Browsing Over 131 Presentations
Emerging preclinical and clinical data with novel antibody drug conjugates in various tumour types (ID 349)
- Giuseppe Curigliano (Milan, Italy)
- Giuseppe Curigliano (Milan, Italy)
Q&A (ID 350)
- Giuseppe Curigliano (Milan, Italy)
- Giuseppe Curigliano (Milan, Italy)
- Matthias Peipp (Kiel, Germany)
Authors will answer your questions! (ID 322)
- Need Person (London, United Kingdom)
- Need Person (London, United Kingdom)
39P - Effect of dose level of the selective FGFR2 inhibitor alofanib on toxicity, pharmacokinetics and preliminary efficacy: A phase Ib study in patients with advanced gastric cancer (RPT835GC1B) (ID 256)
- Ilya Tsimafeyeu (Moscow, Russian Federation)
- Ilya Tsimafeyeu (Moscow, Russian Federation)
- Vasily Kazey (Moscow, Russian Federation)
- Nadezhda Dragun (Saint-Petersburg, Russian Federation)
- Dmitry Reznikov (Saint-Petersburg, Russian Federation)
- Evgenia Gavrilova (Saint-Petersburg, Russian Federation)
- Svetlana Gorbacheva (Moscow, Russian Federation)
- Aiyyna Nikiforova (Saint-Petersburg, Russian Federation)
- Mikhail Byakhov (Reutov, Russian Federation)
- Sergei Tjulandin (Moscow, Russian Federation)
Abstract
Background
FGFR2 molecular changes was observed in gastric cancer at a frequency of 4-15% and associated with shorter progression-free survival (PFS) and overall survival (OS). Alofanib (RPT835) is a novel selective inhibitor that binds allosterically to the extracellular domain of FGFR2.
Methods
The aim of this phase Ib study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, preliminary efficacy and pharmacokinetics (PK) of alofanib administered intravenously daily for 5 days weekly. Patients with advanced or metastatic gastric adenocarcinoma resistant to standard therapy were enrolled in 5 dose levels: 50, 100, 165, 250, and 350 mg/m2, using a 3 + 3 design.
Results
To date, 13 patients have been enrolled in the trial. The MTD was not reached. All patients have not experienced any DLT within the 28-day DLT-assessment window. Intravenous alofanib was safe. There were no correlations between dose level and toxicity. Three grade 3 adverse events (ALT/AST increased at 50 mg/m2, diarrhea at 165 mg/m2, and hyponatremia at 350 mg/m2) were reported. One patient discontinued treatment due to drug related grade 3 uncontrolled diarrhea. Grade 1-2 adverse events included fatigue, diarrhea, nausea, anemia, thrombocytopenia, increased alkaline phosphatase, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia). Grade 1 hyperphosphatemia was founded in 25% of cases. Of the 12 assessed patients, 1 (8%) partial response at 50 mg/m2 and 8 (67%) stable diseases at 50-250 mg/m2 were recorded. After a median follow-up of 4.5 months, the median PFS and OS was not reached. PK parameters have increased with dose. PK values (Cmax, AUC, and t1/2) did not correlate with response, PFS and OS (all P>0.1).
Conclusions
Administration of alofanib by intravenous route as single agent was safe and demonstrated promising antitumor activity in heavily pretreated patients with metastatic gastric cancer. The MTD has not been reached up to 350 mg/m2. PK profiles did not correlate with toxicity and efficacy of alofanib. The study is ongoing.
Clinical trial identification
NCT04071184.
Legal entity responsible for the study
Ministry of Health, Russian Federation.
Funding
Skolkovo Foundation.
Disclosure
N. Dragun, D. Reznikov, E. Gavrilova: Full/Part-time employment: Ruspharmtech LLC. All other authors have declared no conflicts of interest.
10P - Emerging role of Telomeric repeat-containing RNA TERRA in hepatocellular carcinoma (ID 257)
- Michele Manganelli (Brescia, Italy)
- Michele Manganelli (Brescia, Italy)
- Ilaria Grossi (Brescia, Italy)
- Jessica Corsi (Trento, Italy)
- Katarina Jurikovà (Trento, Italy)
- Emilio Cusanelli (Trento, Italy)
- Vito D’agostino (Trento, Italy)
- Sarah Molfino (Brescia, Italy)
- Gianluca Baiocchi (Brescia, Italy)
- Nazario Portolani (Brescia, Italy)
- Alessandro Salvi (Brescia, Italy)
- Giuseppina De Petro (Brescia, Italy)
Abstract
Background
Hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The identification of candidate molecular targets and biomarkers in HCC clinical practice are needed. The signatures of aberrant long non-coding RNAs (lncRNAs) expression in HCC tissues, their extracellular release and stability had led to their exploration as diagnostic and prognostic tools as well as potential therapeutic targets for HCC. Telomeric-Repeat Containing RNA (TERRA) consists of 100nt-9Kb subtelomeric-derived transcripts able to base-pair with TERC RNA, acting as telomerase allosteric inhibitor. Little is known on the role of lncRNA TERRA in HCC.
Methods
By qPCR we measured TERRA expression in tumor and peritumoral (PT) tissues of HCC patients, as well as in plasma and in HCC cells. HCC patients (n.25) did not receive any treatment before surgical resection. By nickel-based isolation method (NBI) we isolated from the conditioned medium (CM) of HA22T/VGH cells the extracellular vesicles (EVs), subsequently analyzed by qNANO instrument.
Results
Global TERRA expression was significantly downregulated in HCC vs PT tissues (p=0.025) and ROC analysis revealed a significant ability to distinguish HCC from PT (p=0.03). Extracellular TERRA transcripts were significantly higher in plasma of HCC patients compared with healthy subjects and logistic regression model strongly evidenced the potential diagnostic ability of circulating TERRA (AUC=0.76; 95% CI=0.624-0.873; p=0.0004). HA22T/VGH cells expressed TERRA, but most of the transcripts are released into the CM, also encapsulated in EVs (mean diameter=185nm, concentration=163x106/ml). Treatment of HCC cells with the multi-kinase inhibitor (KI) sorafenib significantly increased TERRA expression (p=0.001) and decreased (p=0.01) its release in EVs (mean diameter=252nm, concentration=209x106/ml).
Conclusions
Our results provide evidence on TERRA dysregulation in tissues and liquid biopsy of HCC patients, thus focusing on a novel potential non-invasive biomarker of diagnosis and downstream target of the KI. TERRA detected in the EVs of HCC cells open a new field of cancer research to comprehend its role at the extracellular level.
Legal entity responsible for the study
The authors.
Funding
Lega Italiana Lotta ai Tumori (LILT), Italian Ministry of University and Research (FFRB), University of Brescia.
Disclosure
All authors have declared no conflicts of interest.
28P - Hijacking CCAT1/miR-17-5p axis alleviates immune checkpoint blockers resistance in PDL1+ TNBC patients (ID 259)
- Noha Selem (Cairo, Egypt)
- Noha Selem (Cairo, Egypt)
- Heba M. Nafea (Cairo, Egypt)
- Rana A. Youness (Cairo, Egypt)
- MOHAMED ZAKARIA Gad (Cairo, Egypt)
Abstract
Background
The hot tumor nature of triple-negative breast cancer (TNBC) tumors serves as a key player in the prognosis of such patients. Giving a strong rational to support the immune-based therapeutic approaches for this hard-to-treat group of patients. Immune checkpoint blockades (ICBs) have been extensively studied especially PDL1/PD1 blockers. Yet, the number of resistant cases started to escalate. Therefore, it became crucial to probe for molecular engines regulating PDL1 expression. Currently, unveiling novel networks between non-coding RNAs (ncRNAs) and their roles in regulating TNBC has become a research hotspot. Our group has recently reported that miR-17-5p represses the immune suppressive IL-10 production. However, its role in regulating PDL1 is still unprobed in TNBC. CCAT1 is an oncogenic long ncRNA. CCAT1 acts as a sponge for several tumor suppressor miRNAs affecting it is downstream targets. Therefore, the aim of this study is to investigate part of the interactive ncRNA network regulating PDL1 in TNBC patients.
Methods
BC patients (n=35) were recruited. Bioinformatics analysis was executed. TNBC cell lines were cultured and transfected with different oligonucleotides using HiPerFect Transfection Reagent. Total RNA was extracted, reverse transcribed and quantified using qRT-PCR. Cellular viability, colony forming ability and migration were measured using MTT, colony forming and scratch assays, respectively.
Results
In-silico analysis revealed that PDL1 is a potential target for miR-17-5p and CCAT1. miR-17-5p was found to be under-expressed in PDL1+/CCAT+ TNBC tissues compared to its normal counterparts. Ectopic expression of miR-17-5p and/or knocking down of CCAT1 resulted in a prominent reduction PDL1. On the other hand, a mutual interactive loop was observed between miR-17-5p and CCAT1 in TNBC cells; miR-17-5p mimics repressed CCAT1 levels while CCAT1 siRNAs resulted in an induction of miR-17-5p levels. Functionally, CCAT1 siRNAs and miR-17-5p mimics markedly halted TNBC hallmarks.
Conclusions
This study highlights a novel ncRNA circuit regulating PDL1 in TNBC patients. Thus, targeting CCAT1/miR-17-5p axis might provide a potential solution in overcoming the ICBs resistance arises in some TNBC patients.
Legal entity responsible for the study
German University in Cairo.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
2P - Molecular imaging evaluation of a novel Claudin18.2 specific monoclonal antibody labeled with radionuclide (ID 261)
- Hua Zhu (Beijing, China)
- Hua Zhu (Beijing, China)
- Jin Ding (Beijing, China)
- Xiaoyi Chong (Beijing, China)
- Congcong Ji (Beijing, China)
- Cheng Zhang (Beijing, China)
- Fei Teng (Suzhou, China)
- Yi Gu (Suzhou, China)
- Xueming Qian (Suzhou, China)
- Zhi Yang (Beijing, China)
- Lin Shen (Beijing, China)
- Jing Gao (Shenzhen, China)
Abstract
Background
Claudin18.2 (CLDN18.2), a member of tight junction protein family, is strictly limited to differentiated epithelial cells of gastric mucosa and multiple tumor types, such as gastric, esophageal and pancreatic cancers. We have generated a novel species cross-reactive CLDN18.2 specific antibody, and labeled it with “Next Generation” radionuclide I-124 (124I-18B10).
Methods
I-124 was produced by the medical cyclotron using 124Te (p, n) 124I reaction. In the cell-based assay, the uptake of 124I-18B10 in MKN45-CLDN18.2 (CLDN18.2+ cell line) and MKN45 (CLDN18.2- cell line) were detected at 10, 30, 60 and 120 min, and the blocking group using cold 18B10 antibody to block uptake was also evaluated. PDX-bearing mice, which were selected by immunohistochemical (IHC) method and assessed as CLDN18.2+ or CLDN18.2-, were injected with either 18.5 MBq 18F- fluorodeoxyglucose (18F-FDG), or 124I-18B10, or 124I-hIgG via the tail vein, and Micro-PET/CT images were taken at 2, 60 and 120h post injection.
Results
The specific activity of 124I-18B10 was 0.62 mCi/mg antibody and the labeling rate was higher than 95%. The cell-based assay showed that specific uptake of it by the MKN45-CLDN18.2 cells was significantly higher than that of by the MKN45 cells (23.51±0.47 % vs 8.69±0.35 % at 2 h, P<0.05). Both uptake assay and competitive binding assay in the MKN45-CLDN18.2 cells showed that cold 18B10 antibody could significantly reduce the uptake and binding of 124I-18B10 (15.33±0.82 % at 2 h, P<0.05). As expected, the uptake of 124I-hIgG was low (5.21±0.29 % at 2 h). In PDX bearing mice, the uptake of 18F-FDG in tumor sites was low. The distribution of 124I-18B10 in CLDN18.2+ PDX bearing mice was increasingly enriched in the tumor sites over time. The uptake signals of 124I-18B10 in CLDN18.2- PDX bearing mice in all tissues and tumors remained similar at different time points.
Conclusions
The 124I-18B10 antibody has good radio-chemical characteristics and stability. The cell uptake assay and competitive binding assay demonstrated that the probe is highly specific to CLDN18.2. Micro-PET images of PDX bearing mice demonstrated that 124I-18B10 was enriched in the lesion of CLDN18.2 positive tumors rather than negative tumors or normal tissues.
Legal entity responsible for the study
Peking University Cancer Hospital & Institute.
Funding
Has not received any funding.
Disclosure
F. Teng, Y. Gu, X. Qian: Full/Part-time employment: Research, Mabspace Biosciences (Suzhou) Co. Ltd., Suzhou, China. All other authors have declared no conflicts of interest.
41P - The functional GRHL3-FLG axis predicts targeted therapy response in head and neck cancer (ID 264)
- Yuchen Bai (Melbourne, Australia)
- Yuchen Bai (Melbourne, Australia)
- Zixuan Zhao (Beijing, China)
- Bryce J. Denderen (Melbourne, VIC, Australia)
- Charbel Darido (Melbourne, VIC, Australia)
Abstract
Background
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease harbouring the most frequent hotspot mutations in the differentiation genes. Disruption of epithelial differentiation acts as a primary driver of HNSCC development and correlates with a poor patient's prognosis. To date, in addition to the non-selective conventional HNSCC treatments, such as chemotherapies and surgeries, the only FDA-approved targeted therapy Cetuximab, an epidermal growth factor receptor inhibitor, has a low response rate with considerable toxicity. Therefore, determining whether functional differentiation can serve as a molecular vulnerability and/or a predictor of targeted therapy in HNSCC is an area of valuable clinical need.
Methods
A multi-omic approach integrating whole-genome and whole-transcriptome sequencing with drug sensitivity screening was employed in tumours from a spontaneous HNSCC murine model, HNSCC patient’s tumours, and established human cell lines to reveal potential predictive biomarkers for targeted therapies. CRISPR-Cas9-mediated gene knockout and activation validated candidate predictors in HNSCC cell lines treated with inhibitors of the PI3K/mTOR, c-MYC and STAT3 pathways, the key signalling in HNSCC oncogenesis.
Results
We identified a novel Grainyhead-like 3 - Filaggrin (GRHL3-FLG) differentiation axis as a predictive biomarker to targeted therapy response in HNSCC. A subset of HNSCC with functional GRHL3-dependent differentiation was the most sensitive to inhibitors of PI3K/mTOR, c-MYC and STAT3 signaling. Furthermore, we identified the GRHL3 transcriptional target gene FLG as a novel tumour differentiation gene and, more importantly, stratified HNSCC subsets as treatment-resistant based on their FLG mutational profile. Moreover, the loss of FLG in sensitive HNSCC cells resulted in a dramatic resistance to targeted therapies while the GRHL3hi-FLGwt signature predicted a favourable patient's prognosis.
Conclusions
Functional differentiation (GRHL3hi-FLGwt) provides the first example of differentiation-dependent therapy response and establishes a rationale for clinical investigation of differentiation-paired targeted therapy that may improve outcomes in HNSCC and other heterogeneous cancers.
Legal entity responsible for the study
The authors.
Funding
Australian National Health and Medical Research Council, Victorian Cancer Agency.
Disclosure
All authors have declared no conflicts of interest.
48P - Target mining and drug repurposing for hepatocellular carcinoma via bioinformatic and computational approaches (ID 267)
- Gouri Nair (Bangalore, India)
- Gouri Nair (Bangalore, India)
- Ganesan Rajalekshmi Saraswathy (Bangalore, India)
- G.N.S Hema Sree (Bangalore, India)
Abstract
Background
Sorafenib is the only therapy to treat hepatocellular carcinoma (HCC), yet offers limited survival benefits due to drug resistance. Advanced oncotherapeutic research demands a thorough insight into pathological cascades involved in the progression of preneoplastic lesions to HCC. Hence, target mining to unearth key genetic players of HCC followed by screening drug databases against the identified targets will be a rational way forward.
Methods
GSE6764 gene expression profile dataset encompassing microarray data of 10 normal, 10 cirrhosis, 17 dysplastic nodules, 18 early and 17 advanced HCC was analyzed using GEO2R. Subsequently, a protein-protein interaction network was constructed using the Search Tool for the Retrieval of Interacting Genes and visualized through Cytoscape. Crucial targets were identified based on the overall survival (OS) and hazard ratio (HR > 1) of hub genes from the Kaplan-Meier plotter. The identified targets were screened against all FDA-approved drugs by molecular docking studies through extra precision mode (XP) in the Schrodinger drug design suite. Further, the free energy of binding of shortlisted drugs was evaluated by MM/GBSA analysis.
Results
STAT1 and MX1 are substantially overexpressed in cirrhosis while, CCL19 and IL7R are significantly downregulated between dysplastic nodule and cirrhosis. HMMR overexpression is linked with poor prognosis in the evolution of dysplastic nodule to early HCC. Furthermore, overexpression of pathological hallmarks of poor prognosis such as CDK1, CDC20, BUB1, MAD2L1, CCNB2, CENPF, TPX2, TOP2A and PBK was identified in the furtherance from early and advanced HCC. Based on OS with significant HR, CDC20 was shortlisted and subjected to molecular docking and MM-GBSA analysis. Labetalol, a beta-blocker was spotlighted as a hit due to its highest docking score of -7.075, ΔG value -54.08 kcal/mol alongside its stable and stronger ligand-protein complex.
Conclusions
This study reveals a series of key cross-talk genetic underpinnings from pre-neoplastic lesions to HCC and suggests the pertinence of labetalol as a potential repurposable drug in the treatment for HCC.
Legal entity responsible for the study
Gouri Nair.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
43P - Pre-clinical evaluation of potent and orally bioavailable next-generation inhibitors targeting the family of mutants that drive oncogenic BRAF dimer formation (ID 268)
- Yoon-Chi Han (New York, YT, United States of America)
- Yoon-Chi Han (New York, YT, United States of America)
- Pui Yee Ng (Cambridge, AL, United States of America)
- Ryan Schulz (New York, NY, United States of America)
- Shao Ning Yang (New York, United States of America)
- Alana Lelo (New York, United States of America)
- Luisa Shin Ogawa (Cambridge, United States of America)
- Matthew O'Connor (New York, NY, United States of America)
- Noboru Ishiyama (Cambridge, United States of America)
- Ivan Jewett (Cambridge, MA, United States of America)
- Darlene Romashko (New York, NY, United States of America)
- Andrei Salomatov (Cambridge, MA, United States of America)
- Shalabh Thakur (Cambridge, MA, United States of America)
- Sherri Smith (Cambridge, MA, United States of America)
- Elizabeth Buck (New York, NY, United States of America)
- Christopher Roberts (Cambridge, MA, United States of America)
- Matthew Lucas (Cambridge, MA, United States of America)
- Tai-An Lin (New York, United States of America)
Abstract
Background
The canonical BRAF V600E (class I) mutation is a potent oncogene which is uniquely active as a RAS-independent monomer, and which has been successfully targeted by several FDA-approved inhibitors. While active against monomeric BRAF V600E, these first generation BRAF inhibitors induce paradoxical activation of RAS-driven BRAF dimers in cells expressing wild-type RAF, and this can lead to secondary malignancies. More recently, numerous non-canonical BRAF oncogenic mutations including BRAF-fusions have been described as oncogenes that drive RAS-independent (class II) or RAS-dependent (class III) dimers. These non-canonical dimeric BRAF oncogenes are resistant to the first-generation drugs, effective only against the monomeric BRAF V600E mutation. Discovery of an inhibitor directed against the family of dimeric BRAF oncogenic mutations which avoids paradoxical activation is a major unmet need.
Methods
We applied our proprietary Mutation-Allostery-Pharmacology (MAP) platform technology developed by Black Diamond Therapeutics to identify and validate a group of previously uncharacterized non-canonical oncogenic class II and class III BRAF mutation clusters. We further demonstrate that this ensemble of both novel and previously validated non-canonical oncogenic BRAF mutants can form the basis of a differentiated drug discovery program aimed at identifying small molecules that potently and selectively target this family of dimeric BRAF mutations.
Results
Herein, we describe a series of small molecule inhibitors with potent anti-proliferative activity directed against tumor cells harboring dimer-inducing BRAF oncogenic mutations and which are devoid of paradoxical RAF activation. Leading exemplars of BDTX compounds are orally available inhibitors that achieve target engagement of BRAF dimer oncogenes in vivo and robust anti-tumor efficacy in xenograft models in mice.
Conclusions
These data support continued development of rationally designed molecules targeting a broad range of non-canonical BRAF dimer-promoting mutations to extend the prospect of precision medicine in patients with BRAF mutant tumors.
Legal entity responsible for the study
Black Diamond Therapeutics.
Funding
Black Diamond Therapeutics.
Disclosure
Y-C. Han, P.Y. Ng, R. Schulz, S.N. Yang, A. Lelo, L.S. Ogawa, M. O'Connor, N. Ishiyama, I. Jewett, D. Romashko, A. Salomatov, S. Thakur, S. Smith, E. Buck, C. Roberts, M. Lucas, T-A. Lin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Black Diamond Therapeutics.
26P - Targeted photoimmunotherapy of tumour-specific nanomedicine for targeted triple-negative breast cancer therapy (ID 178)
- Yasothamani Vellingiri (Coimbatore, India)
- Yasothamani Vellingiri (Coimbatore, India)
Abstract
Background
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. At present, TNBC patients do not have an approved targeted therapy. Therefore, patients primarily depend on systemic chemotherapy that has inevitable detrimental side effects and show inadequate therapeutic outcomes leading to a high mortality rate. Hence, there is an urgent need to develop targeted therapies for the TNBC population. Emphasizing new nanotherapeutics approaches to combinational therapy could be an effective alternative tactic.
Methods
We designed a self-assembly strategy to design a highly biocompatible organic polyaniline (PANi) smart polymer nanotherapeutic (NPs) doped hyaluronan (HA) converting the PANi emeralidine base (EB) to emeralidine salt (ES) for strong near infrared (NIR)-mediated photothermal cancer treatment (PTCT). Therefore, smartly designed NPs at 808 nm exhibited a high extinction coefficient 8.23 x 108 M-1 cm-1, and adequate photothermal conversion efficiency (PCE) (η=41.6 %) made it an efficient photothermal agent (PTA), highly beneficial for selective CD44-mediated photothermal ablation of TNBC tumors. Furthermore, we have co-encapsulated imiquimod (R837-Toll-like receptor 7 agonist) immunoadjuvant molecules (HA-PANi/R837 NPs) to trigger a strong immune response against post-PTCT tumor.
Results
Encouragingly, targeted HA-PANi/R837 NPs selectively destroyed the tumor under NIR-illumination then released tumor-associated antigens. PTCT also triggered R837 release for the unprecedented role NPs-based immune therapy producing immunological cell death (ICD) of residual tumor cells, efficiently protecting the mice from tumor relapse and metastasis.
Conclusions
The specific high-performance of tumor-targeting homotypic ablation in targeted TNBC models was achieved without noticeable adverse effects on normal cells. Therefore, our smart biocompatible potential nanoplatform could serve as a photothermal immunotherapy modality for future utilization of chemotherapeutics-free clinical treatment. Thus, photothermally activated ICD has the greatest potential of dual-modal cancer therapy, preventing future relapse by the activation of the immune system to recognize and kill the tumor cells.
Legal entity responsible for the study
The author.
Funding
Department of Biotechnology, Government of India.
Disclosure
The author has declared no conflicts of interest.
29P - Non-diploidy related prognostic molecular signature (NPMS) predict an “immunologically hot” phenotype in squamous cell lung cancer (ID 192)
- Zixin HU (Beijing, China)
- Zixin HU (Beijing, China)
- Huijuan Cui (Peking, China)
- Kexin Tan (Beijing, China)
- Jia Lee (Beijing, China)
Abstract
Background
Lung squamous cell carcinoma (LUSC) patients suffer from less targetable onco-drivers and potentially acquire clinical benefit from immune checkpoint inhibitors (ICIs). DNA content aberrations contribute to genomic instability and are initial events of tumorigenesis. We established a non-diploidy related prognostic molecular signature (NPMS) based on differentially expressed genes (DEGs) and investigated the immune features of it.
Methods
We conducted a retrospective analysis based on data downloaded from TCGA database. By integrating CNA and SNV via ABSOLUTE algorithm, we obtained the DNA ploidy status and divided patients into near-diploid and non-diploid group. DEGs were selected and gene functional enrichments were carried out. NPMS was established by all subset multivariate Cox regression to further stratify patients and validated by integrative analysis of GSE73403, GSE41271, GSE4212. Gene sets enrichment analysis was applied to further figure out the mechanism behind NPMS.
Results
Non-diploidy coincided with higher TMB and intratumor heterogeneity. Functional enrichment indicated that DEGs mainly participated in genomic instability. NPMS containing HOXB5, TINAGL1, POLR3GL, APOB, FABP6, SCARF1 was established. Patients with low score had better OS than those with high score (HR 0.60, 95%CI 0.45-0.79, p-value=0.000321). This was validated in the GEO cohorts (HR 0.57, 95%CI 0.37-0.88, p-value=0.0121). Dysregulation of DNA repair and cell cycle checkpoints were higher enriched in high score group. The immune phenotype of high score tended to be "immunologically hot", which was characterized as high density but low activity immune cells infiltrated, accompanied by expression of higher immunosuppressive factors, such as PD-1, CTLA4, IDO1. Meanwhile, the upregulation of IFN-γ signaling pathway, lipid alternation and the high correlation between them were observed.
Conclusions
High NPMS score corresponded with an "immunologically hot" feature thereby led to shorter OS. The crosstalk of upregulated IFN-γ signaling and aberrations of tumor metabolism mignt participate. It's rational to deduced that patients with high score might be the potential ICIs benefited subpopulation.
Legal entity responsible for the study
Z. Hu.
Funding
This work was supported by Horizontal Scientific Research Project of China-Japan Friendship Hospital (Grants No. 2018-HX-26).
Disclosure
All authors have declared no conflicts of interest.