Strategy For Treatment Of Tumors Research Articles

Emerging Chemodynamic Nanotherapeutics for Cancer Treatment.

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species (ROS)-mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals (•OH). Its notable advantages in cancer treatment have been demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine have been devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment. This article is protected by copyright. All rights reserved.

Efficacy and safety of salvage endoscopy in the treatment of residual or recurrent colorectal neoplasia after endoscopic resection: a systematic review and meta-analysis.

To systematically review and meta-analyze the efficacy and safety of salvage endoscopy for residual or recurrence of colorectal tumors after endoscopic resection. Multiple databases including PubMed, EMBASE and the Cochrane Library were searched to screen for eligible studies and perform data extraction and pooled analysis. Sixteen studies on salvage endoscopy for residual or recurrent colorectal cancer after endoscopic resection were included, covering approximately 994 patients. The results of the meta-analysis demonstrated that salvage endoscopic therapy for residual or recurrent colorectal tumors following endoscopic resection achieved an en bloc resection rate of 92% (95% CI 0.85-0.97; I2 = 91%) and an R0 resection rate of 82% (95% CI 0.75-0.87; I2 = 78%). The rates of intraoperative or postoperative bleeding and perforation were 10%/1% and 5%/2%, and the recurrence rate was 2%. Salvage endoscopic resection is an effective and safe treatment strategy for residual or recurrent colorectal tumors after endoscopic resection.

As1411-modified liposomes to enhance drug utilization and augment the anti-tumor efficacy

BackgroundThe utilization of liposomes in drug delivery has garnered significant attention due to their efficient drug loading capacity and excellent biocompatibility, rendering them a promising platform for tumor therapy. However, the average size of liposomes ~ 100 nm leads to liposomes being susceptible to hepatic and renal metabolism to excretion outside the body leading to poor drug delivery efficiency with a total utilization rate of less than 0.7%, resulting in unfavorable treatment outcomes.ResultsWe have developed a novel liposome platform equipped with tumor surface nucleolin-targeting capacity to enhance drug accumulation at the tumor in vivo. The encapsulation of doxorubicin through thin film hydration has resulted in the formation of D@L-AS1411. Through in vivo experiments, we have demonstrated the effective accumulation of D@L-AS1411 at the tumor site and its ability to improve doxorubicin utilization rates by 40%. Additionally, D@L-AS1411 induces immunogenic death of tumor cells, release of tumor-associated antigens, upregulation of calreticulin expression, and recruitment of active T cell infiltration, and ultimately improves the therapeutic efficacy against tumors (70%).ConclusionsBased on the nucleic acid aptamer AS1411, D@L-1411 is developed to specifically enhance the accumulation of Dox at tumor sites, thereby inhibiting and enhancing the anti-tumor effect. In summary, this study not only provides an efficient tumor-targeting delivery platform but also contributes to the improvement of chemotherapy–immunotherapy combination for tumor treatment strategy in the clinic.

Exploration of poly (ADP-ribose) polymerase inhibitor resistance in the treatment of BRCA1/2-mutated cancer.

Breast cancer susceptibility 1/2 (BRCA1/2) genes play a crucial role in DNA damage repair, yet mutations in these genes increase the susceptibility to tumorigenesis. Exploiting the synthetic lethality mechanism between BRCA1/2 mutations and poly(ADP-ribose) polymerase (PARP) inhibition has led to the development and clinical approval of PARP inhibitor (PARPi), representing a milestone in targeted therapy for BRCA1/2 mutant tumors. This approach has paved the way for leveraging synthetic lethality in tumor treatment strategies. Despite the initial success of PARPis, resistance to these agents diminishes their efficacy in BRCA1/2-mutant tumors. Investigations into PARPi resistance have identified replication fork stability and homologous recombination repair as key factors sensitive to PARPis. Additionally, studies suggest that replication gaps may also confer sensitivity to PARPis. Moreover, emerging evidence indicates a correlation between PARPi resistance and cisplatin resistance, suggesting a potential overlap in the mechanisms underlying resistance to both agents. Given these findings, it is imperative to explore the interplay between replication gaps and PARPi resistance, particularly in the context of platinum resistance. Understanding the impact of replication gaps on PARPi resistance may offer insights into novel therapeutic strategies to overcome resistance mechanisms and enhance the efficacy of targeted therapies in BRCA1/2-mutant tumors.

Deep pan-cancer analysis and multi-omics evidence reveal that ALG3 inhibits CD8+ T cell infiltration by suppressing chemokine secretion and is associated with 5-fluorouracil sensitivity

Backgroundα-1,3-mannosyltransferase (ALG3) holds significance as a key member within the mannosyltransferase family. Nevertheless, the exact function of ALG3 in cancer remains ambiguous. Consequently, the current research aimed to examine the function and potential mechanisms of ALG3 in various types of cancer. MethodsDeep pan-cancer analyses were conducted to investigate the expression patterns, prognostic value, genetic variations, single-cell omics, immunology, and drug responses associated with ALG3. Subsequently, in vitro experiments were executed to ascertain the biological role of ALG3 in breast cancer. Moreover, the link between ALG3 and CD8+ T cells was verified using immunofluorescence. Lastly, the association between ALG3 and chemokines was assessed using qRT-PCR and ELISA. ResultsDeep pan-cancer analysis demonstrated a heightened expression of ALG3 in the majority of tumors based on multi-omics evidence. ALG3 emerges as a diagnostic and prognostic biomarker across diverse cancer types. In addition, ALG3 participates in regulating the tumor immune microenvironment. Elevated levels of ALG3 were closely linked to the infiltration of bone marrow-derived suppressor cells (MDSC) and CD8+ T cells. According to in vitro experiments, ALG3 promotes proliferation and migration of breast cancer cells. Moreover, ALG3 inhibited CD8+ T cell infiltration by suppressing chemokine secretion. Finally, the inhibition of ALG3 enhanced the responsiveness of breast cancer cells to 5-fluorouracil treatment. ConclusionALG3 shows potential as both a prognostic indicator and immune infiltration biomarker across various types of cancer. Inhibition of ALG3 may represent a promising therapeutic strategy for tumor treatment.

Highly Permeable Nanoparticles Achieve Efficient Tumor Treatment through Oxygen‐Independent Photonic Thermodynamic Therapy

AbstractPhotodynamic therapy (PDT) represents a promising strategy for tumor treatment. However, the development of PDT‐based antitumor therapies faces challenges stemming from the hypoxic nature of the tumor microenvironment and the limited penetration of photosensitizers. This study presents a novel class of antitumor nanoparticles, designated as ARLN‐FP, engineered to penetrate tumor tissues deeply and inhibit tumor growth through the generation of oxygen‐independent free radicals. With the encapsulation of IR780 and dimethyl 2,2′‐azobis(2‐methylpropionate) (AIBME) in the core of ARLN‐FP, near‐infrared (NIR) laser irradiation of ARLN‐FP with induced heat generation, which subsequentially led to the decomposition of AIBME and the production of free radicals without relying on oxygen. In vitro studies indicated that ARLN‐FP penetrated more than 100 µm into multicellular tumor spheroids, demonstrating its enhanced tissue permeability. Animal studies confirmed the anti‐tumor effects of ARLN‐FP‐mediated photonic thermodynamic therapy, where the oxygen‐independent radical formation contributed to successful tumor eradication, evidenced by a significant tumor inhibition rate of 90.8% after 22 days. This research presents a feasible method to overcome the limitations of traditional oxygen‐dependent photodynamic therapies, which offers a new approach to developing nanomedicines to overcome resistance in deep and hypoxic tumor regions.

Multicenter validation study of a treatment selection MAP for pancreatic neuroendocrine tumors.

Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP. Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP. There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P=0.032) as the only significant independent favorable predictive factor. The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP.

Custom-Design of Multi-Stimuli-Responsive Degradable Silica Nanoparticles for Advanced Cancer-Specific Chemotherapy.

Chemotherapy is crucial in oncology for combating malignant tumors but often encounters obatacles such as severe adverse effects, drug resistance, and biocompatibility issues. The advantages of degradable silica nanoparticles in tumor diagnosis and treatment lie in their ability to target drug delivery, minimizing toxicity to normal tissues while enhancing therapeutic efficacy. Moreover, their responsiveness to both endogenous and exogenous stimuli opens up new possibilities for integrating multiple treatment modalities. This review scrutinizes the burgeoning utility of degradable silica nanoparticles in combination with chemotherapy and other treatment modalities. Commencing the elucidation of degradable silica synthesis and degradation mechanisms, emphasis is placed on the responsiveness of these materials to endogenous (e.g., pH, redox reactions, hypoxia, and enzymes) and exogenous stimuli (e.g., light and high-intensity focused ultrasound). Moreover, this exploration delves into strategies harnessing degradable silica nanoparticles in chemotherapy alone, coupled with radiotherapy, photothermal therapy, photodynamic therapy, gas therapy, immunotherapy, starvation therapy, and chemodynamic therapy, elucidating multimodal synergies. Concluding with an assessment of advances, challenges, and constraints in oncology, despite hurdles, future investigations are anticipated to augment the role of degradable silica in cancer therapy. These insights can serve as a compass for devising more efficacious combined tumor treatment strategies.

Progress of Angiogenesis Signal Pathway and Antiangiogenic Drugs in Nasopharyngeal Carcinoma.

Nasopharyngeal cancer is a rare cancer with unique ethnic and geographic distribution. Since nasopharyngeal cancer often originates from the pharyngeal crypt, early symptoms are not obvious. They are difficult to detect in time, and the disease is usually diagnosed and treated only when it has progressed to an advanced-stage. Since angiogenesis is essential for the growth and invasion of solid tumors, antiangiogenic therapy has become a common treatment strategy for many solid tumors, and it has also achieved remarkable results in the treatment of nasopharyngeal carcinoma, which is prone to recurrence and distant metastasis. In this paper, we review the latest research progress of antiangiogenic drugs for nasopharyngeal carcinoma and their antiangiogenic mechanism of action and further propose some promising antiangiogenic therapeutic targets.

Molecular Modeling of Shockwave-Mediated Blood-Brain Barrier Opening for Targeted Drug Delivery.

Bubble-enhanced shock waves induce the transient opening of the blood-brain barrier (BBB) providing unique advantages for targeted drug delivery of brain tumor therapy, but little is known about the molecular details of this process. Based on our BBB model including 28 000 lipids and 280 tight junction proteins and coarse-grained dynamics simulations, we provided the molecular-level delivery mechanism of three typical drugs for the first time, including the lipophilic paclitaxel, hydrophilic gemcitabine, and siRNA encapsulated in liposome, across the BBB. The results show that the BBB is more difficult to be perforated by shock-induced jets than the human brain plasma membrane (PM), requiring higher shock wave speeds. For the pores formed, the BBB exhibits a greater ability to self-heal than PM. Hydrophobic paclitaxel can cross the BBB and be successfully absorbed, but the amount is only one-third of that of PM; however, the absorption of hydrophilic gemcitabine was almost negligible. Liposome-loaded siRNAs only stayed in the first layer of the BBB. The mechanism analysis shows that increasing the bubble size can promote drug absorption while reducing the risk of higher shock wave overpressure. An exponential function was proposed to describe the relation between bubble and overpressure, which can be extended to the experimental microbubble scale. The calculated overpressure is consistent with the experimental result. These molecular-scale details on shock-assisted BBB opening for targeted drug delivery would guide and assist experimental attempts to promote the application of this strategy in the clinical treatment of brain tumors.

Dendritic polymer prodrug-based unimolecular micelles for pH-responsive co-delivery of doxorubicin and camptothecin with synergistic controlled drug release effect

Combination chemotherapy has been recognized as a more powerful strategy for tumor treatment rather than the single chemotherapy. However, the interactive mechanism of the two hydrophobic chemotherapeutic drugs has not been explored by now. Aiming for a better synergistic effect, such interactive mechanism was investigated in the present work, by designing CPT@DOX-DPUTEA-PEG nanomedicine with encapsulated camptothecin (CPT) and conjugated doxorubicin (DOX). The synergistic controlled drug release effect was found for the two drugs loaded on the different sites of the dendritic polyurethane core. Synergism was achieved on the HepG2 cells with a combination index (CI) of 0.58 in the in vitro cellular experiments. The results demonstrated the promising application of the unimolecular micelles-based nanomedicine with independently loading of two hydrophobic chemotherapeutic drugs.

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti-PD-1/PD-L1 cancer immunotherapy.

Chemotherapy, radiotherapy, and immunotherapy represent key tumour treatment strategies. Notably, immune checkpoint inhibitors (ICIs), particularly anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), have shown clinical efficacy in clinical tumour immunotherapy. However, the limited effectiveness of ICIs is evident due to many cancers exhibiting poor responses to this treatment. An emerging avenue involves triggering non-apoptotic regulated cell death (RCD), a significant mechanism driving cancer cell death in diverse cancer treatments. Recent research demonstrates that combining RCD inducers with ICIs significantly enhances their antitumor efficacy across various cancer types. The use of anti-PD-1/PD-L1 immunotherapy activates CD8+ T cells, prompting the initiation of novel RCD forms, such as ferroptosis, pyroptosis, and necroptosis. However, the functions and mechanisms of non-apoptotic RCD in anti-PD1/PD-L1 therapy remain insufficiently explored. This review summarises the emerging roles of ferroptosis, pyroptosis, and necroptosis in anti-PD1/PD-L1 immunotherapy. It emphasises the synergy between nanomaterials and PD-1/PD-L1 inhibitors to induce non-apoptotic RCD in different cancer types. Furthermore, targeting cell death signalling pathways in combination with anti-PD1/PD-L1 therapies holds promise as a prospective immunotherapy strategy for tumour treatment.

New Treatment Options for Patients With Oncogene-Addicted Non-Small Cell Lung Cancer Focusing on EGFR-Mutant Tumors.

Druggable oncogene-driven non-small cell lung cancer has led to innovative systemic treatment options, improving patients' outcome. This benefit is not only achieved in the metastatic setting but also in the postsurgical setting, such as in lung cancers harboring a common sensitizing EGFR mutation or ALK-rearrangement. To enhance the outcome of these patients, we need to understand the mechanisms of acquired resistance and evaluate the role of new drugs with novel mechanisms of action in the treatment landscape. In this chapter, we review treatment strategies of EGFR-mutant tumors in all stages, the mechanisms of acquired strategies, and novel therapies in this subset.

Tumor Microenvironment Landscapes Supporting EGFR-mutant NSCLC Are Modulated at the Single-cell Interaction Level by Unesbulin Treatment.

Targeting the TME is an attractive strategy for treatment of solid tumors. Here we revealed how EGFR-mutant landscapes are affected at the single-cell resolution level during Unesbulin treatment. This novel drug, by targeting cancer cells and their interactions with crucial TME components, could be envisioned for future therapeutic advancements.

Research Progress in Inhibiting Tumor Cells Through Sugar Metabolism in the TME

In the immune microenvironment, the sugar metabolism of tumor cells determines their own growth, and the disturbance of metabolic process is considered as an important feature of tumor cell growth. Compared with normal cells, the greatest change in the metabolic process of tumor cells is the occurrence of aerobic glycolysis. Even under sufficient oxygen conditions, tumor cells will still absorb a lot of glucose through glycolysis to provide energy for cells, and many important rate-limiting enzymes in the glycolysis process are expressed in different forms in tumor cells and have an important impact on tumor growth. However, the specific mechanism of this conversion and the targeted enzyme's process are not clear. This article analyzes the difference in sugar metabolism between tumor cells and normal cells, specifically summarizes and analyzes the inhibitory effect mechanism of pyruvate kinase and lactate dehydrogenase on tumors, and obtains the conclusion that targeted inhibition of PKM and LDH can inhibit the growth and reproduction of tumor cells. Exploring the inhibition of tumor cell dependence on glucose, studying the glycolysis pathway of tumor cells and targeted drugs inhibiting key enzyme activity can help us further understand the metabolic characteristics and growth mechanism of tumor cells, provide new targets and strategies for tumor treatment, and provide a reference for anti-tumor combination therapy and individualized treatment for patients. However, at present, the research on targeted drug toxicity and side effects has not been solved, and the potential side effects and toxicity are not studied enough. Future research should focus on individualized treatment for patients, pay attention to the differences in the activation degree of glycolysis pathway in tumor cells, and bring better treatment results to tumor patients.

Abstract 2714: Developing an mRNA encoded therapeutic antibody platform to simplify manufacturing and reduce time to clinic

Abstract The manufacturing of therapeutic antibodies requires expensive production, often challenging purification, lengthy stability optimization and complex protein characterization that despite continual improvement, keeps the cost of treatment in the clinic high. Alternatively, leveraging gene-based approaches such as mRNA to express therapeutics circumvents many of the manufacturing challenges and instead rely on in situ production of antibodies within a patient, improving the developability and cost of sophisticated, disease-modifying antibodies. Crucially, recent work demonstrates that therapeutic antibodies translated in vivo from mRNA can be readily detected within hours following infusion into pre-clinical models and can persist up to several days or weeks. Peak levels of circulating mRNA-encoded antibodies are comparable to infused recombinant equivalents dosed to patients and have been shown to be within favorable therapeutic ranges in phase I trials. Here we outline an mRNA-LNP based platform to encode and deliver therapeutic antibodies in vivo that can overcome costly and challenging manufacturing and that demonstrates both robust PK/PD kinetics and potency. We describe how to effectively encode a standard-of-care anti-HER2 antibody - Trastuzumab - using LNP-encapsulated modified mRNA and validate using in vitro as well as in vivo efficacy models. Initial in vitro characterization of mRNA encoded antibodies demonstrates robust translation in producer cell lines, reproducible expression kinetics, retention of antigen specificity and HC:LC integrity when analyzed by ELISA and WB. To evaluate whether Trastuzumab-encoding mRNA-produced protein is detectable in vivo, antibody levels were measured in mouse serum after IV administration of a single dose of mRNA formulated LNPs. Peak plasma concentrations of mRNA-encoded trastuzumab were benchmarked against circulating recombinant Trastuzumab in parallel groups, and pharmacokinetics interrogated. Of note, the majority of mRNA encoded antibody was likely produced in the liver as shown by bioluminescence imaging. To demonstrate the efficacy of the platform, the potency of mRNA-encoded Trastuzumab isolated from producer cell lines will be assessed using in vitro cytotoxicity assays with human PBMCs and HER2+ tumor lines to dissect ADCC or direct tumor growth inhibition. Additionally, to determine whether mRNA-encoded Trastuzumab is able to retain anti-tumor activity in vivo, a mouse tumor xenograft model will be established and the mRNA antibody-dependent effects on tumor volume, growth and morbidity-free survival will be examined. Overall, the data demonstrate that mRNA-encoded therapeutic antibodies could provide an effective, alternate strategy for solid tumor treatment and may unlock a strategy to deliver lead biologics at reduced cost and with improved developability. Citation Format: Roxana Redis, Dan Rocca, Rachel Pooley, Matthew Benson, Namrata Jayanth, Eva Oswald, Alexander Hale, Louise Brackenbury, Justin Bryans. Developing an mRNA encoded therapeutic antibody platform to simplify manufacturing and reduce time to clinic [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 2714.

Abstract 3156: Unveiling the functional role of HDGFRP3 in pediatric medulloblastoma: Implications for growth, progression, and radioresistance

Abstract Introduction: Medulloblastoma (MB) is the most common malignant brain cancer in children. Although long-term survival has improved in recent years, only a modest percentage of patients survive high-risk disease. The quality of life for those who survive is substantially reduced due to the high toxicity associated with the radiation and chemotherapy. Therefore, identification of safe and potent therapeutic approaches that can sensitize the therapy response in MB without inducing toxicity will lead to more efficient treatment of MB patients. We recently discovered that targeting HDGFRP3, a protein highly expressed in MB, and can block MB growth and improve the efficacy of radiation therapy. HDGFRP3 is a multifaceted protein that plays important roles in diverse cellular processes. Our investigation sheds light on the functional role of HDGFRP3 in MB, focusing on its involvement in growth, progression, and radioresistance where we report HDGFRP3 as a novel oncogenic driver of these processes. Methods: Human MB cell lines (DAOY, D556, D425, and HDMB03) were purchased from the American Type Culture Collection and cultured in standard medium. MB cancer cells were transfected with siRNA specific to HDGFRP3. These knockdown cells were analyzed for cell viability, migration, invasion, colony formation, stemness, cell cycle, apoptosis assays for functional role assessment. Real-time qPCR and western blotting were performed to validate the downstream targets of HDGFRP3 in MB models. Results: Our findings demonstrate that HDGFRP3 functions as an oncogene in MB, as its overexpression promotes cancer growth, while its depletion results in decreased tumor growth in MB models. Furthermore, we provide evidence that HDGFRP3 knockdown results in decreased migratory potential of MB cells as well as a reduction in stemness. Interestingly, HDGFRP3 depletion improved the efficacy of standard of care radiation in multiple MB models. At present, in vivo studies are validate the oncogenic role of HDGFRP3 in preclinical animal models of MB. Conclusions: In conclusion, our data suggests HDGFRP3 facilitates MB growth, progression, stemness as well as resistance to radiation therapy. Our comprehensive investigation into HDGFRP3's functional role in MB presented here provides valuable insights into its potential as a therapeutic target and opens avenues for further research into novel treatment strategies for the pediatric brain tumors. Citation Format: Saif S. Nirzhor, Prabhakar Pitta Venkata, Shahad Abdulsahib, Panneerdoss Subbarayalu, Santosh Timilsina, Manjeet K. Rao. Unveiling the functional role of HDGFRP3 in pediatric medulloblastoma: Implications for growth, progression, and radioresistance [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 3156.

Abstract 7378: Using game theory to investigate the therapeutic potential of disrupting tumor-microenvironment interactions

Abstract Cancer is a complex disease involving the interplay of several types of malignant and nonmalignant cells. The growth of tumors and surrounding stromal cells can be modeled as an ecosystem, where populations of cancerous and healthy cells interact and compete for resources. In this work, we have explored the application of game theoretic models of cancer to the design of novel anticancer therapies. Notably, a game theoretic-model of tumor-stromal interactions can capture the impact of interactions between cell types and can be used to investigate frequency-dependent parameters describing the impact of drug action during the initiation and growth of metastatic cancers. Previous studies using game theoretic models to describe cancer have focused on explaining progression patterns of specific tumors with known tumor-stromal interactions. This study takes a more general approach to cancer growth dynamics, modeling cancer as a simple game between healthy and cancer cells. This simplified model is used to make general predictions about cancer progression and the efficacy of treatment strategies. Our work suggests that disruption of beneficial interactions between healthy and cancer cells may be a viable treatment strategy for small tumors and preventing metastasis by ensuring that the healthy cell strategy is evolutionarily stable. The efficacy of treatment strategies that disrupt cancer cell cooperation or tumor-stromal dynamics changes as the cancer cell frequency changes. Our work suggests that drugs that target tumor-stromal cell interactions would need to be combined with other types of treatments to be effective against large tumors. Although based on a simplistic model of cancer initiation and progression, the framework derived here can be extended to the real-world design of experimental anticancer therapeutics, and fundamental analyses of this nature can be of practical utility in setting strategy for Target Product Profile design. Citation Format: Debra Van Egeren, Andrew Chen, Madison Stoddard, Lin Yuan, Arijit Chakravarty. Using game theory to investigate the therapeutic potential of disrupting tumor-microenvironment interactions [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 7378.

Abstract 6064: Discovery of potent and selective EP300 degraders with anti-cancer activity

Abstract E1A binding protein (EP300) and CREB binding protein (CBP) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcriptional co-activators. Dysregulation of one or both proteins has been implicated in various cancers, and functional genomic screens have demonstrated a bidirectional synthetic lethal relationship between the two genes in tumor cells. Due to the high homology between EP300 and CBP, identifying chemical matter that selectively targets EP300 or CBP has proven challenging. Here, we describe a potent, highly selective heterobifunctional degrader of EP300 with biological activity in CBP-deficient and EP300-dependent tumor cells. Targeted degradation of EP300 protein resulted in a stronger suppression of cell growth and survival than targeting the bromodomain or HAT activity of EP300/CBP with small molecule inhibitors. Anti-proliferative effects have been demonstrated in multiple cancer types, including malignant lymphomas and castration-resistant prostate tumors, highlighting the essential role of EP300 in mediating oncogenic transcription required for tumor cell growth and survival. Degradation of EP300 in vivo attenuated androgen-driven transcription and inhibited tumor growth in VCAP (AR+) prostate tumor xenografts. Importantly, no evidence of overt toxicity or thrombocytopenia was observed at therapeutically efficacious doses. These findings indicate that selective targeting of EP300 with targeted protein degradation is a safe and effective treatment strategy for advanced tumors. Citation Format: Mark Zimmerman, Ammar Adam, Hafiz Ahmad, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie Di Bernardo, Thomas Dixon, Danette Daniels, Claudia Dominici, GiNell Elliot, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, Dave Lahr, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Darshan Sappal, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Qianhe Zhou, Laura La Bonte. Discovery of potent and selective EP300 degraders with anti-cancer activity [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 6064.

The H2O2 Self-Sufficient 3D Printed β-TCP Scaffolds with Synergistic Anti-Tumor Effect and Reinforced Osseointegration.

Tumor recurrence and massive bone defects are two critical challenges for postoperative treatment of oral and maxillofacial tumor, posing serious threats to the health of patients. Herein, in order to eliminate residual tumor cells and promote osteogenesis simultaneously, the hydrogen peroxide (H2O2) self-sufficient TCP-PDA-CaO2-CeO2 (TPCC) scaffolds are designed by preparing CaO2 or/and CeO2 nanoparticles (NPs)/chitosan solution and modifying the NPs into polydopamine (PDA)-modified 3D printed TCP scaffolds by rotary coating method. CaO2 NPs loaded on the scaffolds can release Ca2+ and sufficient H2O2 in the acidic tumor microenvironment (TME). The generated H2O2 can further produce hydroxyl radicals (·OH) under catalysis effect by peroxidase (POD) activity of CeO2 NPs, in which the photothermal effect of the PDA coating enhances its POD catalytic effect. Overall, NPs loaded on the scaffold chemically achieve a cascade reaction of H2O2 self-sufficiency and ·OH production, while functionally achieving synergistic effects on anti-tumor and bone promotion. In vitro and in vivo studies show that the scaffolds exhibit effective osteo-inductivity, induced osteoblast differentiation and promote osseointegration. Therefore, the multifunctional composite scaffolds not only validate the concept of chemo-dynamic therapy (CDT) cascade therapy, but also provide a promising clinical strategy for postoperative treatment of oral and maxillofacial tumor.