Treatment Of Cancer Research Articles

Vascular endothelial growth factor pathway’s influence on bevacizumab efficacy in metastatic colorectal cancer treatment

Vascular endothelial growth factor pathway’s influence on bevacizumab efficacy in metastatic colorectal cancer treatment

Immune checkpoint inhibitor therapy as a neoadjuvant treatment for muscle-invasive bladder carcinoma

Abstract Background and objectives Immunotherapy has become a standard treatment for patients with advanced urothelial carcinoma, and neoadjuvant immunotherapy is being extensively explored. This review highlights the initial findings and key clinical therapeutic insights on immune checkpoint inhibitors in the early treatment of muscle-invasive bladder cancer across diverse patient populations. Materials and methods Relevant trials were retrieved from PubMed/MEDLINE and clinical trials databases. In addition, abstracts of major international oncology meetings (American Society of Clinical Oncology, American Association for Cancer Research, European Society of Medical Oncology, and European Council of Clinical Oncology) were reviewed until the European Society of Medical Oncology 2023 congress. The review also incorporated results from several exploratory investigations disclosed in recent years. Results This review focused on neoadjuvant immune checkpoint inhibitor monotherapy, combination therapy, and clinical biomarkers in relation to cisplatin-based chemotherapy tolerance. Most available literature consists of clinical investigations involving small sample, single-arm Phase II trials, with the primary endpoint being the pathologic complete response rate. The preliminary results from these studies are promising, demonstrating stage reduction rates comparable to or even exceeding those of standard chemotherapy, without compromising subsequent radical cystectomy. Conclusions Early results of immune checkpoint inhibitors in the neoadjuvant treatment of bladder cancer have demonstrated promising efficacy. However, these findings require confirmation in large Phase III clinical trials, with particular emphasis on long-term survival benefits and identifying patients who respond to treatment.

PVACview: an interactive visualization tool for efficient neoantigen prioritization and selection

Abstract Background Neoantigen-targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. At least 100 clinical trials involving these therapies have been initiated globally. Accurate identification and prioritization of neoantigens is crucial for designing these trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of massively parallel DNA and RNA sequencing technologies, it is now possible to computationally predict neoantigens based on patient-specific variant information. However, numerous factors must be considered when prioritizing neoantigens for use in personalized therapies. Complexities such as alternative transcript annotations, various binding, presentation and immunogenicity prediction algorithms, and variable peptide lengths/registers all potentially impact the neoantigen selection process. There has been a rapid development of computational tools that attempt to account for these complexities. While these tools generate numerous algorithmic predictions for neoantigen characterization, results from these pipelines are difficult to navigate and require extensive knowledge of the underlying tools for accurate interpretation. This often leads to over-simplification of pipeline outputs to make them tractable, for example, limiting prediction to a single RNA isoform or only summarizing the top ranked of many possible peptide candidates. In addition to variant detection, gene expression, and predicted peptide binding affinities, recent studies have also demonstrated the importance of mutation location, allele-specific anchor locations, and variation of T-cell response to long versus short peptides. Due to the intricate nature and number of salient neoantigen features, presenting all relevant information to facilitate candidate selection for downstream applications is a difficult challenge that current tools fail to address. Results We have created pVACview, the first interactive tool designed to aid in the prioritization and selection of neoantigen candidates for personalized neoantigen therapies including cancer vaccines. pVACview has a user-friendly and intuitive interface where users can upload, explore, select, and export their neoantigen candidates. The tool allows users to visualize candidates at multiple levels of detail including variant, transcript, peptide, and algorithm prediction information. Conclusions pVACview will allow researchers to analyze and prioritize neoantigen candidates with greater efficiency and accuracy in basic and translational settings. The application is available as part of the pVACtools software at pvactools.org and as an online server at pvacview.org.

Abstract B027: An Innovative cell-penetrating peptide-based RNAi Therapy to Overcome B-Raf/MEK Inhibitor Resistance in Melanoma

Abstract Small-molecule-targeted therapies have revolutionized cancer treatment, including for B-RafV600E-mutated melanoma, where B-Raf and combined B-Raf/MEK inhibitors (BRAFi/MEKi) prolong progression-free survival and overall survival. However, resistance to these therapies quickly develops, driven by mechanisms such as the expression of alternative spliced isoforms of B-RafV600E and mutated MEK1 variants. The need for novel strategies to overcome such resistance is critical. In this study, we developed and evaluated a novel RNAi-based therapeutic using our designed cell-penetrating peptide HE25 to specifically target and silence resistance-associated spliced isoforms of B-RafV600E, restoring the efficacy of existing treatments. In a recently published work (Tuttolomondo et al., 2024), we demonstrated that HE25 effectively reduced SARS-CoV-2 replication when complexed with siRNA targeting the virus's RNA-dependent RNA polymerase. HE25 facilitated siRNA internalization via multiple receptors involved in viral entry, including ACE2, integrins, and NRP1, through endocytosis, highlighting its versatility as a delivery platform with potential applications beyond cancer research. Initially, we established a vemurafenib-resistant A375 melanoma cell line (A375-VR), which revealed an alternatively spliced B-RafV600E isoform driving resistance to vemurafenib. Through cDNA Sanger sequencing, we confirmed that this alternatively spliced isoform lacks the regulatory domain, leading to constitutive B-Raf activation and rendering vemurafenib ineffective. Given these findings, we hypothesized that specifically silencing this isoform with our siRNA-HE25 complex could synergize with B-Raf inhibition, thereby overcoming vemurafenib resistance. The B-RafV600E-targeting siRNA encapsulated within HE25 significantly inhibited the proliferation of both A375 and A375-VR cells in vitro, with no toxic effects on non-cancerous melanocytes. In vivo, B-RafV600E siRNA-HE25 treatment significantly reduced tumor growth in A375 melanoma xenografts compared to a non-targeting siRNA control. We also developed A375-VTR cells resistant to combined vemurafenib and MEK inhibitor trametinib. This cell line also expressed the shortened B-RafV600E isoform and its silencing by the B-RafV600E siRNA/HE25 system was confirmed by Western blotting. Indeed, in A375-VTR cells, the combination of vemurafenib and B-RafV600E siRNA/HE25 was more effective than the combination of vemurafenib and trametinib. Our strategy holds promise for personalized cancer treatment by targeting resistance-related mutations or alternatively spliced isoforms. Future work will optimize this approach for broader clinical use and explore its efficacy in combination with existing therapies. These findings suggest that siRNA-based therapeutics via HE25 offer a promising solution for overcoming resistance in B-RafV600E-mutated melanoma and resistance mechanisms in other cancer types. This strategy should enable tailored treatments with broad applicability across cancer types. Citation Format: Martina Tuttolomondo, Mikkel Green Terp, Chiara Brienza, Morten Frier Gjerstorff, Henrik Jørn Ditzel. An Innovative cell-penetrating peptide-based RNAi Therapy to Overcome B-Raf/MEK Inhibitor Resistance in Melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B027.

Abstract PR001: Targeting mRNA methyltransferase in RNA-dependent DNA repair in cancer therapy

Abstract The treatment of many solid tumors presents significant challenges with chemotherapy, radiation therapy, and the limited effectiveness of immunotherapy. Targeted therapy offers a promising approach, yet the lack of validated targets limits its applicability across the spectrum of solid tumors. Our past studies have revealed that an R-loop and mRNA-dependent DNA repair (RDDR) pathway, induced by damage at the transcribed regions of the genome, contributes to cell survival and drug resistance in cancer cells. This is particularly due to the high levels of transcription and DNA damage in these cells. We identified the RNA methyltransferase TRDMT1 as the primary modifier of mRNA methyl-5-cytosine in the RDDR pathway. Overcoming technical difficulties in monitoring RNA modifications, we developed the first TRDMT1 inhibitor (TRDMT1i) using in-house built cell-based and in vitro assays. We have identified highly potent and specific lead compounds that significantly reduce TRDMT1 activity at nanomolar concentrations. Our current lead TRDMT1 inhibitors meets most of the criteria that are required for optimal lead. Initial assessments involving the screening of normal and cancer cell lines, xenograft models, and patient specimens indicate that TRDMT1i sensitizes tumors with genomic instability when used as monotherapy. We aim to develop TRDMT1i as an investigational new drug (IND) for future clinical trials, initially targeting ovarian cancer as a monotherapy or in combination therapy for first-line maintenance and systematic therapy. Our goal is to pioneer the discovery of the RDDR pathway, leading to the development of innovative platforms and next-generation medications to revolutionize the targeting of mRNA modifications in cancer treatment. Citation Format: Li Lan. Targeting mRNA methyltransferase in RNA-dependent DNA repair in cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR001.

A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial

Abstract Purpose: Pancreatic adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against the conventional treatment in PDAC. Methods: Phase III trial of advanced PDAC where patients were randomized (1:2) to a conventional treatment treated at physician’s discretion (arm A), or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole exome sequencing (WES) and to generate avatar mouse models and patient derived organoids for phenotypic drug screening, with final treatment recommended by molecular tumor board. The primary objective was median overall survival (OS). Results: 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to Arm B. WES was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only 4 (10.2%) received personalized treatment, while 35 could not be receive matched therapy due to rapid clinical deterioration, delays in obtaining study results or absence of actionable targets. Median OS was 8.7 and 8.6 months (p=0.849) and median progression-free survival was 3.8 and 4.3 months (p=0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had median OS of 19.3 months. Conclusions: Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention to treat analysis. Survival was improved in the subset of patients who did receive matched therapy.

Abstract B025: Redox reprogramming by SOD1 knockdown: A novel liposomal siRNA strategy to overcome platinum resistance in ovarian cancer

Abstract Platinum resistance remains a significant obstacle in the treatment of advanced-stage ovarian cancer, frequently leading to therapeutic failure. Our previous research identified Superoxide Dismutase 1 (SOD1) as a key antioxidant target for re-sensitizing platinum-resistant ovarian cancer cells to platinum-based therapies through both enzymatic inhibition and RNA interference (RNAi) utilizing a graphene-based siRNA delivery platform. Building on these findings, we have now developed a liposomal formulation of chemically modified siRNA targeting SOD1, which demonstrates potent knockdown efficiency and significantly enhances the sensitivity of resistant ovarian cancer cells to cisplatin in vivo. While SOD1 inhibition or knockdown via RNAi effectively re-sensitizes resistant cells to cisplatin, the underlying redox-sensitive signaling pathways remain largely unexplored in ovarian cancer. Our current study reveals that SOD1 knockdown acts as a redox switch, triggering cellular reprogramming in drug-resistant cells through post-translational cysteine modifications. This reprogramming leads to the rewiring of critical cancer hallmarks, culminating in the restoration of a cisplatin-sensitive phenotype. These findings suggest that a liposomal, chemically modified SOD1 siRNA formulation could serve as a promising therapeutic approach for reversing platinum resistance in ovarian cancer by exploiting redox-mediated reprogramming of cancer hallmarks. This study not only underscores the therapeutic potential of targeting SOD1 but also highlights the broader implications of redox signaling in the etiology of platinum resistance, providing a novel avenue for therapeutic intervention. Citation Format: Attila Szenasi, Sonia Rocha, Mu Wang. Redox reprogramming by SOD1 knockdown: A novel liposomal siRNA strategy to overcome platinum resistance in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B025.

Abstract B017: Discovery of cancer-specific small RNAs using a new unbiased analysis of cohort sequence data

Abstract It is well-established that small RNAs such as microRNAs can have important roles as oncogenes or tumor suppressors. The majority of studies of small RNAs in cancer have focused on examining the often subtle deregulation of specific, well-characterized molecules, aiming to understand their role in tumorigenesis. However, these efforts have predominantly concentrated on known, well-annotated RNA sequences, potentially overlooking novel, cancer-specific molecules. In this study, we sought to apply a new computational approach to uncover small RNA molecules that are uniquely associated with cancer and are completely absent from all non- cancerous tissues. To achieve this, we developed an unbiased approach that can detect cancer- specific sequences even if they are lowly abundant, do not overlap with existing genome annotations and even if they do not map to the human reference genome. We applied our framework to hundreds of small RNA-seq samples across a diverse range of cancer types from two large-scale public resources: The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Through this comprehensive analysis, we identified a series of small RNA molecules that are exclusively present in tumor samples and completely absent in adjacent normal tissues across multiple cancer types. Furthermore, these molecules were not detected in a large cohort comprising over 2,500 non-cancerous public samples, underscoring their specificity to cancerous conditions. Some of these molecules are also associated with different patient metadata. For example, one of these candidates exhibited significant correlation with poor patient survival in both Lung Adenocarcinoma and Endometrial Carcinoma within both the TCGA and CPTAC datasets. The discovery of such cancer-specific small RNAs holds immense potential for clinical applications. These molecules could serve as highly specific diagnostic and prognostic biomarkers, aiding in the early detection and stratification of cancers. Moreover, their unique presence in cancer cells, positions them as promising targets for the development of novel therapeutic interventions. In summary, our findings highlight the importance of exploring the full spectrum of small RNAs in cancer research. By moving beyond the constraints of known annotations, we have uncovered previously unknown molecules that could improve cancer diagnostics, prognostics, and treatment. Citation Format: Panagiotis Kalogeropoulos, Maria Alejandra Ulloa, Marc Friedländer. Discovery of cancer-specific small RNAs using a new unbiased analysis of cohort sequence data [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B017.

Development and optimization of multivesicular gefitinib liposomal transdermal system employing lipoid S100 for breast cancer: pharmacokinetics, bioavailability, and skin irritation studies in Wistar rats

Abstract Background Conventional therapies in cancer treatment face challenges including drug resistance, lack of specificity, and severe adverse reactions. This study explores the potential of liposomal transdermal delivery systems as an alternative to current therapies with improved BA and PK. The objective of the study was to formulate gefitinib liposomes by thin film hydration technique (TFH) using lipoid S100. A central composite design (CCD) was used to develop and optimize GEF-LIP-TDDs and to analyze the optimum concentrations of the selected variables (phospholipid, cholesterol) in liposomal formation. The model fitting was performed using Design-Expert (Stat-Ease, Ver 13). The GEF liposomes were evaluated for %EE, mean particle size and PDI. The optimized liposomes were fabricated as a transdermal patch by mercury substrate method and evaluated for %drug content, in vitro diffusion, in vivo biodistribution (PK and BA), and skin irritation studies in female Albino Wistar rats. The stability of the optimized transdermal patch was also assessed for 3 months. Results The CCD model was significant with F-value of 37.97, P-value of 0.0500 and R 2 of 0.9644. The average vesicle size, PDI, and ZP of GEF-LIPs (F1–F13) were found to be between 112.8 to 373.7 nm, 0.186 to 0.510 and − 3.69 to − 82.2 mV, respectively. F3-GEF-LIP exhibited a mean vesicle size of 96.07 nm, ZP of − 46.06 mV, and a PDI of 0.423. F3-GEF-LIP demonstrated exceptional %EE (97.79) and sustained release effect (%CDR, 83.32) following a diffusion-controlled mechanism. TEM images confirmed liposomes of multivesicular type (MVV, < 100 nm). Importantly, optimized F3-GEF-LIP-TD showed no signs of edema in Wistar rats. The biodistribution of F3-GEF-LIP-TD was similar to pure GEF and was higher in the liver (p < 0.05). The BA of F3-GEF-LIP-TD was observed to be 74.05 ± 0.11% in comparison with oral GEF-LIP (65.25 ± 0.08%) and pure GEF (58.10 ± 0.17%). Conclusion TFH technique offers stable liposomes with high reproducibility. Our findings imply that GEF-LIP-TD provides enhanced BA and tissue distribution and can be considered as a substitution for orals or in combination for treating breast cancer. Lipoid S100 is a potential lipid for developing stable multivesicular nanoliposomes. Graphical abstract

Performance of an AI-powered visualization software platform for precision surgery in breast cancer patients

AbstractSurgery remains the primary treatment modality in the management of early-stage invasive breast cancer. Artificial intelligence (AI)-powered visualization platforms offer the compelling potential to aid surgeons in evaluating the tumor’s location and morphology within the breast and accordingly optimize their surgical approach. We sought to validate an AI platform that employs dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to render three-dimensional (3D) representations of the tumor and 5 additional chest tissues, offering clear visualizations as well as functionalities for quantifying tumor morphology, tumor-to-landmark structure distances, excision volumes, and approximate surgical margins. This retrospective study assessed the visualization platform’s performance on 100 cases with ground-truth labels vetted by 2 breast-specialized radiologists. We assessed features including automatic AI-generated clinical metrics (e.g., tumor dimensions) as well as visualization tools including convex hulls at desired margins around the tumor to help visualize lumpectomy volume. The statistical performance of the platform’s automated features was robust and within the range of inter-radiologist variability. These detailed 3D tumor and surrounding multi-tissue depictions offer both qualitative and quantitative comprehension of cancer topology and may aid in formulating an optimal surgical approach for breast cancer treatment. We further establish the framework for broader data integration into the platform to enhance precision cancer care.

Discovery of Novel 5-Cyano-3-phenylindole-Based LSD1/HDAC Dual Inhibitors for Colorectal Cancer Treatment

Discovery of Novel 5-Cyano-3-phenylindole-Based LSD1/HDAC Dual Inhibitors for Colorectal Cancer Treatment

Abstract A024: Assessing Mitondiral Priming in Leukemia Using BH3 Complex Specific Antibodies (PRIMABS): Prediciting Patient Response to Apoptosis Inducing Drugs

Abstract Diagnostic tools for cancer therapy that enable oncologists to inform patients about the likely benefits of their treatment versus toxicity will empower patients to make evidence-based decisions about the management of their disease, and in some cases, their last phase of life. Here we provide a novel approach that measures key drug response features of individual cancer cells with the potential for providing prognostic/predictive diagnostic utility for practicing precision medicine. Most cancer treatments work though activation of the cell suicide program of apoptosis. This process is tightly regulated by the BCL-2 family of proteins whose members either prevent or promote cell death. The relative levels of, and the specific interactions between the pro-survival and pro-apoptotic family members that dictates the fate of all cells and determines their propensity to undergo apoptosis. Cells that more readily die in response to various stimuli are referred to as “primed”. Hence, the degree of priming of a tumor sample can be predictive of responses to anti-cancer drugs and can be established using a technique called “BH3 profiling”. The relevance of this method has been demonstrated but it has had only limited application. To address this limitation a unique panel of antibody-based reagents that are mitochondrial PRIMing state detecting Antibodies (PRIMABS), have been developed by our lab, as a novel approach to implementing personalized medicine and developing predicative diagnostic tests. These antibodies enable the degree of tumor cell priming to be determined directly, unlike BH3 profiling which is an indirect measure. The key innovation lies in the approach taken to determine the presence (or absence) of the critical pro-survival : pro-apoptotic protein complexes , as these are the principal determinants of cell priming.. Such PRIMAB reagents have hitherto not been available. Here we provide data outlining the methodology development as well as evidence demonstrating feasibility of PRIMABTM Dx platform for predicting AML and CLL patient response in retrospective studies. Our platform provides a PD biomarker that will become a clinical predictor of cancer cell response to treatments tat are intended to induce apopstosis in tumor cells. The PRIMABTM -DX platform will enable heretofore hard to achieve clinical applicability of priming measurements. This will be significant due to the important prognostic implications of PRIMAB-DxTM readouts and will provide insights into drug resistance and sensitivity mechanisms and lead to new treatment options for cancer patients. Citation Format: Michael Cardone. Assessing Mitondiral Priming in Leukemia Using BH3 Complex Specific Antibodies (PRIMABS): Prediciting Patient Response to Apoptosis Inducing Drugs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A024.

Abstract PR004: Second generation RNA Polymerase I inhibitor PMR-116 targets ribsomal RNA synthesis to potently treat a broad spectrum of malignancies

Abstract Purpose and rational for the study: The purpose of the study was to develop novel 2nd generation ribosomal RNA synthesis inhibitors for cancer treatment. Ribosome biogenesis (RiBi) is essential for cell growth and proliferation. Transcription of ribosomal RNA genes by Pol I is a critical step in RiBi and is tightly regulated by tumor suppressors and oncoproteins. Indeed, the ability of the potent oncoprotein, MYC, to drive RiBi is necessary for its oncogenic activity (Bywater et al., Cancer Cell, 2011). These data suggested that targeting RiBi, might be a promising strategy to treat malignancies, especially those driven by MYC. To test this, we developed the 1st small molecule inhibitor of Pol I transcription, CX-5461 (Drgyin et al., Cancer Research 2011). While CX-5461 has shown promising activity in pre-clinical studies (Bywater et al., Cancer Cell, 2011; Rebello et al., Clin Cancer Res., 2016; Hein et al., Blood, 2017) and in early Phase trials (Khot et al., Cancer Discovery, 2019; Hilton et al., Nat Commun. 2022) its mechanism of action remains controversial with evidence of off-target activity inducing DNA damage through inhibition of TOPO2a (Cameron et al., Biomedicines, 2024; Koh et al., Nature Genetics, 2024). Thus, to determine if selective inhibition of Pol I transcription in the absence of DNA damage can be used to therapeutical treat cancer in vivo, we developed a series of more selective 2nd generation Pol I inhibitors with our lead compound being PMR-116. Methods and summary of data: We demonstrate that PMR-116 is selective for inhibition of Pol I over Poll II transcription and functions by stalling the Pol I complex at the rDNA promoter. PMR-116, exhibits improved drug-like properties and pharmacokinetics compared to 1st generation CX-5461. As a single agent PMR-116 efficiently treats a range of pre-clinical models of hematologic and solid tumors including lymphoma, AML, hepatocellular carcinoma and prostate cancer. MYC expression positively correlates with sensitivity to PMR-116 in human cancer cell lines and high MYC tumors in vivo are exceptionally sensitive to PMR-116. In contrast to CX-5461, the therapeutic response to PMR-116 occurs in the absence of DNA damage suggesting that DNA damage is not an obligatory response to Pol I transcription inhibition but rather an off-target effect of the 1st generation drug. Small molecule drug combination screens in AML cells demonstrate that PMR-116 works synergistically to reduce cell viability with a range of drugs including carfilzomib and quisinostat used for treatment of hematologic malignancies. Conclusions: Our data establishes inhibition of RNA polymerase I as a bone fide therapeutic target for cancer therapy and demonstrated that PMR-116 is a promising new broad- spectrum anti-cancer drug particularly for those tumors driven by MYC, which are highly refractory to standard therapies. Based on these data we have launched a Phase I clinical trial of PMR-116 in patients with advanced solid tumors (CTRN12620001146987). Citation Format: Rita Ferreira, Katherine M. Hannan, Konstantin Panov, Thejanni Udumanne, Amee J George, Zaka Yuen, Perlita Poh, Eric Kusnadi, Alisee Huglo, Mitchell Lawrence, Mustapha Haddach, Denis Drygin, Luc Furic, Ross D Hannan, Nadine Hein. Second generation RNA Polymerase I inhibitor PMR-116 targets ribsomal RNA synthesis to potently treat a broad spectrum of malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR004.

The impact of financial incentives promoting biosimilar products in oncology: A quasi-experimental study using administrative data

Background Biosimilars have the potential to save a significant amount of money in cancer treatment costs. However, barriers exist in the adoption of biosimilar products. Japan introduced a new health policy in 2022 to promote the use of biosimilars in oncology by offering financial incentives to eligible hospitals. This study aims to examine the association between these financial incentives and prescription patterns. Methods The study analyzed Diagnosis Procedure Combination (DPC) data to assess the impact of the new health policy on the use of biosimilar products in oncology. The policy provided an additional fee for hospitals using biosimilar products. The study included patients with specific types of cancer and analyzed the proportion of monthly biosimilar prescriptions using the number of prescriptions of reference and biosimilar products. A generalized synthetic control method was used for analysis. Results From April 2020 to March 2023, the study involved 27,737 patients in 114 hospitals, with 63 eligible hospitals receiving financial incentives. The average number of prescriptions of the drugs (rituximab, trastuzumab, and bevacizumab) increased gradually in both eligible and ineligible hospitals. The financial incentives were associated with a significant increase in the proportion of biosimilar product prescriptions, with a monthly increase of 0.092 per month (95% CI, 0.040–0.145) [9.2%, 95% CI, 4.0–14.5] compared to ineligible hospitals. Conclusion Our study indicates that providing financial incentives to hospitals to utilize biosimilar products increased their prescriptions. Japan’s recent health policy of moderate financial incentives is an effective approach to increasing prescriptions of biosimilar products.

Interstitial HDR brachytherapy for anal cancer—results and quality of life

Abstract Purpose While anal cancer is a very rare oncological diagnosis representing less than 2% of lower gastrointestinal tract cancers, the incidence has doubled in the past 20 years. Radical radiochemotherapy with sequential or simultaneous boost is now the standard treatment modality. Interstitial HDR brachytherapy is one of the boost application options. Implementation of new radiotherapy techniques has resulted in improved therapeutic outcomes; however, it is still associated with acute and especially late toxicity. Gastrointestinal disorders and sexual dysfunction are the most frequent factors affecting the long-term quality of cured patients’ lives. Methods A total of 96 patients consecutively treated between 2000 and 2022 with external beam radio-/chemotherapy and an interstitial brachytherapy boost for histologically verified nonmetastatic anal squamous cell carcinoma were evaluated. The median follow-up time was 15.4 years (range 13.4–17.3 years). The primary objective of the study was to assess local control (LC) and quality of life (QoL). The Czech versions of internationally validated EORTC questionnaires were used to evaluate life quality—the basic EORTC QOL-C30 v.3 and the specific QOL-ANL 27 questionnaire. Results Local control was 85.5% at 5 years, 83.4% at 10 years, 83.4% at 15 years, and 83.4% at 20 years, and there was no dependence on clinical stage. The most common forms of acute toxicity were cutaneous and hematological but were gastrointestinal for late toxicities. In the evaluation of quality of life, 80.5% of patients alive at the time participated. In the EORTC quality of life questionnaire C30 v.3, patients rated the functional scale score as 86.2 points (standard deviation [SD] = 12.6) and the symptom score as 15.5 points (SD = 12.5). The global health score achieved 68.4 points (SD = 23.6). The most common symptoms were fatigue with 25.6 points (SD = 20.2) and diarrhea with 19.0 points (SD = 27.8). In the QOL-ANL 27 questionnaire, symptom scales assessing bowel symptoms were scored 27.5 points (SD = 19) in non-stoma patients and 11.9 points (SD = 17.2) in stoma patients. In the single-item symptom scales, the highest scores were rated for frequency of urination with 26.4 points (SD = 30.8), need to be close to a toilet with 22.4 points (SD = 27.3), and self-cleaning more often with 25.3 points (SD = 31.8). In the functional scales assessing sex life and interest, men and women reported scores of 45.2 (SD = 23) and 45.5 points (SD = 19), respectively. Conclusion Boost with interstitial HDR brachytherapy is an established safe method of anal cancer treatment, with excellent results and limited late toxicity. Functioning scales were rated relatively highly in QoL questionnaires, and the overall global health score was comparable to published data. Gastrointestinal difficulties, fatigue, and sexual dysfunction dominated the symptom scales in our cohort.

The role of gut microbial β-glucuronidases in carcinogenesis and cancer treatment: a scoping review

Abstract Introduction The human gut microbiota influence critical functions including the metabolism of nutrients, xenobiotics, and drugs. Gut microbial β-glucuronidases (GUS) enzymes facilitate the removal of glucuronic acid from various compounds, potentially affecting anti-cancer drug efficacy and reactivating carcinogens. This review aims to comprehensively analyze and summarize studies on the role of gut microbial GUS in cancer and its interaction with anti-cancer treatments. Its goal is to collate and present insights that are directly relevant to patient care and treatment strategies in oncology. Methods This scoping review followed PRISMA-ScR guidelines and focused on primary research exploring the role of GUS within the gut microbiota related to cancer etiology and anti-cancer treatment. Comprehensive literature searches were conducted in PubMed, Embase, and Web of Science. Results GUS activity was only investigated in colorectal cancer (CRC), revealing increased fecal GUS activity, variations in the gut microbial composition, and GUS-contributing bacterial taxa in CRC patients versus controls. Irinotecan affects gastrointestinal (GI) health by increasing GUS expression and shifting gut microbial composition, particularly by enhancing the presence of GUS-producing bacteria, correlating with irinotecan-induced GI toxicities. GUS inhibitors (GUSi) can mitigate irinotecan's adverse effects, protecting the intestinal barrier and reducing diarrhea. Conclusion To our knowledge, this is the first review to comprehensively analyze and summarize studies on the critical role of gut microbial GUS in cancer and anti-cancer treatment, particularly irinotecan. It underscores the potential of GUSi to reduce side effects and enhance treatment efficacy, highlighting the urgent need for further research to integrate GUS targeting into future anti-cancer treatment strategies.

β-blockers and statins: exploring the potential off-label applications in breast, colorectal, prostate, and lung cancers

Despite advances in cancer treatment, current cancer incidence and prevalence still demand multimodal treatments to enhance survival and clinical outcomes. Drugs used in cardiology, such as β-blockers and statins have gained attention for their potential roles in oncology. This review focused on their possible complementary use in solid tumors, including breast, colorectal, lung, and prostate cancers. The involvement of the autonomic nervous system in promoting tumor growth can be disrupted by β-blockers, potentially hindering cancer progression. Statins, known for their pleiotropic effects, may also inhibit cancer growth by reducing cholesterol availability, a key factor in cell proliferation. We will provide an update on the impact of these therapies on cancer treatment and surveillance, discuss the underlying mechanisms, and explore their effects on the heart, contributing to the growing field of cardio-oncology.

Cost-effectiveness analysis of trifluridine/tipiracil combined with bevacizumab vs. monotherapy for third-line treatment of colorectal cancer

BackgroundThe combination of trifluridine/tipiracil (FTD/TPI) and bevacizumab has demonstrated promising efficacy and safety in the treatment of colorectal cancer (CRC). This study aims to evaluate the cost-effectiveness of trifluridine/tipiracil combined with bevacizumab vs. trifluridine/tipiracil monotherapy as a third-line treatment regimen for colorectal cancer within the Chinese healthcare system, providing an economic basis for clinical application.MethodsBased on data from the SUNLIGHT Phase III clinical trial, a dynamic Markov model was constructed with a cycle length of 4 weeks and a simulation duration of 10 years. Direct medical costs and quality-adjusted life years (QALYs) were calculated. The incremental cost-effectiveness ratio (ICER) was compared with the willingness-to-pay threshold (WTP = ¥268,200.00/QALY) to assess the economic viability of the treatment regimen. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to verify the robustness of the model results.ResultsThe cost of trifluridine/tipiracil combined with bevacizumab treatment (¥838,492.74) was higher than that of trifluridine/tipiracil monotherapy (¥357,396.97), with greater health benefits (2.45 QALYs vs. 1.54 QALYs). The ICER was ¥527,577.36/QALY, exceeding the willingness-to-pay threshold. One-way sensitivity analysis indicated that drug costs and utility values during the progression-free period significantly impacted model outputs. Probabilistic sensitivity analysis further confirmed the robustness of the results, showing that at a willingness-to-pay threshold of ¥494,000.00, the probability of the combined treatment being cost-effective was 50%.ConclusionTrifluridine/tipiracil combined with bevacizumab, as a third-line treatment for colorectal cancer, does not have a cost-effectiveness advantage compared to trifluridine/tipiracil monotherapy in economic evaluations.

New strategies for lung cancer diagnosis and treatment: applications and advances in nanotechnology

AbstractLung cancer leads in causing cancer-related mortality worldwide, continually posing a significant threat to human health. Current imaging diagnostic techniques, while offering non-invasive detection, suffer from issues such as insufficient sensitivity and the risks associated with radiation exposure. Pathological diagnosis, the gold standard for confirmation, also faces challenges like invasiveness and high costs. In treatment, surgery, radiotherapy, and chemotherapy are the main modalities, each encountering challenges related to precision, environmental adaptability, and side effects. Nanotechnology’s advancement provides new solutions for the diagnosis and treatment of lung cancer, promising to enhance diagnostic accuracy and reduce side effects during treatment. This article introduces the main types of nanomaterials used in the field of lung cancer, offering a comprehensive overview of current research on the application of nanotechnology in early screening, diagnosis, treatment, and monitoring of lung cancer, and summarizing ongoing clinical research findings.

Current status of evaluation and treatment of early-stage remnant gastric cancer

Because of early diagnosis and improved prognosis, patients with gastric cancer are now surviving longer and remnant gastric cancer after gastrectomy is becoming more common. Remnant gastric cancer is traditionally considered a malignancy with a dismal outcome. However, recent advances in diagnostic and therapeutic strategies have improved outcomes. In recent years, the development of endoscopic therapy has provided us with new therapeutic ideas. Although with some drawbacks, such as limited working space, gastric fibrosis and staples under the suture line, endoscopic management is still an effective treatment option with potential long-term survival advantage. For gastrectomy patients, endoscopic surveillance should also be recommended, for prompt surveillance and detection in the early remnant gastric cancer. This review aims to provide an overview of remnant gastric cancer, especially focusing on its pathogenesis as well as new advances in the diagnosis and endoscopic treatment of early-stage remnant gastric cancer.