Emodin reduces tumor burden by diminishing M2-like macrophages in colorectal cancer

2022 ◽  
Author(s):  
Alexander T Sougiannis ◽  
Brandon N. VanderVeen ◽  
Ioulia Chatzistamou ◽  
Jason L Kubinak ◽  
Mitzi Nagarkatti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Model ◽  
Tumor Burden ◽  
M1 Macrophages ◽  
Chemically Induced ◽  
Poor Understanding ◽  
Exposed Bone ◽  
The Impact ◽  
Nos2 Expression

Emodin, a natural anthraquinone, has been shown to have anti-tumorigenic properties and may be an effective therapy for colorectal cancer (CRC). However, its clinical development has been hampered by a poor understanding of its mechanism of action. The purpose of this study was to 1) evaluate the efficacy of emodin in mouse models of intestinal/colorectal cancer and 2) to examine the impact of emodin on macrophage behavior in the context of CRC. We utilized a genetic model of intestinal cancer (ApcMin/+) and a chemically induced model of CRC (AOM/DSS). Emodin was administered orally (40 mg/kg or 80 mg/kg in AOM/DSS and 80mg/kg in ApcMin/+) 3x/week to observe its preventative effects. Emodin reduced polyp count and size in both rodent models (p<0.05). We further analyzed the colon microenvironment of AOM/DSS mice and found that mice treated with emodin exhibited lower pro-tumorigenic M2-like macrophages and a reduced ratio of M2/M1 macrophages within the colon (p<0.05). Despite this, we did not detect any significant changes in M2-associated cytokines (IL10, IL4, and Tgfb1) nor M1-associated cytokines (IL6, TNFα, IL1β, and IFNγ) within excised polyps. However, there was a significant increase in NOS2 expression (M1 marker) in mice treated with 80 mg/kg emodin (p<0.05). To confirm emodin's effects on macrophages, we exposed bone marrow-derived macrophages (BMDMs) to C26 colon cancer cell conditioned media. Supporting our in vivo data, emodin reduced M2-like macrophages. Overall, these data support the development of emodin as a natural compound for prevention of CRC given its ability to target pro-tumor macrophages.

scholarly journals A Novel Lactic Acid Bacteria Mixture: Macrophage-Targeted Prophylactic Intervention in Colorectal Cancer Management

2020 ◽  
Vol 8 (3) ◽  
pp. 387
Author(s):  
Petra Hradicka ◽  
Jane Beal ◽  
Monika Kassayova ◽  
Andrew Foey ◽  
Vlasta Demeckova
Keyword(s):  
Colorectal Cancer ◽  
Male Rats ◽  
Cancer Management ◽  
Immune Parameters ◽  
Chemically Induced ◽  
Tnf Α ◽  
Vitro Model ◽  
Macrophage Subsets

Colorectal cancer (CRC) is one of the most common forms of cancer. Its onset from chronic inflammation is widely accepted. Moreover, dysbiosis plays an undeniable role, thus the use of probiotics in CRC has been suggested. They exhibit both anti- and pro-inflammatory properties and restore balance in the microbiota. The aim of this study was to investigate the immunomodulatory properties of six lactobacilli with probiotic features in an in vitro model of macrophage-like cells and to test these pooled probiotics for their anti-tumour properties in a chemically induced CRC model using Wistar male rats. Upon co-culture of M1- and M2-like macrophages with lactobacilli, cytokine release (TNF-α, IL-1β, IL-18, IL-23) and phagocytic activity using fluorescent-labelled bacteria were tested. The effects of orally administered probiotics on basic cancer and immune parameters and cytokine concentration (TNF-α, IL-1β, IL-18) in colon tumours were studied. Tested lactobacilli exhibited both pro- and anti-inflammatory properties in in vitro conditions. In vivo study showed that the administration of probiotics was able to decrease multiplicity, volume and total tumour numbers, restore colon length (p < 0.05) and increase IL-18 production (p < 0.05) in tumour tissue. These data indicate both an immunomodulatory effect of probiotics on distinct macrophage subsets and a protective effect against chemically-induced CRC.

scholarly journals Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer

2020 ◽  
Vol 117 (35) ◽  
pp. 21598-21608
Author(s):  
Yoshiro Itatani ◽  
Takamasa Yamamoto ◽  
Cuiling Zhong ◽  
Alfredo A. Molinolo ◽  
Jane Ruppel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Risk Factor ◽  
Genetic Model ◽  
Myeloid Cell ◽  
High Plasma ◽  
Anti Vegf ◽  
Chemically Induced ◽  
Genetic Abnormalities ◽  
Metastasis Models

We testedcis-ApcΔ716/Smad4+/−andcis-ApcΔ716/Smad4+/−KrasG12Dmice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for responsiveness to anti-VEGF therapy. We found that even tumors incis-ApcΔ716/Smad4+/−KrasG12Dmice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) incis-ApcΔ716/Smad4+/−andcis-ApcΔ716/Smad4+/−KrasG12Dmice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.

scholarly journals Fusobacterium nucleatum facilitates cetuximab resistance in colorectal cancer via the PI3K/AKT and JAK/STAT3 pathways

2020 ◽  
Author(s):  
Hu Han ◽  
Yan Li ◽  
Wan Qin ◽  
Lu Wang ◽  
Han Yin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fusobacterium Nucleatum ◽  
Therapy Resistance ◽  
Tumor Burden ◽  
Wild Type ◽  
Poor Clinical Outcome ◽  
Functional Studies ◽  
Cetuximab Therapy

AbstractInfectious pathogens contribute to about 20% of the total tumor burden. Fusobacterium nucleatum (Fn) has been associated with the initiation, progression, and therapy resistance in colorectal cancer (CRC). The over-abundance of Fn has been observed in patients with right-sided CRC than in those with left-sided CRC. While the KRAS/NRAS/BRAF wild-type status of the CRC conferred better response to cetuximab in patients with left-sided CRC than with right-sided CRC. However, treatment failure remains the leading cause of tumor relapse and poor clinical outcome in patients with CRC. Here, we have studied the association of Fn to cetuximab resistance. Our functional studies indicate that Fn facilitates resistance of CRC to cetuximab in vitro and in vivo. Moreover, Fn was found to target the PI3K/AKT and JAK/STAT3 pathways, which altered the response to cetuximab therapy. Therefore, assessing the levels and targeting Fn and the associated signaling pathways may allow modulating the treatment regimen and improve prognoses of CRC patients.

scholarly journals Andean Berry (Vaccinium meridionale Swartz) Juice in Combination With Aspirin Modulated Apoptotic Signaling in Colon Cancer In Vitro and In Vivo

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 261-261
Author(s):  
Sandra Arango-Varela ◽  
Ivan Luzardo ◽  
Maria Maldonado-Celis
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
In Silico ◽  
Aberrant Crypt Foci ◽  
Apoptotic Signaling ◽  
Polyphenolic Composition ◽  
Apoptotic Effects ◽  
The Impact

Abstract Objectives This research aimed to assess the impact of Andean Berry (Vaccinium meridionale Swartz) juice (ABJ) in combination with Aspirin in the apoptotic signaling in colon cancer in vitro and in vivo. We hypothesized that ABJ + Aspirin would produce the most effective anti-proliferative and pro-apoptotic effects in vitro and in vivo. Methods The polyphenolic composition of ABJ was carried out by HPLC-DAD. ABJ (0–30% v/v), Aspirin (0–20 mM), and their mixture were evaluated for their pro-apoptotic effects in human SW480 colorectal cancer cells, followed by human apoptosis proteomic and bioinformatic analysis and in silico docking potential between ABJ components and selected pro-apoptotic targets. For the in vivo assays, colorectal cancer was induced with two injections (separated 1 week each) of azoxymethane (AOM: 15 mg/kg body weight, BW), and treatments were evaluated for its chemopreventive and chemoprotective effects. Hence, 30 male and female Balb/c mice were randomly divided in 5 groups: negative control (basal diet, BD); and four AOM-induced groups: positive control (BD), Aspirin (25 mg/kg BW + BD), ABJ (30% v/v in drinking water ABJ + BD), and ABJ + Aspirin (30% v/v ABJ + 25 mg/kg BW Aspirin + BD). Macroscopic and histopathological parameters were evaluated in vivo. Results The mixture displayed the highest antiproliferative effects (+46%), arrested cell cycle at the G2/M phase, decreased cloning efficiency, but reduced Caspase 3/7 activity, suggesting an alternative apoptotic pathway, compared to untreated SW480 cells. Several pro-apoptotic (cytochrome C, TNFRSF1A, Bax, and Bad) and anti-apoptotic (Hsp70/Hsp32) proteins were decreased. ABJ flavonoids (rutin and kaempferol) exhibited the highest in silico affinity with proteins like TRAILR2 or Catalase. Both chemopreventive and chemoprotective approaches showed similar body/liver weight outcomes, but the mixture displayed the strongest aberrant crypt foci reduction in vivo. The chemopreventive approach was more effective in protecting the colon from AOM. Conclusions Results suggested the potential of ABJ to reduce Aspirin use in the alleviation of colorectal cancer markers in vitro and in vivo, modulating alternate pro-apoptotic signaling. Funding Sources The funding provided by COLCIENCIAS and DGAPA-CTIC-UNAM is appreciated.

scholarly journals Retinitis Pigmentosa Results in Neurodegeneration Concomitant With Neuroinflammation, Extracellular Matrix Disorganization and the Upregulation of Neuroprotective Pathways in Glial Cells and Neurons

2020 ◽  
Author(s):  
Christina B. Bielmeier ◽  
Saskia Roth ◽  
Sabrina I. Schmitt ◽  
Stefaniya K. Boneva ◽  
Anja Schlecht ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Molecular Mechanisms ◽  
Genetic Model ◽  
Immunofluorescent Staining ◽  
System Response ◽  
Photoreceptor Degeneration ◽  
The Impact

Abstract BackgroundHereditary retinal degenerations like retinitis pigmentosa (RP) are amongst the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. Here, we in-depth characterized the transgenic VPP mouse model, a genetic model for autosomal dominant RP. MethodsWe examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescent staining and 3D reconstruction. ResultsOne month-old VPP mice showed a significantly higher number of apoptotic photoreceptor cells that resulted in a significantly thinner ONL in three months-old VPP mice, concomitant with an increase in reactivity of microglia and Müller cells. By RNASeq analysis we identified 9,256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, amongst others, dysregulation of TGF-β regulated extracellular matrix organization, factors of the (ocular) immune system/response and apoptosis. ConclusionThe predominant effect pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated and VEGF signaling that were significantly associated with the VPP transgene-induced photoreceptor degeneration. Thus, modulation of these processes might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.

scholarly journals Leukemic Stress Targets the mTOR Pathway to Suppress Residual HSC in the BM Microenvironment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3730-3730
Author(s):  
John T Butler ◽  
Sherif Abdelhamed ◽  
Lina Gao ◽  
Jeong Lim ◽  
Terzah M Horton ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Conflicts Of Interest ◽  
Chemotherapy Resistance ◽  
Hematopoietic Cells ◽  
Tumor Burden ◽  
Mtor Pathway ◽  
Hematopoietic Stem ◽  
The Impact

The remodeling of the bone marrow (BM) microenvironment that occurs along with the progressive spread of acute myeloid leukemia (AML) cells can be considered a constitutive aspect of leukemogenesis. To date most studies have focused on the functional and in part inflammatory adaptation of stroma, and its potential role in extrinsic chemotherapy resistance. Much less is known about the impact of leukemic stress on residual hematopoietic cells. We previously identified the trafficking of select microRNAs (miRs-) in extracellular vesicles (EVs) between AML cells and hematopoietic progenitor cells (HPC). These studies revealed the mechanism underlying the suppression of HPC function in the AML niche (Hornick, Doron et. al., Science Signaling 2016). Several groups, including ours also noted the relative resistance of residual hematopoietic stem cells (HSC) to elimination from the BM of xenografted animals. In the current study we set out to understand how leukemic stress in the AML xenograft niche shapes HSC fate and function. Using AML cell lines (Molm14, U937, HL60) we established NSG xenografts, systematically tracking peripheral blood AML chimerism to recover murine hematopoietic cells at low or negative tumor burden, and replicating key assays using purified EV for intrafemoral injections. In immunofluorescent studies we initially confirmed the uptake of GFP labeled xenograft-derived EVs across the spectrum of HPC and HSC (KSL/CD150+/CD48-), as well as the successive loss and peripheral displacement of HPCs, and gains in HSC frequency in the leukemic niche. These HSC were found to be enriched for G0 cell cycle status with an increase in phospho- p53, but showed no evidence of apoptosis or senescence. To understand the mechanism underlying their apparent quiescence, we performed in vitro proteomics studies of AML EV exposed HPSC identified downregulation of ribosomal biogenesis pathways. We then confirmed in vivo that residual HSC from AML xenografts experienced a loss of protein synthesis (OPP assay). We next reasoned that deficits in ribosome dysfunction and protein synthesis may reflect deregulation by specific miRNAs highly abundant in AML EV. Here, we had an opportunity to profile EV miRNA from the plasma of 12 unselected AML patients at diagnosis versus 12 control samples, and we confirmed a significant enrichment for specific miRNAs, including miR-1246. Raptor is a component of the mTOR pathway and an annotated target of miR-1246. We demonstrated in a series of experiments that miR-1246 translationally suppresses Raptor and downregulates protein synthesis in residual HSC from AML xenografts. The transfection of synthetic anti-miR1246 sequences on the other hand reversed the effects of AML EV in murine HSC. In aggregate we show that direct crosstalk between AML and hematopoietic cells adds to the adaptive changes that occur in the AML niche. Our experiments suggest a functional significance for EV miRNA that can be detected in AML patient plasma in the regulation of residual BM HSC. More broadly, the mechanisms by which leukemic stress alters hematopoietic function remain underexplored, but our observations suggest that leukemia derived EV contribute to changes in competitive fitness of residual HSC. Disclosures No relevant conflicts of interest to declare.

scholarly journals IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Lei Zhang ◽  
Wen Liu ◽  
Fangyan Liu ◽  
Qun Wang ◽  
Mengjiao Song ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Screening Tests ◽  
Therapeutic Drug ◽  
Solute Carrier Family ◽  
Colorectal Cancer Cells ◽  
Solute Carrier ◽  
The Impact

Ferroptosis, implicated in several diseases, is a new form of programmed and nonapoptotic cell death triggered by iron-dependent lipid peroxidation after inactivation of the cystine/glutamate antiporter system xc–, which is composed of solute carrier family 7 membrane 11 (SLC7A11) and solute carrier family 3 membrane 2 (SLC3A2). Therefore, inducing ferroptosis through inhibiting the cystine/glutamate antiporter system xc– may be an effective way to treat cancer. In previous screening tests, we found that the benzopyran derivative 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) significantly inhibited the viability of colorectal cancer cells. However, the impact of IMCA on ferroptosis remains unknown. Hence, this study investigated the effect of IMCA on ferroptosis and elucidated the underlying molecular mechanism. Results showed that IMCA significantly inhibited the cell viability of colorectal cancer cells in vitro and inhibited tumor growth with negligible organ toxicity in vivo. Further studies showed that IMCA significantly induced the ferroptosis of colorectal cancer cells. Mechanistically, IMCA downregulated the expression of SLC7A11 and decreased the contents of cysteine and glutathione, which resulted in reactive oxygen species accumulation and ferroptosis. Furthermore, overexpression of SLC7A11 significantly attenuated the ferroptosis caused by IMCA. In addition, IMCA regulated the activity of the AMPK/mTOR/p70S6k signaling pathway, which is related to the activity of SLC7A11 and ferroptosis. Collectively, our research provided experimental evidences on the activity and mechanism of ferroptosis induced by IMCA and revealed that IMCA might be a promising therapeutic drug for colorectal cancer.

scholarly journals CircASXL1 knockdown represses the progression of colorectal cancer by downregulating GRIK3 expression by sponging miR-1205

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Guojiu Fang ◽  
Yibin Wu ◽  
Xueli Zhang
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Apoptosis ◽  
Tumor Formation ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Ionotropic Receptor ◽  
The Impact ◽  
Cell Colony

Abstract Background Colorectal cancer (CRC) is a common aggressive tumor that poses a heavy burden to human health. An increasing number of studies have reported that circular RNA (circRNA) is involved in the progression of CRC. In this study, the special profiles of circASXL1 (circ_0001136) in CRC progression were revealed. Methods The expression of circASXL1, microRNA-1205 (miR-1205), and glutamate ionotropic receptor kainate type subunit 3 (GRIK3) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression was determined by Western blot or immunohistochemistry. Cell colony-forming ability was investigated by colony formation assay. Cell cycle and apoptosis were demonstrated using cell-cycle and cell-apoptosis analysis assays, respectively. Cell migration and invasion were detected by wound-healing and transwell migration and invasion assays, respectively. The binding sites between miR-1205 and circASXL1 or GRIK3 were predicted by circBank or miRDB online database, and identified by dual-luciferase reporter assay. The impact of circASXL1 on tumor formation in vivo was investigated by in vivo tumor formation assay. Results CircASXL1 and GRIK3 expression were apparently upregulated, and miR-1205 expression was downregulated in CRC tissues and cells relative to control groups. CircASXL1 knockdown inhibited cell colony-forming ability, migration and invasion, whereas induced cell arrest at G0/G1 phase and cell apoptosis in CRC cells; however, these effects were attenuated by miR-1205 inhibitor. Additionally, circASXL1 acted as a sponge for miR-1205, and miR-1205 was associated with GRIK3. Furthermore, circASXL1 silencing hindered tumor formation by upregulating miR-1205 and downregulating GRIK3 expression. Conclusion CircASXL1 acted an oncogenic role in CRC malignant progression via inducing GRIK3 through sponging miR-1205. Our findings provide a theoretical basis for studying circASXL1-directed therapy for CRC.

scholarly journals Comparison of the Impact of Xanthohumol and Phenethyl Isothiocyanate and Their Combination on Nrf2 and NF-κB Pathways in HepG2 Cells In Vitro and Tumor Burden In Vivo

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3000
Author(s):  
Marta Cykowiak ◽  
Violetta Krajka-Kuźniak ◽  
Robert Kleszcz ◽  
Małgorzata Kucińska ◽  
Hanna Szaefer ◽  
...  
Keyword(s):  
Generation X ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Tumor Burden ◽  
Ros Generation ◽  
Phenethyl Isothiocyanate ◽  
Induced Apoptosis ◽  
The Impact

Background: Increasing evidence suggests that combinations of phytochemicals are more efficient than single components in the modulation of signaling pathways involved in cancer development. In this study, the impact of phenethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), xanthohumol, (X), and resveratrol (RES) and their combinations on the activation and expression of Nrf2 and NF-κB in human hepatocytes and HCC cells were evaluated. Methods: THLE-2 and HepG2 cells were exposed to single phytochemicals and their combinations for 24 h. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cells survival were assessed. The tumor burden was evaluated in mice carrying xenografts. Results: All phytochemicals enhanced the activation and expression of Nrf2 and its target genes SOD and NQO1 in HepG2 cells. The increased expression of NQO1 (~90%) was associated with increased ROS generation. X + PEITC downregulated NF-κB activation reducing binding of its active subunits to DNA resulting in diminished COX-2 expression. In contrast to single phytochemicals, X + PEITC induced apoptosis. Moderate reduction of tumor burden in mice carrying xenografts following X and PEITC or their combination was observed. Conclusions: Since Nrf2 is overexpressed in HCC its reduced activation together with diminished level of NF-κB by X + PEITC may be considered as a strategy to support conventional HCC therapy.

A phase I/II study of PI3Kinase inhibition with copanlisib combined with the anti-PD-1 antibody nivolumab in relapsed/refractory solid tumors with expansions in MSS colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4114-TPS4114
Author(s):  
Christopher Jakubowski ◽  
Natalie B Collins ◽  
Elizabeth Ann Sugar ◽  
Maureen Berg ◽  
Haihui Cao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Phase I ◽  
Solid Tumors ◽  
Fixed Dose ◽  
Second Phase ◽  
The Impact ◽  
Resistance Multiple ◽  
Résistance Multiple

TPS4114 Background: Certain somatic mutations are thought to promote immune evasion and resistance to immunotherapy. PIK3CA was identified in an in vivo genomic screen for mechanisms of resistance to anti-PD1 therapy. MC38 cells (murine colon adenocarcinoma) were engineered to express a library of human cancer-associated mutations from TCGA. Resultant tumors in vivo were exposed to immune pressure with anti-PD1 therapy. Cells that proliferated were then analyzed for mutations that impart immune resistance. Multiple activating mutations in PIK3CA conferred resistance to anti-PD1 therapy. Coadministered PI3K inhibition reversed this resistance. Multiple studies have shown the impact of the phosphatidylinositol 3-kinase (PI3K) pathway on the tumor microenvironment, and 20% of colorectal cancer (CRC) tumors have an activating mutation of PI3K. Methods: A multi-center, open-label, phase I/II study with the combination copanlisib and nivolumab, a PD1 inhibitor, in relapsed/refractory solid tumors with expansions in relapsed/refractory microsatellite-stable (MSS) CRC was developed. Copanlisib is an inhibitor of PI3K and exhibits its most potent inhibitory effect on the isoforms PI3Kα and PI3Kδ. The first phase seeks to determine the maximum tolerated dose (MTD) of copanlisib with fixed dose nivolumab of 480 mg given every 4 weeks. Following determination of the MTD the second phase seeks to determine the 6-month objective response rate of the combination in MSS CRC patients and contains two cohorts 1) PIK3CA wildtype, 2) PIK3CA mutated. The study is planned with 21 evaluable subjects per cohort and allows early termination for lack of efficacy. Tumor assessments will be made using RECIST 1.1. Patients will have a pre-treatment biopsy followed by nivolumab on Day 1 of each 4 week cycle and copanlisib on Day 1, 8 and 15. A second biopsy will occur after six weeks. Eligibility criteria includes completed NGS for PI3K status, and patients must have received at least 2 prior lines of standard therapy. Patients can not have received a prior checkpoint inhibitor or PI3K inhibitor. Secondary and exploratory objectives, in addition to survival and safety outcomes, include exploring immune cell subsets in the local tumor microenvironment and in the peripheral circulation, as well as investigating immune activation and suppressive pathways through RNA expression and additional NGS techniques. The clinical study was activated in January 2019 (NCT03711058). Clinical trial information: NCT03711058 .

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