFs and the response of PDAC cells to radiotherapy are unknown. Using patient samples and orthotopic PDAC biological models, we showed that radiotherapy increased inducible nitric oxide synthase (iNOS) in the tumor tissues. Mechanistic in vitro studies showed that, although undetectable in radiotherapy-activated tumor cells, iNOS expression and nitric oxide (NO) secretion were significantly increased in CAFs secretome following radiotherapy. Culture of PDAC cells with conditioned media from radiotherapy-activated CAFs increased iNOS/NO signaling in tumor cells through NF-κB, which, in turn, elevated the release of inflammatory cytokines by the tumor cells. Increased NO after radiotherapy in PDAC contributed to an acidic microenvironment that was detectable using the radiolabeled pH (low) insertion peptide (pHLIP). In murine orthotopic PDAC models, pancreatic tumor growth was delayed when iNOS inhibition was combined with radiotherapy. These data show the important role that iNOS/NO signaling plays in the effectiveness of radiotherapy to treat PDAC tumors. SIGNIFICANCE: A radiolabeled pH-targeted peptide can be used as a PET imaging tool to assess therapy response within PDAC and blocking iNOS/NO signaling may improve radiotherapy outcomes.

The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach

Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

Enhancing the Bystander and Abscopal Effects to Improve Radiotherapy Outcomes.

In this paper, we summarize published articles and experiences related to the attempt to improve radiotherapy outcomes and, thus, to personalize the radiation treatment according to the individual characteristics of each patient. The evolution of ideas and the study of successively published data have led us to envisage new biophysical models for the interpretation of tumor and healthy normal tissue response to radiation. In the development of the model, we have shown that when mesenchymal stem cells (MSCs) and radiotherapy are administered simultaneously in experimental radiotherapy on xenotumors implanted in a murine model, the results of the treatment show the existence of a synergic mechanism that is able to enhance the local and systemic actions of the radiation both on the treated tumor and on its possible metastasis. We are convinced that, due to the physical hallmarks that characterize the neoplastic tissues, the physical–chemical tropism of MSCs, and the widespread functions of macromolecules, proteins, and exosomes released from activated MSCs, the combination of radiotherapy plus MSCs used intratumorally has the effect of counteracting the pro-tumorigenic and pro-metastatic signals that contribute to the growth, spread, and resistance of the tumor cells. Therefore, we have concluded that MSCs are appropriate for therapeutic use in a clinical trial for rectal cancer combined with radiotherapy, which we are going to start in the near future.

Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-\u03baB Pathway

Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Combination treatment showed the best tumour inhibition compared to that of orlistat alone or RT alone. These results suggest that prostate cancer treated by conventional RT could be improved by orlistat via inhibition of FASN.

Buparlisib with thoracic radiotherapy and its effect on tumour hypoxia: A phase I study in patients with advanced non-small cell lung carcinoma

BackgroundPre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosensitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia. MethodsThis was a 3 + 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18F-fluoromisonidazole positron-emission tomography–computed tomography at baseline and following 1 week of buparlisib. ResultsTwenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were ≤grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD. ConclusionThis is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes.

Combined Effect of Moringa oleifera and Ionizing Radiation on Survival and Metastatic Activity of Pancreatic Cancer Cells.

Background: Radiotherapy is one of the main treatments for malignancies. Radioresistance is a major obstacle in this treatment, calling for new treatments to improve radiotherapy outcome. Herbal medicine has low toxicity and could be a source for new radio-enhancing agents. Moringa oleifera (moringa) is a well-known medicinal plant with antiproliferative and antimetastatic properties. Possible mechanisms of moringa anticancer activity may be related to the expression of PARP-1, Bcl-2, COX-2, p65, p-IκB-a, and others. Purpose: The aims of the present study were to investigate effect of moringa alone and combined with radiation on survival and metastatic activity of pancreatic cancer cells and on tumor growth. Methods and Results: The combination of moringa and radiation significantly inhibited PANC-1 cell survival in a dose-dependent manner, as tested by clonogenic and XTT assays. Moreover, standard transwell cell migration/invasion assays demonstrated reduced metastatic activity of these cells. Pyruvate mitigated the inhibitory effect of combined treatment on cell survival. Flow cytometry of moringa-treated cells revealed induction of apoptosis. Western blot analysis found that the combined treatment decreased expression of the pro-apoptotic protein Bcl-2, and downregulated the key component of DNA repair pathways PARP-1 and the NF-κB-related proteins IκB-α, p65-subunit, and COX-2. Moringa significantly inhibited growth of subcutaneous tumors generated by PANC-1 cells in nude mice. Immunohistochemical analysis demonstrated moringa’s antiproliferative and antiangiogenic effects. Conclusions: Moringa decreased pancreatic cancer cell survival and metastatic activity and significantly inhibited tumor growth. The combination of moringa plus radiation resulted in an additional inhibitory effect that provided the rationale for further investigation of this combination as a novel strategy to overcome pancreatic cancer cell radioresistance.

PO-248 The role of ER stress in arginine deprivation-induced radiosensitization and cell death of HNSCC cells

IntroductionPancreatic ductal adenocarcinoma (pdac) is one of the most lethal human cancers. about 20–30% of pdac are described to be auxotrophic for arginine and thus might be particularly sensitive to arginine deprivation therapy (adt). although radiotherapy for treatment of pdca is controversially discussed, the abnormal metabolism of pdac in combination with radiation is an attractive approach for targeted therapy. previously, we could show that adt is efficient in radiosensitizing auxotrophic pdacs to photons. recent clinical studies imply a benefit of proton radiotherapy for pdac patients. we therefore systematically compared the sensitivity of pdac cells to photon and proton irradiation in combination with adt as well as gemcitabine treatment.Material and methodsHuman and murine auxotrophic pdacs cells mimicking a patient cohort were studied. adt was achieved with 2 u/ml of recombinant human arginase +/- citrulline, a physiological precursor of arginine. single doses ≤ 30 gy of 200 kv x-rays or 150 mev double-scattered protons were applied. treatment response was assessed by 2-d clonogenic survival and/or 3-d spheroid control probability (scp) assays.results and discussionsadt led to a sensitization of pdac cells to x-rays in 2-d and 3-d culture. proton irradiation significantly reduced the scp and spheroid control dose 50% (scd50) relative to x-rays in the 3-d assay as reflected by a relative biological effectiveness (rbe) of 2.0. combining protons with adt further increased the rbe to 2.4. gemcitabine treatment did not improve radiotherapy outcome. however, the triple combination of adt, gemcitabine and proton irradiation had a highly synergistic effect (rbe = 3.0). extended mechanistic studies are ongoing.ConclusionFor pdac, adt in combination with gemcitabine and proton irradiation seems to be a very promising treatment strategy and should be further explored for translation into clinical trials.

PO-247 Beneficial therapeutic ménage à trois: enzymotherapeutic arginine-deprivation, gemcitabine and proton irradiation for pancreatic cancer treatment - a systematic in vitro study

IntroductionPancreatic ductal adenocarcinoma (pdac) is one of the most lethal human cancers. about 20–30% of pdac are described to be auxotrophic for arginine and thus might be particularly sensitive to arginine deprivation therapy (adt). although radiotherapy for treatment of pdca is controversially discussed, the abnormal metabolism of pdac in combination with radiation is an attractive approach for targeted therapy. previously, we could show that adt is efficient in radiosensitizing auxotrophic pdacs to photons. recent clinical studies imply a benefit of proton radiotherapy for pdac patients. we therefore systematically compared the sensitivity of pdac cells to photon and proton irradiation in combination with adt as well as gemcitabine treatment.Material and methodsHuman and murine auxotrophic pdacs cells mimicking a patient cohort were studied. adt was achieved with 2 u/ml of recombinant human arginase +/- citrulline, a physiological precursor of arginine. single doses ≤ 30 gy of 200 kv x-rays or 150 mev double-scattered protons were applied. treatment response was assessed by 2-d clonogenic survival and/or 3-d spheroid control probability (scp) assays.results and discussionsadt led to a sensitization of pdac cells to x-rays in 2-d and 3-d culture. proton irradiation significantly reduced the scp and spheroid control dose 50% (scd50) relative to x-rays in the 3-d assay as reflected by a relative biological effectiveness (rbe) of 2.0. combining protons with adt further increased the rbe to 2.4. gemcitabine treatment did not improve radiotherapy outcome. however, the triple combination of adt, gemcitabine and proton irradiation had a highly synergistic effect (rbe = 3.0). extended mechanistic studies are ongoing.ConclusionFor pdac, adt in combination with gemcitabine and proton irradiation seems to be a very promising treatment strategy and should be further explored for translation into clinical trials.