Efficacy Of Anticancer Therapy Research Articles

Harnessing endocytic pH gradients for cascaded formation of intracellular condensates to inhibit autophagy: A pathway to cancer therapy

Cancer cells rely on autophagy to degrade damaged organelles and survive in the harsh environment for progression and metastasis. Autophagy inhibition can improve the efficacy of anticancer therapy because many anticancer drugs can induce protective autophagy in cancer cells. However, current clinically available autophagy inhibitors are rare and have adverse effects with limited selectivity. This work develops an intracellular biomolecular condensate for autophagy inhibition to kill cancer without apparent side effects. A modularly designed amphiphilic peptide (PNP) can self-assemble to form toxic nanofibrous condensates successively from nanoparticles with the pH changes of the endocytic pathway. Mechanistic studies by CLSM and FRAP demonstrate that the PNP finally forms solid nanofibrous condensates in the lysosome after cell endocytosis. Bio-EM and cell transfection with adenovirus expressing mCherry-GFP-LC3B fusion protein (autophagy marker) experiments indicate the autophagy inhibition by PNP nanofibrous condensates. In vitro experiments show that PNP can significantly boost the activity of the clinical drug by 150-fold against drug-resistant lung cancer cells by inducing G2/M phase arrest of the cell cycle. Furthermore, PNPs demonstrate effective tumor targeting and permeability in vivo, inhibiting tumor growth and reducing the side effects of clinical chemotherapy drugs. Overall, this work provides a simple and feasible strategy for designing intracellular condensates to inhibit autophagy for cancer therapy.

Gastric cancer actionable genomic alterations across diverse populations worldwide and pharmacogenomics strategies based on precision oncology.

Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data. Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins. Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.

A Platinum-Aluminum Bimetallic Salen Complex for Pro-senescence Cancer Therapy.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.

Noninvasive Analysis of Peptidoglycan from Living Animals.

The role of the intestinal microbiota in host health is increasingly revealed in its contributions to disease states. The host-microbiome interaction is multifactorial and dynamic. One of the factors that has recently been strongly associated with host physiological responses is peptidoglycan from bacterial cell walls. Peptidoglycan from gut commensal bacteria activates peptidoglycan sensors in human cells, including the nucleotide-binding oligomerization domain-containing protein 2. When present in the gastrointestinal tract, both the polymeric form (sacculi) and depolymerized fragments can modulate host physiology, including checkpoint anticancer therapy efficacy, body temperature and appetite, and postnatal growth. To utilize this growing area of biology toward therapeutic prescriptions, it will be critical to directly analyze a key feature of the host-microbiome interaction from living hosts in a reproducible and noninvasive way. Here we show that metabolically labeled peptidoglycan/sacculi can be readily isolated from fecal samples collected from both mice and humans. Analysis of fecal samples provided a noninvasive route to probe the gut commensal community including the metabolic synchronicity with the host circadian clock. Together, these results pave the way for noninvasive diagnostic tools to interrogate the causal nature of peptidoglycan in host health and disease.

79 Biomarker of response to immunotherapy

79 Biomarker of response to immunotherapy

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma.

The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC. In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways. Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC. Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

Probiotics intervention in colorectal cancer: From traditional approaches to novel strategies.

The intestine harbors a large population of microorganisms that interact with epithelial cells to maintain host healthy physiological status. These intestinal microbiota engage in the fermentation of non-digestible nutrients and produce beneficial metabolites to regulate host homeostasis, metabolism, and immune response. The disruption of microbiota, known as dysbiosis, has been implicated in many intestinal diseases, including colorectal cancer (CRC). As the third most common cancer and the second leading cause of cancer-related death worldwide, CRC poses a significant health burden. There is an urgent need for novel interventions to reduce CRC incidence and improve clinical outcomes. Modulating the intestinal microbiota has emerged as a promising approach for CRC prevention and treatment. Current research efforts in CRC probiotics primarily focus on reducing the incidence of CRC, alleviating treatment-related side effects, and potentiating the efficacy of anticancer therapy, which is the key to successful translation to clinical practice. This paper aims to review the traditional probiotics and new interventions, such as next-generation probiotics and postbiotics, in the context of CRC. The underlying mechanisms of probiotic anti-cancer effects are also discussed, including the restoration of microbial composition, reinforcement of gut barrier integrity, induction of cancer cell apoptosis, inactivation of carcinogens, and modulation of host immune response. This paper further evaluates the novel strategy of probiotics as an adjuvant therapy in boosting the efficacy of chemotherapy and immunotherapy. Despite all the promising findings presented in studies, the evaluation of potential risks, optimization of delivery methods, and consideration of intra-patient variability of gut microbial baseline must be thoroughly interpreted before bench-to-bedside translation.

Intratumor microbiota in cancer pathogenesis and immunity: from mechanisms of action to therapeutic opportunities.

Microbial species that dwell human bodies have profound effects on overall health and multiple pathological conditions. The tumor microenvironment (TME) is characterized by disordered vasculature, hypoxia, excessive nutrition and immunosuppression. Thus, it is a favorable niche for microbial survival and growth. Multiple lines of evidence support the existence of microorganisms within diverse types of cancers. Like gut microbiota, intratumoral microbes have been tightly associated with cancer pathogenesis. Intratumoral microbiota can affect cancer development through various mechanisms, including induction of host genetic mutation, remodeling of the immune landscape and regulation of cancer metabolism and oncogenic pathways. Tumor-associated microbes modulate the efficacy of anticancer therapies, suggesting their potential utility as novel targets for future intervention. In addition, a growing body of evidence has manifested the diagnostic, prognostic, and therapeutic potential of intratumoral microorganisms in cancer. Nevertheless, our knowledge of the diversity and biological function of intratumoral microbiota is still incomplete. A deeper appreciation of tumor microbiome will be crucial to delineate the key pathological mechanisms underlying cancer progression and hasten the development of personalized treatment approaches. Herein, we summarize the most recent progress of the research into the emerging roles of intratumoral microbiota in cancer and towards clarifying the sophisticated mechanisms involved. Moreover, we discuss the effect of intratumoral microbiota on cancer treatment response and highlight its potential clinical implications in cancer.

Therapeutic potential of single-nucleotide polymorphism-mediated interleukin-6 receptor blockade in cancer treatment: A Mendelian randomization study

BackgroundInterleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous. MethodsAn inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study. ResultsThe selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results. ConclusionTherefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.

Potential anti-cancer activity of Moringa oleifera derived bio-active compounds targeting hypoxia-inducible factor-1 alpha in breast cancer.

Breast cancer (BC) will become a highly detected malignancy in females worldwide in 2023, with over 2 million new cases. Studies have established the role of hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls cellular response to hypoxic stress, and is essential for BC spread. HIF-1 is implicated in nearly every critical stage of the metastatic progression, including invasion, EMT, intravasation, extravasation, angiogenesis, and the formation of metastatic niches. HIF-1 overexpression has been associated with poor prognosis and increased mortality in BC patients. This is accomplished by controlling the expression of HIF-1 target genes involved in cell survival, angiogenesis, metabolism, and treatment resistance. Studies have indicated that inhibiting HIF-1 has an anti-cancer effect on its own and that inhibiting HIF-1-mediated signaling improves the efficacy of anti-cancer therapy. Approximately 74 % of recognized anti-cancer drugs are sourced from plantspecies. Studies on anti-cancer characteristics of phytochemicals derived from Moringa oleifera (MO), also known as the 'Tree of Life', have revealed a high therapeutic potential for BC. In this review, we have highlighted the various mechanisms through which bioactive compounds present in MO may modulate HIF and its regulatory genes/pathways, toprove their efficacy in treating and preventing BC.

Pentagalloyl Glucose-Targeted Inhibition of P-Glycoprotein and Re-Sensitization of Multidrug-Resistant Leukemic Cells (K562/ADR) to Doxorubicin: In Silico and Functional Studies.

Combining phytochemicals with chemotherapeutic drugs has demonstrated the potential to surmount drug resistance. In this paper, we explore the efficacy of pentagalloyl glucose (PGG) in modulating P-gp and reversing multidrug resistance (MDR) in drug-resistant leukemic cells (K562/ADR). The cytotoxicity of PGG was evaluated using a CCK-8 assay, and cell apoptosis was assessed using flow cytometry. Western blotting was used to analyze protein expression levels. P-glycoprotein (P-gp) activity was evaluated by monitoring the kinetics of P-gp-mediated efflux of pirarubicin (THP). Finally, molecular docking, molecular dynamics simulation, and molecular mechanics with generalized Born and surface area solvation (MM-GBSA) calculation were conducted to investigate drug-protein interactions. We found that PGG selectively induced cytotoxicity in K562/ADR cells and enhanced sensitivity to doxorubicin (DOX), indicating its potential as a reversal agent. PGG reduced the expression of P-gp and its gene transcript levels. Additionally, PGG inhibited P-gp-mediated efflux and increased intracellular drug accumulation in drug-resistant cells. Molecular dynamics simulations and MM-GBSA calculation provided insights into the binding affinity of PGG to P-gp, suggesting that PGG binds tightly to both the substrate and the ATP binding sites of P-gp. These findings support the potential of PGG to target P-gp, reverse drug resistance, and enhance the efficacy of anticancer therapies.

Self-Medication during and after Cancer: A French Nation-Wide Cross-Sectional Study.

(1) Background: Little data are available in Western countries regarding self-medication practices in the context of cancer. The aim of this study was to describe the prevalence of self-medication practices during (cancer patients) and after cancer (cancer survivors). (2) Methods: This multicenter, cross-sectional, and online study was designed to assess self-medication prevalence. Other objectives were explored, notably the medication types, the perceived risks, and the relation with symptoms and quality of life. (3) Results: Among the 518 patients analyzed, 56.4% declared they practiced self-medication. Dietary supplements and pain medications were used by more than half of the patients. Self-medication was practiced in order to manage the adverse effects of anticancer therapies (63.8%), for which pain was the leading indication (39%), and to improve the efficacy of anticancer therapies (43.8%, cancer patients). Patients believed that self-medication could not lead to drug interactions with anticancer therapies (84.9%, cancer patients), or to adverse effects (84.6%, cancer patients and survivors). Self-medication practices were associated with altered social functioning, pain, insomnia, and financial difficulties. (4) Conclusions: Self-medication was performed by more than half of the responders (ongoing or past cancer) and could be a marker of the undermanagement of cancer and treatment-related adverse effects.

Multicentre, interventional, single-arm study protocol of telemonitored circadian rhythms and patient-reported outcomes for improving mFOLFIRINOX safety in patients with pancreatic cancer (MultiDom, NCT04263948)

IntroductionCircadian clocks regulate cellular proliferation and drug effects. Tolerability and/or efficacy of anticancer therapies have been improved by their administration according to circadian rhythms, while being predicted by circadian robustness....

Extracellular vesicles derived from a specific strain of commensal bacteria promote anticancer immune responses and synergize with anticancer therapies

Abstract Commensal microbiota regulates cancer development and influences the efficacy of anticancer therapies. To develop a novel microbiota-based anticancer therapy, we screened human intestinal bacteria for their ability to induce IL-12 production in dendritic cells (DCs). A specific strain of Lactobacillusbacteria and their extracellular vesicles (EVs) induced a high level of IL-12 production without a concomitant induction of IL-10 secretion. In addition, DCs stimulated with the LactobacillusEVs promoted differentiation of Th1 and Tc1 cells in vitro. In mice, oral or intravenous administration of the LactobacillusEVs reduced tumor growth in both subcutaneous tumor cell implantation and spontaneous colon cancer models by enhancing the production of IFN-γ and cytotoxic effector molecules in tumor-infiltrating T cells. The EVs also enhanced anticancer efficacy of an anti-PD-1 antibody and oxaliplatin treatment. The tumor growth inhibition by the LactobacillusEVs was abrogated when mice were treated with IL-12-blocking antibody, confirming that the anticancer effect of the EVs depends on their ability to induce IL-12 production. By biochemical and genetic analyses, we identified that bacterial DNA within the LactobacillusEVs is the main factor inducing IL-12 production in DCs via stimulation of TLR9. Accordingly, DNA purified from EVs of the specific Lactobacillusstrain, but not of a closely related other Lactobacillusstrain, was able to stimulate IL-12 secretion. Moreover, the EVs did not show IL-12 induction and cancer suppressive function in TLR9-deficient mice. Our results suggest that a rational selection of commensal bacteria-derived EVs can be a strategy to develop a new cancer immunotherapy. Supported by grants from the National Research Foundation of Korea (2017M3A9F3047085, 2020R1A2C2011307)

Prolactin-induced protein (PIP) increases the sensitivity of breast cancer cells to drug-induced apoptosis

We have previously shown that high expression of prolactin-induced protein (PIP) correlates with the response of breast cancer (BC) patients to standard adjuvant chemotherapy (doxorubicin and cyclophosphamide), which suggests that the absence of this glycoprotein is associated with resistance of tumor cells to chemotherapy. Therefore, in the present study, we analyzed the impact of PIP expression on resistance of BC cells to anti-cancer drugs and its biological role in BC progression. Expression of PIP and apoptotic genes in BC cell lines was analyzed using real-time PCR and Western blotting. PIP was detected in BC tissue specimens using immunohistochemistry. The tumorigenicity of cancer cells was analyzed by the in vivo tumor growth assay. Apoptotic cells were detected based on caspase-3 activation, Annexin V binding and TUNEL assay. The interaction of PIP with BC cells was analyzed using flow cytometry. Using two cellular models of BC (i.e. T47D cells with the knockdown of the PIP gene and MDA-MB-231 cells overexpressing PIP), we found that high expression of PIP resulted in (1) increased sensitivity of BC cells to apoptosis induced by doxorubicin (DOX), 4-hydroperoxycyclophosphamide (4-HC), and paclitaxel (PAX), and (2) improved efficacy of anti-cancer therapy with DOX in the xenograft mice model. Accordingly, a clinical study revealed that BC patients with higher PIP expression were characterized by longer 5-year overall survival and disease-free survival. Subsequent studies showed that PIP up-regulated the expression of the following pro-apoptotic genes: CRADD, DAPK1, FASLG, CD40 and BNIP2. This pro-apoptotic activity is mediated by secreted PIP and most probably involves the specific surface receptor. This study demonstrates that a high expression level of PIP sensitizes BC cells to anti-cancer drugs. Increased sensitivity to chemotherapy is the result of pro-apoptotic activity of PIP, which is evidenced by up-regulation of specific pro-apoptotic genes. As high expression of PIP significantly correlated with a better response of patients to anti-cancer drugs, this glycoprotein can be a marker for the prognostic evaluation of adjuvant chemotherapy.

Abstract 4916: Spatial analysis of local drug induced changes in tumor microenvironment predicts effective treatment combinations in breast cancer

Abstract Anticancer therapeutics primarily designed to target tumor intrinsic mechanisms may also affect components of tumor microenvironment (TME) - immune cells and non-immune stroma. Recent literature reenforces the concept that complex interactions between drugs, neoplastic cells and cells of TME determine the efficacy of anticancer therapies. Systems understanding of these interactions can serve to predict effective treatment combinations simultaneously attacking tumor cell vulnerabilities, enhancing immune surveillance, and mitigating stromal mediators of resistance. The key challenge is to find such TME-modulating combinations in a fast and more informative way. We have developed an integrated analytical platform termed Multiplex Implantable Microdevice Assay (MIMA) to rapidly decompose cancer complexity in drug response and find biomarkers with predictive value for combination therapy efficacy including immunotherapy efficacy. The system deploys a (i) miniaturized implantable microdevice for localized intratumoral drug delivery and (ii) multiplex immunostaining to measure 30+ proteins in single cells at each drug well. Computational analyses of local drug-induced changes provide information about the composition, functional state and spatial cell organization of the tumor and associated TME ultimately bringing new insights into drug mechanisms of action. We used MIMA in genetically engineered mouse models of breast cancer to evaluate effects of five targeted anticancer agents (olaparib, palbociclib, venetoclax, panobinostat, lenvatinib) and two chemotherapies (doxorubicin, paclitaxel) and predicted synergistic antitumor effects with anti-PD-1, anti-CD40, anti-CSF1R immunotherapies and vasculature modulating agents. Some of the most effective combinations were not reported before. A pan-HDAC inhibitor, panobinostat, that synergized with anti-PD-1, induced immunogenic cell death and infiltration of antigen presenting neutrophils. Further longitudinal spatial analyses revealed that mechanisms of resistance co-emerged with these response phenotypes and became prominent over time. We measured fibroblast, protumorigenic macrophage and cytotoxic B cell recruitment associated with heavy deposition of collagen VI, increased immune suppression and emergence of invasive and cancer stem cells. Combination with stroma modulating agent, losartan, improved the efficacy of panobinostat/anti-PD-1 in systemic studies implying that normalization of non-immune stroma might favorably alter aspects of TME for immune and targeted therapy efficacy. All in all, MIMA may represent a new approach to predict effective combination regimens for individual cancer patients. Extended MIMA use and computational modeling of the spatial cell patterns could provide actionable information for development of effective drug doses and schedules. Citation Format: Zuzana Tatarova, Dylan C. Blumberg, Gordon B. Mills, Lisa M. Coussens, Oliver Jonas, Joe W. Gray. Spatial analysis of local drug induced changes in tumor microenvironment predicts effective treatment combinations in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4916.

Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer.

Over the last decade, more sophisticated preclinical colorectal cancer (CRC) models have been established using patient-derived cancer cells and 3D tumoroids. Since patient derived tumor organoids can retain the characteristics of the original tumor, these reliable preclinical models enable cancer drug screening and the study of drug resistance mechanisms. However, CRC related death in patients is mostly associated with the presence of metastatic disease. It is therefore essential to evaluate the efficacy of anti-cancer therapies in relevant in vivo models that truly recapitulate the key molecular features of human cancer metastasis. We have established an orthotopic model based on the injection of CRC patient-derived cancer cells directly into the cecum wall of mice. These tumor cells develop primary tumors in the cecum that metastasize to the liver and lungs, which is frequently observed in patients with advanced CRC. This CRC mouse model can be used to evaluate drug responses monitored by microcomputed tomography (µCT), a clinically relevant small-scale imaging method that can easily identify primary tumors or metastases in patients. Here, we describe the surgical procedure and the required methodology to implant patient-derived cancer cells in the cecum wall of immunodeficient mice.

Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis.

Gut microbiota are recognized to be important for anticancer therapy, yet the underlying mechanism is not clear. Here, through the analysis of clinical samples, we identify the mechanism by which the gut microbial metabolite butyrate inhibits HCC and then explore new strategies for HCC treatment. In our study, we demonstrate that gut microbial metabolite butyrate improves anticancer therapy efficacy by regulating intracellular calcium homeostasis. Using liquid chromatography-mass spectrometry analysis, we found that butyrate metabolism is activated in HCC patients compared with healthy individuals. Butyrate levels are lower in the plasma of HCC patients by gas chromatography-mass spectrometry (GC-MS) analysis. Butyrate supplementation or depletion of short-chain Acyl-CoA dehydrogenase (SCAD) gene (ACADS), encoding a key enzyme for butyrate metabolism, significantly inhibits HCC proliferation and metastasis. The profiling analysis of genes upregulated by butyrate supplementation or ACADS knockdown reveals that calcium signaling pathway is activated, leading to dysregulation of intracellular calcium homeostasis and production of reactive oxygen species. Butyrate supplementation improves the therapy efficacy of a tyrosine kinase inhibitor sorafenib. On the basis of these findings, we developed butyrate and sorafenib coencapsulated mPEG-PLGA-PLL nanoparticles coated with anti-GPC3 antibody (BS@PEAL-GPC3) to prolong the retention time of drugs and enhance drug targeting, leading to high anticancer efficacy. BS@PEAL-GPC3 nanoparticles significantly reduce HCC progression. In addition, BS@PEAL-GPC3 nanoparticles display excellent HCC targeting with excellent safety. In conclusion, our findings provide new insight into the mechanism by which the gut microbial metabolites inhibit HCC progression, suggesting a translatable therapeutics approach to enhance the clinical targeted therapeutic efficacy.

Abstract IA035: DCIS to IDC progression - a key step of immune escape

Abstract The cellular and molecular mechanisms underlying ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. We have analyzed genetic, gene expression, epigenetic profiles of cells composing the tumor and identified cell type-specific changes during tumor progression. Importantly, we detected significant changes in the immune cell composition during tumor progression implying immune escape in invasive tumors and active adaptive immune response in DCIS. We demonstrate that these progression stage-specific alterations are also present in a rat model of breast cancer and that combined targeting of multiple components of the tumor ecosystem increases the efficacy of anti-cancer therapies. Our data highlight the role of microenvironmental, especially immune-related changes in driving breast tumor progression and emphasize the importance of studying pre-invasive tumors. Citation Format: Kornelia Polyak. DCIS to IDC progression - a key step of immune escape [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA035.

Polymorphic microbes: a new emerging hallmark of cancer.

Recognition of the microbiome (and 'polymorphic microbes' within them) as a new emerging hallmark of cancer reflects a wide body of rapidly evolving research. Microbes may be directly carcinogenic, impact host immune responses to promote malignancy, and may be key effectors in determining the efficacy of anticancer therapy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.