Radiosensitizer Research Articles

Immunotherapy in indolent Non-Hodgkin's Lymphoma

Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell NHL and T cell NHL. Treatment of NHL was based on the subtype of NHL and its staging. NHL is divided into aggressive and indolent NHL (iNHL). Subtypes of iNHL include: Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL). Chemotherapy was the main stay treatment of iNHL until the emergence of Rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly efficacious in B cell iNHL, It became the mainstay treatment in follicular lymphoma (FL) as a single agent modality or in combination with chemotherapy. The anti-CD20 Rituximab played an important role in the development of the treatment of iNHL to become FDA approved in 1997. It was also proven effective in multiple other types of lymphoma. MAB through targeting the cell surface antigen leads to a direct or immune mediated cytotoxicity. This carries few side effects, including allergic reactions. Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism. Alternative mechanisms of resistance included the presence of soluble antigens that could act by binding to the antibody present before the drug itself can bind the lymphoma cell. Thus, the interest in immunotherapy grew further to explore the possibility of conjugating an immune mediated drug to a radio-sensitizing agent in order to enhance the selectivity of the drug. Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3rd generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab. Moreover, further studies came up to evaluate the role of immunotherapy in combination chemotherapy as a pathway to evade the resistance mechanisms. Side effects of the treatment were mainly infusion related adverse reactions, myelosuppression in conjugated forms leading to immunosuppression and subsequently to infectious complications. Another important aspect in immunotherapy is the half-lives of the medication which is an important factor that can influence the evaluation of the response. The MAB treatment showed important benefit in the treatment of iNHL and it continuously shows how rapidly it can develop to provide optimum care and benefit to patients with iNHL.

Breast radiotherapy with kilovoltage photons and gold nanoparticles as radiosensitizer: An in vitro study.

PurposeWe investigated the dose enhancement and internalization of gold nanoparticles (AuNPs) used as a radiosensitizer agent for rotational radiotherapy of breast cancer using a kilovoltage (kV) X‐ray beam.MethodsHuman breast cancer cells MDA‐MB‐231 were incubated with or without 100 μg/mL (4.87 nM) or 200 μg/mL (9.74 nM) 15 nm AuNPs and irradiated with 100 kV, 190 kV, or 6 MV X‐rays. To assess the toxicity of the AuNPs, we performed a Sulforhodamine B assay. Using atomic absorption spectroscopy, scanning electron microscopy, transmission electron microscopy, and time‐lapse optical microscopy (rate of 2 frames per minute), we carried out a quantitative assessment of the amount of gold internalized by MDA‐MB‐231 cells and a characterization of the static and dynamical aspects of this internalization process.ResultsNo effect of AuNPs alone was shown on cell viability. Time‐lapse optical microscopy showed for the first time AuNPs cellular uptake and the dynamics of AuNPs internalization. Electron microscopy demonstrated AuNPs localization in endosomal vesicles, preferentially in the perinuclear region. After irradiation at doses up to 2 Gy, cell survival fraction curves showed increased mortality with AuNPs, with respect to irradiation without AuNPs. The highest effect of radioenhancement by AuNPs (at 9.74 nM AuNPs concentration) was observed at 190 kV showing a dose enhancement factor of 1.33 ± 0.06 (1.34 ± 0.02 at 100 kV), while at 6 MV it was 1.14 ± 0.06.ConclusionsThe observed radio‐sensitization effect is promising for future radio‐enhanced kV radiotherapy of breast cancer and quantitatively in the order of previous observations for 15 nm AuNPs. These results of a significant dose enhancement were obtained at 15 nm AuNPs concentration as low as several nanomolar units, at dose levels typical of a single dose fraction in a radiotherapy session. Dynamical behavior of the 3D spatial distribution of 15 nm AuNPs outside the nucleus of single breast cancer cell was observed, with possible implications for future models of AuNPs sensitization.

STEM-12. THE SMALL MOLECULE DRUG CBL0137 INCREASES THE LEVEL OF DNA DAMAGE AND THE EFFICACY OF RADIOTHERAPY FOR GLIOBLASTOMA

Abstract Glioblastoma (GBM) is a fatal and incurable brain tumor, with an average life expectancy after diagnosis of only 12-15 months. A main reason for the lethality of GBM is inevitable recurrence, caused by a small population of the tumor cells, called cancer stem cells (CSCs). These cells are aggressive, infiltrative, and resistant to current GBM treatments of chemotherapy and radiotherapy. We use a small molecule drug, CBL0137, which inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy and hence lead to increased CSC death and prolonged survival in preclinical models. Clonogenic assays were used to show that CSCs were radiosensitized after CBL0137 treatment. We saw increased DNA damage when GBM CSCs were treated with CBL0137, as well as a decrease in foci resolution over time, when CBL0137 was combined with irradiation. In order to elucidate if the increase in DNA damage was directly due to the inhibition of the FACT complex, we depleted the level of FACT in our GBM CSCs. FACT depletion also led to increased DNA damage, and even more so when combined with irradiation. To validate whether combination therapy sensitized CSCs to radiotherapy in vivo, we used a subcutaneous mouse model and showed combination treatment decreased CSCs frequency in these tumors as well as decreased tumor volume. With an orthotopic model of GBM, we showed that CBL0137 treatment followed by radiotherapy significantly increased survival of mice bearing tumors over either treatment alone. Together, this work establishes a new treatment paradigm for GBM, which sensitizes radio-resistant GBM CSCs to irradiation, a critical component of patient care. Radio-sensitizing agents, including CBL0137, pose an exciting new therapeutic capable of increasing the efficacy of irradiation, by inclusively targeting CSCs.

Gold Nanoparticles as Potential Radiosensitizing and Cytotoxic Agents

Gold Nanoparticles as Potential Radiosensitizing and Cytotoxic Agents

Exposure-response modeling improves selection of radiation and radiosensitizer combinations

A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate.

One Pot Synthesis of PEGylated Bimetallic Gold-Silver Nanoparticles for Imaging and Radiosensitization of Oral Cancers.

BackgroundRadiotherapy is an important treatment modality for many types of head and neck squamous cell carcinomas. Nanomaterials comprised of high atomic number (Z) elements are novel radiosensitizers enhance radiation injury by production of free radicals and subsequent DNA damage. Gold nanoparticles are upcoming as promising radiosensitizers due to their high (Z) biocompatibility, and ease for surface engineering. Bimetallic nanoparticles have shown enhanced anticancer activity compared to monometallic nanoparticles.Materials and MethodsPEG-coated Au–Ag alloy nanoparticles (BNPs) were synthesized using facile one pot synthesis techniques. Size of ~50±5nm measured by dynamic light scattering. Morphology, structural composition and elemental mapping were analyzed by electron microscopy and SAXS (small-angle X-ray scattering). The radiosensitization effects on KB oral cancer cells were evaluated by irradiation with 6MV X-rays on linear accelerator. Nuclear damage was imaged using confocal microscopy staining cells with Hoechst stain. Computed tomography (CT) contrast enhancement of BNPs was compared to that of the clinically used agent, Omnipaque.ResultsBNPs were synthesized using PEG 600 as reducing and stabilizing agent. The surface charge of well dispersed colloidal BNPs solution was −5mV. Electron microscopy reveals spherical morphology. HAADF-STEM and elemental mapping studies showed that the constituent metals were Au and Ag intermixed nanoalloy. Hydrodynamic diameter was ~50±5nm due to PEG layer and water molecules absorption. SAXS measurement confirmed BNPs size around 35nm. Raman shift of around 20 cm−1 was observed when BNPs were coated with PEG. 1H NMR showed extended involvement of −OH in synthesis. BNPs efficiently enter cytoplasm of KB cells and demonstrated potent in vitro radiosensitization with enhancement ratio ~1.5–1.7. Imaging Hoechst-stained nuclei demonstrated apoptosis in a dose-dependent manner. BNPs exhibit better CT contrast enhancement ability compared to Omnipaque.ConclusionThis bimetallic intermix nanoparticles could serve a dual function as radiosensitizer and CT contrast agent against oral cancers, and by extension possibly other cancers as well.

MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.

In vitro Study of Radiosensitivity Effects of Galbanic Acid on Ovarian Tumor Cells (OVCAR-3 Cell Line)

Background and aims: Radiotherapy ranks among the most important procedures in ovarian cancer therapy. However, radioresistance is becoming more prevalent and is one of the main causes of poor clinical outcomes. To overcome this problem, radiosensitizers may be used. The present study aimed to evaluate the radiosensitizing properties of galbanic acid (GBA) on ovarian cancer cells in vitro. Materials and methods: OVCAR-3 cells, an ovarian cancer cell line, were treated with increasing concentrations of GBA (5, 10, 20, and 40 μg/mL) for 24, 48, and 72 h to determine its half-maximal inhibitory concentration (IC50). Cell viability was assessed by alamar Blue assay. The cells treated with 10 μg/mL GBA for 24 h were exposed to increasing doses of radiation (1, 2, and 4 Gy) and the survival fraction was investigated by clonogenic assay. Results: Assessment of cell viability indicated that GBA caused toxicity in a dose-dependent manner. Additionally, GBA pretreatment significantly improved the radiosensitivity of the cells, and survival fraction data indicated synergy between GBA and radiation. Conclusion: Taken together, the current findings highlight GBA as a potent radiosensitizing agent; however, further research is required to determine the molecular mechanisms of the observed effect both in vitro and in vivo. It is also suggested that the radiosensitization effect of GBA on other cell types should be studied in the future.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Magnetic Mesoporous Silica Nanoparticles Incorporated with miR-451 Suppress Development of Cervical Cancer and Enhance Radio Sensitization in Cervical Cancer

Cervical cancer (CC) is one of the most common gynecological malignancies with high mortality, threatening female’s health and reducing their life quality. This study evaluated the synergistic effect of magnetic mesoporous silica nanoparticles (MMSNs), miR-451 on radio sensitivity and cell apoptosis in CC. Magnetic mesoporous silica (Fe3O4/SiO2) nanoparticles were prepared and loaded with miR-451. Then the CC cells were treated with Fe3O4/SiO2 nanoparticles, miR-451-loaded Fe3O4/SiO2 nanoparticles (control group) and untreated (blank group). Cell proliferation was determined by MTT assay, while apoptosis and Hoechst were assessed by flow cytometry. As colony formation assay was conducted to evaluate cell sensitivity to radiotherapy, Western blot analysis detected the expression of apoptosis- and radiosensitization-related genes. Iron oxide particles were present inside and outside the SiO2 channel with characteristic peaks for Fe and skeleton of silica. The miR-451-loaded Fe3O4/SiO2 nanoparticles had an obvious absorption peak with drug loading rate and encapsulation rate reaching 6% and 91%. The release content of drugs increased with decreased pH. Of note, combined treatment with miR-451 and Fe3O4/SiO2 nanoparticles significantly decreased cancer cell proliferation and increased apoptosis (34.36±2.31%), compared to control group and blank group. Furthermore, the levels of D0 (1.67), Dq (0.94), N (1.56), and SF2 (0.43) declined in the presence of miR-451-Fe3O4/SiO2 nanoparticles, accompanied with elevation of ATM and γ-H2AX expression. Meanwhile, the treated CC cells had decreased expressions of DNA damage repair related genes ATM and γ-H2AX. MMSNs carrying miR-451 decreased cell proliferation activity and increased apoptosis and sensitized the CC cells to radiotherapy, to improve tissue repairing. These findings may provide a novel insight into pathogenesis of CC.

Curcumins antineoplastic, radiosensitizing and radioprotective properties.

Curcumin is an ingredient in the turmeric plant that gives yellow color to dishes and is used as a spice. It has been used locally/topically and systemically in the treatment of diseases in Far Eastern societies, especially in Indian and Chinese traditional medicine. Curcumin is a natural substance that does not show toxic properties in overdose. In addition to its anti-inflammatory, anti-oxidant, anti-neoplastic, anti-viral, anti-microbial, anti-angiogenic properties, platelet aggregation, apoptosis, and wound healing have been demonstrated in different studies. In recent years, it has been used as a radiosensitizing agent and a radioprotector in radiation therapy. Although curcumin has low bio-availability, it seems to be the ideal molecule due to its low molecular weight, high activity in inhibiting the growth of tumor cells and protecting normal tissues from the side effects of radiation. Curcumin in combination with radiotherapy was discussed in the light of the literature.

UV Light-Activated GdYVO4:Eu3+ Nanoparticles Induce Reactive Oxygen Species Generation in Leukocytes Without Affecting Erythrocytes In Vitro.

Nanoparticles (NPs) have been reported to be promising enhancement agents for radiation therapy. The aim of the study was to assess the cytotoxicity of UV non-treated and UV pretreated GdYVO4:Eu3+ nanoparticles against erythrocytes and leukocytes by detecting eryptosis and reactive oxygen species (ROS) generation. Levels of intracellular ROS in erythrocytes and leukocytes using a ROS-sensitive dye 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), as well as eryptosis rate utilizing annexin V staining, following direct exposure to UV-activated and nonactivated NPs were detected by flow cytometry. Blood cells were collected from 9 intact WAG rats. Neither the UV light-untreated GdYVO4:Eu3+ NPs nor the treated ones promoted eryptosis and ROS generation in erythrocytes. Low concentrations of UV light-untreated NPs did not induce oxidative stress in leukocytes, evidenced by unaffected intracellular ROS levels. UV light treatment grants prooxidant properties to NPs, confirmed by NP-induced ROS overproduction in leukocytes. High concentrations of both UV light-treated and untreated NPs altered the redox state of leukocytes. UV light treatment imparts prooxidant properties to GdYVO4:Eu3+ NPs, making them promising radiosensitizing agents in cancer radiation therapy.

Enhanced radiotherapy efficacy of breast cancer multi cellular tumor spheroids through in-situ fabricated chitosan-zinc oxide bio-nanocomposites as radio-sensitizing agents

Overwhelming evidence has shown that three-dimensional multicellular tumor spheroids (MCTSs) as a mimic of in-vivo tumor can accurately exhibit cellular responses to treatments. So, we compared the capability of pure zinc oxide nanoparticles (ZnO-NPs) and chitosan-ZnO bio-nanocomposites (CS-ZnO BNCs) for enhancing the radiosensitization of MDA-MB-231 breast cancer cells (BCCs) in the 3D-MCTSs model. ZnO-NPs and CS-ZnO BNCs were synthesized by a facile co-precipitation method. FE-SEM images revealed that the uniform spherical ZnO-NPs with an average diameter of 35 nm were successfully dispersed on chitosan. MDA-MB-231 MCTSs which were formed in a non-adherent culture plate, possessed functional features of in-vivo tumor. The priority of such culture method to conventionally used 2D monolayer (or parental) cell culture is the mimicking of tumor microenvironment. The toxicity of CS-ZnO BNCs and ZnO-NPs against the MDA-M−231 BCCs was evaluated using MTT-colorimetric assay, which demonstrated superior biocompatibility of CS-ZnO BNCs compared to pure ZnO-NPs (even at high concentration of 100 μg/mL). Survival fraction analysis of cells under clinical X-ray irradiation (6 MV) showed that MCTSs had a higher radioresistance compared to parental cells. Besides, the clonogenic potential of irradiated MCTSs was significantly decreased by the addition of CS-ZnO BNCs similar to that of monolayer cells. The sensitivity enhancement ratios (SER) for MCTSs and monolayer cells were calculated 1.5 and 1.63, respectively. Further, tracking of radiobiological properties and apoptosis induction of MCTSs showed that CS-ZnO BNCs not only could lead to the creation of higher radiation-induced complex DNA break and apoptosis death in MCTSs, but also weakened DNA repair mechanisms. It was found that non-toxic concentration of CS-ZnO BNCs has promising potential to enhance radiosensitivity of resistant-MCTSs as a superior in-vitro tumor model. So, CS-ZnO BNCs can be a prominent candidate for overcoming the resistance of BCCs to radiotherapy.

Эволюция методов радиосенсибилизации в лучевой терапии злокачественных новообразований

Publications survey devoted to the usage of radio sensitizers for radiation therapy of the tumors is demonstrated. Currently such radiomodification agents as platinum, fluorouracil, gold, gadolinium, iodine, etc. are widely used in oncology. General application methods and ways of introducing heavy metals compounds are highlighted. Their influence on the indexes of the acute and chronic toxicity among patients suffering malignancies is estimated.

Coralyne Radiosensitizes A549 Cells by Upregulation of CDKN1A Expression to Attenuate Radiation Induced G2/M Block of the Cell Cycle.

Coralyne is a synthetic analog of berberine related to protoberberine-isoquinoline alkaloids. Isoquinoline derivatives and analogs are renowned as potent radiosensitizers with potential medical application. In the present study, we investigated the effect of coralyne on the cell death, cytoskeletal changes and cell cycle progression of irradiated A549 cells. A clonogenic assay revealed that coralyne pretreatment decreased the viability of A549 cells in a time- and dose-dependent manner. Moreover, exposure to coralyne and ionizing radiation (IR) markedly altered the filamentous actin cytoskeletal architecture and integrin-β binding sites of A549 cells. Treatment with 1–25 µM coralyne in combination with 2 Gy of IR significantly reduced the percentage of cells in G2/M phase compared with 2 Gy IR alone. These results indicate that coralyne is a potent radiosensitizing agent that may find an application in medicine.

A review on radiation induced nausea and vomiting: "Current management strategies and prominence of radio sensitizers".

Radiations dissipated are high energy waves used mostly as treatment intervention in controlling the unwanted multiplication of cell. About 60%-65% of cancer treatment requires radiation therapy and 40%-80% of radiation therapy causes RINV which are true troublemakers. Radiation therapy (RT) is targeted therapy mostly used to treat early stages of tumour and prevent their reoccurrence. They mainly destroy the genetic material (DNA) of cancerous cells to avoid their unwanted growth and division. The RINV affects the management and quality of life of patients which further reduces the patient outcome. RINV depends on RT related factors (dose, fractionation, irradiation volume, RT techniques) and patient related factors like (gender, health conditions, age, concurrent chemotherapy, psychological state, and tumour stage). RT is an active area of research and there is only limited progress in tackling the RINV crisis. Advanced technological methods are adopted that led to better understanding of total lethal doses. Radiation therapy also affects the immunity system that leads to radiation induced immune responses and inflammation. Radio sensitizers are used to sensitize the tumour cells to radiations that further prevent the normal cell damage from radiation exposure. There is a need for future studies and researches to re-evaluate the data available from previous trials in RINV to make better effective antiemetic regimen. The article focuses on radiation therapy induced nausea and vomiting along with their mechanism of action and treatment strategies in order to have a remarkable patient care.

Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma.

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

Will the Use of Biomarkers Improve Bladder Cancer Radiotherapy Delivery?

Advances in the field of cancer biology and molecular techniques have led to a better understanding of the molecular underpinnings driving cancer development and outcomes. Simultaneously, advances in imaging have allowed for improved sensitivity in initial staging, radiotherapy planning and follow-up of numerous cancers. These two phenomena have led to the development of biomarkers that can guide therapy in multiple malignancies. In bladder cancer, there is extensive ongoing research into the identification of biomarkers that can help tailor personalised approaches for treatment based on the intrinsic tumour biology. However, the delivery of bladder cancer radiotherapy as part of trimodality therapy currently has a paucity of biomarkers to guide treatment. Here we summarise the existing literature and ongoing investigations into potential predictive and prognostic molecular and imaging biomarkers that may one day guide selection for utilisation of radiotherapy as part of trimodality therapy, guide selection of the radiosensitising agent, guide radiation dose and target, and guide surveillance for recurrence after trimodality therapy.

Abstract PO-071: Characterizing transcriptomic indicators of radiosensitivity in cancer and identifying sensitizing therapeutic agents

Abstract While radiation therapy is an integral method for cancer treatment, clinical choices are not currently informed by the genetic and molecular profile of a patient’s tumor. Though it has been shown that genetic features implicate variability, the exact relationship between these features and radiosensitivity is poorly understood. Our work focuses on predicting radiosensitivity of squamous cell carcinoma from molecular features. First, we employ RadioGx, a computational platform for integrative analysis of radiogenomic datasets, to identify a gene expression signature predictive of radiosensitivity. To mitigate the high-dimensionality of gene expression data, we employ pathway-level transcriptomic modeling methods to identify cellular programs associated with radiation sensitivity. Our pancancer radiosensitivity model achieves a Pearson’s correlation of 0.47 with measured radiosensitivity from a radiogenomic dataset using only high level transcriptomic features. Second, we use that gene expression signature to query the Connectivity Map via the PharmacoGx resource and identify candidate radiosensitizers - compounds that may induce the radiosensitivity signature. Further validation is necessary to evaluate the efficacy of these compounds at improving radiosensitivity in both model systems and patient contexts. These results implicate cellular processes in radiosensitivity and advance an approach for identifying radiosensitizing agents through integration of large scale datasets. Citation Format: Ian Smith, Rachel Bell, Meghan Lambie, Benjamin Haibe-Kains, Scott Bratman. Characterizing transcriptomic indicators of radiosensitivity in cancer and identifying sensitizing therapeutic agents [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-071.

Combining Gold Nanoparticles with Other Radiosensitizing Agents for Unlocking the Full Potential of Cancer Radiotherapy.

About half of cancer patients (50%) receive radiotherapy (RT) for the treatment of local tumors. However, one of the main obstacles in RT is the close proximity of adjacent organs at risk, resulting in treatment doses being limited by significant tissue toxicity, hence preventing the necessary dose escalation that would guarantee local control. Effective local cancer therapy is needed to avoid progression of tumors and to decrease the development of systemic metastases which may further increase the possibility of resection. In an effort to do so, radiosensitizing agents are introduced to further increase damage to the tumor while minimizing normal tissue toxicity. Cisplatin and docetaxel (DTX) are currently being used as radiation dose enhancers in RT. Recent research shows the potential of gold nanoparticles (GNPs) as a radiosensitizing agent. GNPs are biocompatible and have been tested in phase I clinical trials. The focus will be on exploring the effects of adding other radiosensitizing agents such as DTX and cisplatin to the GNP-RT platform. Therefore, a combined use of local radiosensitizing agents, such as GNPs, with currently available radiosensitizing drugs could make a significant impact in future RT. The ultimate goal is to develop treatments that have limited or nonexistent side effects to improve the quality of life of all cancer patients.