Agents In Oncology Research Articles

A multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis of the immune microenvironment of bile duct cancers (BDC) pre and post neoadjuvantchemotherapy (NACT).

e16151 Background: NACT is increasingly being used in the management of locally advanced BTC. Emerging evidence suggests a potential key contributing role of tumor infiltrating immune cells in the prognosis & response to therapy. We set out to characterize immune modulation of tumor immune microenvironment composition in BTC following NACT. Methods: Patients (pts) with locally advanced BTC who underwent a diagnostic biopsy, then NACT followed by resection between 2014 & 2018 were identified & consented after IRB approval. MICSSS, a sample-sparing chromogenic consecutive multiplex tissue staining method, was performed with a series of immune markers (Table), to characterize T cell subsets, B cells, macrophages, mature dendritic cells (DCs), and immune checkpoints on pre & post NACT formalin-fixed paraffin-embedded tumor tissue sections. Density was calculated for each marker (+ve cells/mm2) following annotation of tissues by tumor, fibrosis, necrosis, stromal & tumor infiltrating lymphocyte-enriched areas. Results: Nine pts were enrolled. Final analysis included 5 pts with adequate tissue. Median age = 48 (41-56), with 4 female, 4 intrahepatic cholangiocarcinomas & 1 gallbladder. All pts received Gemcitabine/Cisplatin as NACT with a median of 5 (4-7) cycles. Median time from diagnosis to surgery was 4.3 (1.4-7.8) months & last cycle to surgery was 0.9 (0.6-1.5) month. All pts were MMR proficient, 1 Her2+ & 2 with FGFR2 amplification. NACT on average produced a depletion of all immune markers (Table). Given the small N, each pt was considered their own control & changes in mean cell densities post NACT were calculated. Pt2 with a 40-fold increase in PDL1 expression & 5-fold decrease in CD8:FOXP3 ratio notably had the shortest disease-free interval (DFI). Pt3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold combined with a decrease in PDL1. Conclusions: Preliminary results suggest NACT may modulate immune microenvironment despite overall immune cell depletion. Future studies should focus on strategies to expand immune modulation of the tumor microenvironment in BTC by NACT, including immune oncology agent priming prior to or after NACT.[Table: see text]

Mitigation of doxorubicin-induced cardiotoxicity with an H2O2-Activated, H2S-Donating hybrid prodrug

Doxorubicin (DOX) is one of the most effective anticancer agents in clinical oncology. Its continued use, however, is severely limited by its dose-dependent cardiotoxicity which stems, in part, from its overproduction of reactive oxygen species (ROS) and often manifests itself as full-blown cardiomyopathy in patients, years after the cessation of treatment. Therefore, identifying DOX analogs, or prodrugs, with a diminished cardiotoxic profile is highly desirable. Herein, we describe a novel, H2O2-responsive DOX hybrid codrug (mutual prodrug) that has been rationally designed to concurrently liberate hydrogen sulfide (H2S), a purported cardioprotectant with anticancer activity, in an effort to maintain the antitumor effects of DOX while simultaneously reducing its cardiotoxic side effects. Experiments with cardiomyoblast cells in culture demonstrated a rapid accumulation of prodrug into the cells, but diminished apoptotic effects compared with DOX, dependent upon its release of H2S. Cells treated with the prodrug exhibited significantly higher Nrf2 activation relative to DOX-treated cells. Preliminary indications, using a mouse triple-negative breast cancer cell line sensitive to DOX treatment, are that the prodrug maintains considerable toxicity against the tumor-inducing cell line, suggesting significant promise for this prodrug as a cardioprotective chemotherapeutic to replace DOX.

Predicting Approximate Clinically Effective Doses in Oncology Using Preclinical Efficacy and Body Surface Area Conversion: A Retrospective Analysis.

The correlation between efficacious doses in human tumor-xenograft mouse models and the human clinical doses of approved oncology agents was assessed using published preclinical data and recommended clinical doses. For 90 approved small molecule anti-cancer drugs, body surface area (BSA) corrected mouse efficacious doses were strongly predictive of human clinical dose ranges with 85.6% of the predictions falling within three-fold (3×) of the recommended clinical doses and 63.3% within 2×. These results suggest that BSA conversion is a useful tool for estimating human doses of small molecule oncology agents from mouse xenograft models from the early discovery stage. However, the BSA based dose conversion poorly predicts for the intravenous antibody and antibody drug conjugate anti-cancer drugs. For antibody-based drugs, five out of 30 (16.7%) predicted doses were within 3× of the recommended clinical dose. The body weight-based dose projection was modestly predictive with 66.7% of drugs predicted within 3× of the recommended clinical dose. The correlation was slightly better in ADCs (77.7% in 3×). The application and limitations of such simple dose estimation methods in the early discovery stage and in the design of clinical trials are also discussed in this retrospective analysis.

Quantification of Nanoscale Dose Enhancement in Gold Nanoparticle-Aided External Photon Beam Radiotherapy.

Simple SummaryGold nanoparticles (AuNPs) have become common in radiation oncology research through the past decades. Their radiosensitization effect could offer a novel approach to cancer diagnosis and radiotherapy as well. The aim of this study is the assessment of dose enhancement attributed to the incubation of AuNPs in an irradiated target. The present work is focused on investigating the impact of AuNPs properties in dose increase under different irradiation conditions using 6 MV photon beams with and without a flattening filter via Monte Carlo simulations. Results from the simulated scenarios depict a sufficient dose raise especially at close distances to AuNPs, depending on the presence of a flattening filter in the path of the photon beam, AuNPs size, the type of modeled distribution and their concentration. Therefore, the obtained enhanced dose deposition due to AuNPs presence in an irradiated region could lead to more sufficient tumor cell destruction than irradiation alone.The recent progress in Nanotechnology has introduced Gold Nanoparticles (AuNPs) as promising radiosensitizing agents in radiation oncology. This work aims to estimate dose enhancement due to the presence of AuNPs inside an irradiated water region through Monte Carlo calculations. The GATE platform was used to simulate 6 MV photon histories generated from a TrueBeam® linear accelerator with and without a Flattening Filter (FF) and model AuNPs clusters. The AuNPs size, concentration and distribution pattern were examined. To investigate different clinical irradiation conditions, the effect of field size, presence of FF and placement of AuNPs in water were evaluated. The range of Dose Enhancement Factors (DEF = DoseAu/DoseWater) calculated in this study is 0.99 ± 0.01–1.26 ± 0.02 depending on photon beam quality, distance from AuNPs surface, AuNPs size and concentration and pattern of distribution. The highest DEF is reported for irradiation using un-flattened photon beams and at close distances from AuNPs. The obtained findings suggest that dose deposition could be increased in regions that represent whole cells or subcellular targets (mitochondria, cell nucleus, etc.). Nevertheless, further and consistent research is needed in order to make a step toward AuNP-aided radiotherapy in clinical practice.

ROADMAPS: An Online Database of Response Data, Dosing Regimens, and Toxicities of Approved Oncology Drugs as Single Agents to Guide Preclinical In Vivo Studies.

ROADMAPS includes data that can be used to identify tolerable dosing regimens with activity against a variety of human tumors in different mouse strains, providing a resource for planning preclinical studies.

Efficacy of inactivated vaccines in patients treated with immunosuppressive drug therapy.

Inactivated vaccines are generally considered safe in immunocompromised patients but the ability of immunocompromised patients to generate an effective immune response to vaccines is uncertain. Although recent reviews have focused on the effects of vaccines in patients who are immunocompromised due to various disease states (primary immunodeficiency), the effects of immunosuppressive drug therapy (secondary immunodeficiency) has received relatively less attention. This review evaluates evidence regarding the efficacy of inactivated vaccines against influenza, COVID‐19, and other diseases in patients treated with immunosuppressive oncologic agents, immunosuppressants used for transplant recipients, and immunosuppressants used for autoimmune disorders. Although evidence is mixed for many immunosuppressive agents and vaccines, most studies have found an attenuated immune response to inactivated vaccines, with the majority of data indicate anti‐B‐cell antibodies have a more severe and prolonged negative effect on vaccine efficacy.

Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate.

As one of the major therapeutic options for cancer treatment, chemotherapy has limited selectivity against cancer cells. Consequently, this therapeutic strategy offers a small therapeutic window with potentially high toxicity and thus limited efficacy of doses that can be tolerated by patients. Antibody-drug conjugates (ADCs) are an emerging class of anti-cancer therapeutic drugs that can deliver highly cytotoxic molecules directly to cancer cells. To date, twelve ADCs have received market approval, with several others in clinical stages. ADCs have become a powerful class of therapeutic agents in oncology and hematology. ADCs consist of recombinant monoclonal antibodies that are covalently bound to cytotoxic chemicals via synthetic linkers. The linker has a key role in ADC outcomes because its characteristics substantially impact the therapeutic index efficacy and pharmacokinetics of these drugs. Stable linkers and ADCs can maintain antibody concentration in blood circulation, and they do not release the cytotoxic drug before it reaches its target, thus resulting in minimum off-target effects. The linkers used in ADC development can be classified as cleavable and non-cleavable. The former, in turn, can be grouped into three types: hydrazone, disulfide, or peptide linkers. In this review, we highlight the various linkers used in ADC development and their design strategy, release mechanisms, and future perspectives.

Precision Oncology, Signaling, and Anticancer Agents in Cancer Therapeutics.

The global alliance for genomics and healthcare facilities provides innovative solutions to expedite research and clinical practices for complex and incurable health conditions. Precision oncology is an emerging field explicitly tailored to facilitate cancer diagnosis, prevention, and treatment based on patients' genetic profiles. Advancements in "omics" techniques, next-generation sequencing, artificial intelligence, and clinical trial designs provide a platform for assessing the efficacy and safety of combination therapies and diagnostic procedures. Data were collected from PubMed and Google Scholar using keywords "Precision medicine," "precision medicine and cancer," "anticancer agents in precision medicine," and reviewed comprehensively. Personalized therapeutics, including immunotherapy and cancer vaccines, serve as a groundbreaking solution for cancer treatment. Herein, we take a measurable view of precision therapies and novel diagnostic approaches targeting cancer treatment. The contemporary applications of precision medicine have also been described, along with various hurdles identified in the successful establishment of precision therapeutics. This review highlights the key breakthroughs related to immunotherapies, targeted anticancer agents, and target interventions related to cancer signaling mechanisms. The success story of this field in context to drug resistance, safety, patient survival, and improving quality of life is yet to be elucidated. We conclude that, in the near future, the field of individualized treatments may truly revolutionize the nature of cancer patient care.

5-ALA-mediated fluorescence of musculoskeletal tumors in a chick chorio-allantoic membrane model: preclinical in vivo qualification analysis as a fluorescence-guided surgery agent in Orthopedic Oncology

BackgroundFluorescence-guided surgery (FGS) with 5-aminolevulinic acid (5-ALA) and other contrast agents has shown its efficacy in improving resection margins, local recurrence and survival rates in several medical disciplines. It is the objective of this study to analyze the engraftment rate of musculoskeletal tumor specimens on the chick chorio-allantoic membrane (CAM), the rate of tumor fluorescence (PDD), and the effects of photodynamic therapy (PDT) after exposure of tumors to 5-ALA in an in vivo environment.MethodsA total of 486 CAMs were inoculated with macroscopic tumor grafts (n = 26; n = 478 eggs) and primary cell culture suspensions (n = 2; n = 8 eggs) from 26 patients on day 10 of egg development. On day 16, 2 mg/200 µl 5-ALA were topically applied per egg. After 4 h of incubation, Protoporphyrin IX was excited using blue light (420 ± 10 nm). Tumor fluorescence (PDD) was photo-documented. A subgroup of specimens was additionally exposed to red light (635 nm ± 10 nm; PDT). After the termination of the experiment, CAM-grown tumors were histopathologically analyzed.ResultsBenign and borderline tumors (chondroblastoma, giant cell tumor of bone and atypical chondrogenic tumor) presented with high rates of detectable fluorescence. Comparable results were found for chondrosarcoma, osteosarcoma and Ewing’s sarcoma among bone and dedifferentiated liposarcoma, myxofibrosarcoma and undifferentiated pleomorphic sarcoma among soft tissue sarcomas. Overall, tumor fluorescence was negative for 20.2%, single-positive (+) for 46.9% and double-positive (++) for 32.9% of macroscopic xenografts, and negative in 20% and (+) in 80% of primary cell culture tumors. Macroscopic tumor xenografts (n = 478) were identified as viable in 14.8%, partially viable in 2.9% and partially to completely regressive in 45.2%. All (n = 8) tumors grown from primary cell culture were viable. After PDT, tumor samples were found viable in 5.5%, partially viable in 5.5% and partially to completely regressive in 68%. Egg survival increased with decreasing PDT doses.ConclusionsThe CAM model proves to be a suitable in vivo model for the investigation of short-term observation questions in musculoskeletal tumors. The findings of this study warrant further investigation of PDT effects on musculoskeletal tumors and a possible incorporation of 5-ALA FGS in clinical Orthopedic Oncology care.

POSA65 Utilization-Based Managed Entry Agreements: Is There a Future for These Arrangements Across the EU4?

Many high-cost orphan and oncology agents require some form of managed entry agreement (MEA) to help EU payers marry the clinical value with the financial costs of such therapies. In the US, manufacturers launching high-cost therapies with weight-based dosing and/or a need for titration have implemented patient utilization adjustment (PUA) contracts to mitigate the risk of escalating or variable costs associated with individualized dosing. We aim to understand what potential value EU4 payers assign to a PUA contract and how this compares to existing contract structures.

Vascular Resections in Association With Pancreatic Resections for Locally Advanced Pancreatic Cancer.

Locally advanced pancreatic cancer has been considered for a long period of time as an unresectable lesion and therefore, all patients have been traditionally addressed to the oncological services for palliative purposes. However, due to the wide usage of newer oncological agents in association with improved surgical techniques, radical surgical procedures became feasible. The aim of this study was to present the different surgical procedures that were performed in locally advanced pancreatic cancer patients in order to achieve radical resections. Between 2019 and 2020, six cases were submitted to pancreatic and vascular resections in Fundeni Clinical Hospital. In all cases, surgery with curative intent was attempted; portal vein resection was performed in five cases, whereas arterial resection was performed in three cases. Reconstruction was performed by direct re-anastomosis, by placing cadaveric or synthetic grafts. The postoperative outcomes were favourable in all cases. Vascular resections can be safely associated with pancreatic resections in cases presenting locally advanced pancreatic lesions, with acceptable morbidity rates.

DDRE-42. TOWARDS PRECISION MEDICINE: AUTOMATED DRUG SCREENING PLATFORM UTILIZING TUMOR-ORGANOIDS TO IDENTIFY PATIENT-SPECIFIC DRUG-RESPONSES IN MENINGIOMA

Abstract Tumor-organoids (TO) are mini-tumors generated from tumor tissue preserving its genotype and phenotype by maintaining the cellular heterogeneity and important components of the tumor microenvironment. We recently developed a protocol to reliably establish TOs from meningioma (MGM) in large quantities. The use of TOs in combination with lab automation holds great promise for drug discovery and screening of comprehensive drug libraries. This might help to tailor patient-specific therapy in the future. The aim of our study was to establish an automated drug screening platform utilizing TOs. For this purpose, we established TOs by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples in the high-throughput format of 384-well plates. The drug screening was performed fully automated by utilizing the robotic liquid handler Hamilton Microlab STAR and a drug library containing 166 FDA-approved oncology agents. Viability was assessed with CellTiterGlo3D. In total, we performed the drug screening with 166 drugs on TOs from 11 patients suffering from MGM (n=8 WHO°I, n=2 WHO°II, n=1 WHO°III). The top five most effective drugs resulted in a decrease of TO viability ranging from 84.6–63.3%. K-means clustering analysis resulted in groupings of drugs with similar modes of action. One cluster consisted of epigenetic drugs while another cluster consisted of several proteasome inhibitors. However, when looking at a patient-individual level, in 11 patients 44 of 166 drugs, were among the top 10 most effective drugs, providing strong evidence for heterogeneous drug-responses in MGM patients. Taken together, we successfully developed an automated drug screening platform pipeline utilizing TOs from MGM to identify patient-specific drug-responses. The observed intra-individual differences of drug responses mandate for a personalized testing of comprehensive drug libraries in TOs to tailor more effective therapies in MGM patients.

Alternate dosage formulations of oral targeted anticancer agents.

Oral anticancer therapies have demonstrated superior outcomes compared to traditional cytotoxic chemotherapy in many disease states. However, certain patients may not be candidates for these agents due to odynphagia or dysphagia. The purpose of this review is to summarize the data for extemporaneous compounding of oral anticancer agents. Food and drug administration approvals of oncology agents were reviewed to identify oral anticancer therapies. In order to find alternative administration options: the package inserts of each of these agents were reviewed, each medication was searched in a tertiary drug information resource, the medical information teams of each drug manufacturer were contacted to inquire about proprietary data, sites with pediatric trials were contacted, a primary literature search was performed, and listservs for national pharmacy and oncology organizations were reviewed. Eighty-five food and drug administration-approved oral anticancer therapies were identified to be included. Of those agents, nine (11%), had information in the package insert related to alternative administration. After further research, 46 (54%) of the agents had some information related to alternate formulations for administration. The recipes and stability of each of these compounds is included. The majority of agents do not have Phase I or II trials that assess safety or pharmacokinetics of alternative formulations. Clinicians should exercise caution when recommending or administering these agents outside of food and drug administration-approved indicated use and utilize clinical judgment in assessing the risks and benefits of altering anticancer compounds. However, the alternative administration considerations presented can increase access to oncology patients who have difficulty swallowing.

Preclinical Evaluation of a Fluorescent Probe Targeting Receptor CDCP1 for Identification of Ovarian Cancer.

Optimal cytoreduction for ovarian cancer is often challenging because of aggressive tumor biology and advanced stage. It is a critical issue since the extent of residual disease after surgery is the key predictor of ovarian cancer patient survival. For a limited number of cancers, fluorescence-guided surgery has emerged as an effective aid for tumor delineation and effective cytoreduction. The intravenously administered fluorescent agent, most commonly indocyanine green (ICG), accumulates preferentially in tumors, which are visualized under a fluorescent light source to aid surgery. Insufficient tumor specificity has limited the broad application of these agents in surgical oncology including for ovarian cancer. In this study, we developed a novel tumor-selective fluorescent agent by chemically linking ICG to mouse monoclonal antibody 10D7 that specifically recognizes an ovarian cancer-enriched cell surface receptor, CUB-domain-containing protein 1 (CDCP1). 10D7ICG has high affinity for purified recombinant CDCP1 and CDCP1 that is located on the surface of ovarian cancer cells in vitro and in vivo. Our results show that intravenously administered 10D7ICG accumulates preferentially in ovarian cancer, permitting visualization of xenograft tumors in mice. The data suggest CDCP1 as a rational target for tumor-specific fluorescence-guided surgery for ovarian cancer.

Doxorubicin Paradoxically Ameliorates Tumor-Induced Inflammation in Young Mice.

Doxorubicin (DOX) is one of the most widely used chemo-therapeutic agents in pediatric oncology. DOX elicits an inflammatory response in multiple organs, which contributes to DOX-induced adverse effects. Cancer itself causes inflammation leading to multiple pathologic conditions. The current study investigated the inflammatory response to DOX and tumors using an EL4-lymphoma, immunocompetent, juvenile mouse model. Four-week old male C57BL/6N mice were injected subcutaneously with EL4 lymphoma cells (5 × 104 cells/mouse) in the flank region, while tumor-free mice were injected with vehicle. Three days following tumor implantation, both tumor-free and tumor-bearing mice were injected intraperitoneally with either DOX (4 mg/kg/week) or saline for 3 weeks. One week after the last DOX injection, the mice were euthanized and the hearts, livers, kidneys, and serum were harvested. Gene expression and serum concentration of inflammatory markers were quantified using real-time PCR and ELISA, respectively. DOX treatment significantly suppressed tumor growth in tumor-bearing mice and caused significant cardiac atrophy in tumor-free and tumor-bearing mice. EL4 tumors elicited a strong inflammatory response in the heart, liver, and kidney. Strikingly, DOX treatment ameliorated tumor-induced inflammation paradoxical to the effect of DOX in tumor-free mice, demonstrating a widely divergent effect of DOX treatment in tumor-free versus tumor-bearing mice.

Correlation Between Early Endpoints and Overall Survival in Non-Small-Cell Lung Cancer: A Trial-Level Meta-Analysis.

Early endpoints, such as progression-free survival (PFS), are increasingly used as surrogates for overall survival (OS) to accelerate approval of novel oncology agents. Compiling trial-level data from randomized controlled trials (RCTs) could help to develop a predictive framework to ascertain correlation trends between treatment effects for early and late endpoints. Through trial-level correlation and random-effects meta-regression analysis, we assessed the relationship between hazard ratio (HR) OS and (1) HR PFS and (2) odds ratio (OR) PFS at 4 and 6 months, stratified according to the mechanism of action of the investigational product. Using multiple source databases, we compiled a data set including 81 phase II–IV RCTs (35 drugs and 156 observations) of patients with non-small-cell lung cancer. Low-to-moderate correlations were generally observed between treatment effects for early endpoints (based on PFS) and HR OS across trials of agents with different mechanisms of action. Moderate correlations were seen between treatment effects for HR PFS and HR OS across all trials, and in the programmed cell death-1/programmed cell death ligand-1 and epidermal growth factor receptor trial subsets. Although these results constitute an important step, caution is advised, as there are some limitations to our evaluation, and an additional patient-level analysis would be needed to establish true surrogacy.

Treatment of Refractory Medicine Related Osteonecrosis of Jaw With Piezosurgical Debridement and Autologous Platelet Rich Fibrin: Feasibility Study.

Medicine related osteonecrosis of jaw (MRONJ) is incidental in patients receiving certain bone modifying agents in oncology. These lesions may not respond to conservative management and aggravate. Autologous platelet derivatives contain bone growth factors, which help in bone regeneration. The aim of this pilot study is to develop protocol for treatment of refractory MRONJ with pizosurgical debridement and advanced platelet rich fibrin.In this feasibility study, refractory MRONJ lesions were treated by piezosurgical debridement and insertion of autologous advanced platelet rich fibrin in 15 patients. One patient had 2 lesion sites, so in all 16 MRONJ sites were treated. These patients were evaluated at the end of 1 month and 4 months for healing of MRONJ lesion. Statistical analysis was done by using Fisher test for response assessment in relation to variable. Eight lesions (50%) showed complete healing at the end of 1 month. At the end of 4 months 13 lesions (81.50%) were completely healed, 2 lesions (12.5%) were downgrades, and 1 lesion (6.25%) did not respond to treatment. Number of doses of bone modifying agent was only factor found associated with nonhealing of MRONJ when treated with this protocol.In this pilot study, feasibility of use of piezosurgical debridement and platelet rich fibrin was evaluated. The results of the study suggest complete healing can be achieved with this treatment protocol. Further research with increased sample size is warranted to determine optimum use of autologous platelet concentrates in treatment of MRONJ.

Abstract ND07: HER2-TTC: A Targeted thorium conjugate to treat HER2 expressing cancers with potent alpha radiation

Abstract HER2-TTC (BAY 2701439) is a new representative of the Targeted Thorium Conjugates (TTCs), a novel class of radiotherapeutics for the treatment of cancer. It is comprised of the α-particle emitter thorium-227 complexed to a 3,2-HOPO chelator and conjugated to a human epidermal growth factor receptor 2 (HER2) targeted monoclonal antibody derived from trastuzumab. The targeted binding of HER2-TTC exposes tumor cells that express HER2 to a cytotoxic dose of alpha radiation. The high energy alpha-particles induce clustered double-strand DNA damage in targeted and adjacent tumor cells, which have a high likelihood to result in cell death in a cell cycle-independent fashion. Alpha particles have a short range of < 100 μm (less than 10 cell diameters), which minimizes damage to surrounding healthy tissue. The mechanism of action for TTCs is not dependent on any specific tumor type or affected by known resistance mechanisms provided that the target tumor epitope continues to be expressed. Potential combinations with inhibitors of DNA damage response (DDR) pathways may lead to synergistic anti-tumor activity. Preclinically, HER2-TTC has demonstrated substantial and selective anti-tumor activity in different models including breast, gastric, lung, bladder, colorectal cancer, with a range of HER2 expressions (IHC scores of 1+ to 3+). These included trastuzumab and T-DM1 resistant models, and models with low HER2 expression (IHC2+/ISH- or IHC1+). HER2-TTC has also demonstrated synergistic efficacy in combination with olaparib in a BRCAmut model. Preclinical data also support potential combinations with immune oncology agents, likely due to immunogenic cell death induced by alpha radiation. HER2-TTC has recently entered a First in Human study (NCT04147819) in patients with advanced tumors that express HER2. These include HER2 high expressing (IHC3+ or ISH+) breast and gastric/gastroesophageal carcinoma relapsed/refractory to trastuzumab/T-DM1, cancers with low HER2 expression, and other tumors that express HER2 such as colorectal cancer, non-small cell lung cancer, salivary, bladder and endometrial tumors. Citation Format: Jenny Karlsson. HER2-TTC: A Targeted thorium conjugate to treat HER2 expressing cancers with potent alpha radiation [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 ND07.

Clinical BET Inhibitor RG6146 Demonstrates Potent and on-Target Activity in Pre-Clinical Models of Hematological Malignancy and Combines with Anti-CD20 and BCL-2 Inhibition to Provide Superior Efficacy

Bromodomain and extra terminal (BET) family of bromodomains BET proteins are epigenetic ‘readers’ that bind acetylated histone residues and transcription factors at the chromatin interface and drive the expression of oncogenic transcription programs. BET inhibition using small molecules is an anti-cancer strategy being evaluated in early phase clinical trials. RG6146 is a novel small molecule, non-covalent inhibitor of (BET) family of bromodomains and potently inhibits BRD2, BRD3, BRD4 and BRDT. RG6146 is in clinical development for hematological malignancies including diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and solid tumors including triple negative breast cancer and ovarian cancer. In this study, we comprehensively examined the pre-clinical activity of RG6146 in vitro and in vivo in hematological cancer cell lines and xenograft models.RG6146 demonstrated broad activity across a panel of hematological and solid cancer cell lines in vitro . Cell lines derived from hematological malignancies were among the most sensitive to RG6146 with IC50s ranging from 0.02 uM to 5 uM, with an average of 0.39 uM (n=38 lines) in sensitive cell line lines. Sensitivity to RG6146 was accompanied by potent down-regulation of c-myc and induction of apoptosis. IC50s in Diffuse Large B-cell Lymphoma (DLBCL) cell lines averaged 0.05 uM, compared to multiple myeloma (MM) cell lines which demonstrated on average 10 fold greater sensitivity.The anti-tumor activity of RG6146 was tested in xenograft models representing Non-Hodgkins lymphoma (NHL) and MM. Consistent with in vitro findings, RG6146 displayed potent single agent activity in MM xenograft models with distinct %TGI ranging from (86-94) or tumor regression, compared with NHL models which displayed less single agent activity. To explore the potential utility of RG6146 in combination with other oncology agents, double and triple combinations with the BCL-2 selective inhibitor, venetoclax, and anti-CD20 antibody, obinutuzumab, were tested in the WSU-DLCL2 NHL model. While there was no enhanced efficacy observed for the double combinations of either RG6146 or venetoclax with obinutuzumab over obinutuzumab alone, the triple combination of RG6146, venetoclax and obinutuzumab resulted in distinct tumor regressions and prolonged tumor growth control. The combination of RG6146 and venetoclax were well tolerated and showed superior efficacy and induced tumor regressions in MM xenograft model KMS-12BM which harbors the translocation t(11:14).Together these data indicate that RG6146 is a potent BET-bromondomain inhibitor with potential utility in hematological malignancies, including NHL and MM, and may enhance the efficacy of other oncology agents such as CD20 antibodies and Bcl-2 inhibitors. DisclosuresRueflibrasse:Roche: Employment. Friess:Roche: Employment. Lechner:Roche: Employment. Wellinger:Roche: Employment. Brouwer:Roche: Employment. Pierceall:Roche: Employment.

Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth.

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.