Browsing Over 131 Presentations
Invited discussant of abstracts 19O and 33O (ID 344)
- Anthony W. Tolcher (San Antonio, TX, United States of America)
- Anthony W. Tolcher (San Antonio, TX, United States of America)
Tumour-targeted immune-stimulating antibody conjugates (ISACs): A new class of immuno-oncology therapeutics (ID 38)
- Shelley Ackerman (Redwood City, CA, United States of America)
- Shelley Ackerman (Redwood City, CA, United States of America)
18P - Mutational landscape of metastatic lung squamous cell carcinoma associated with basal cell hyperplasia (ID 197)
- Tatiana S. Gerashchenko (Tomsk, Russian Federation)
- Tatiana S. Gerashchenko (Tomsk, Russian Federation)
- Anastasia A. Schegoleva (Tomsk, Russian Federation)
- Anna A. Khozyainova (Tomsk, Russian Federation)
- Evgeny O. Rodionov (Tomsk, Russian Federation)
- Olga V. Pankova (Tomsk, Russian Federation)
- Vladimir M. Perelmuter (Tomsk, Russian Federation)
- Evgeny V. Denisov (Tomsk, Russian Federation)
Abstract
Background
Prevention and early detection of distant metastasis are critical for improving the outcome of patients with lung cancer. Previously, we showed that the presence of isolated basal cell hyperplasia (BCH) in the small bronchi distant from the tumor is associated with a high risk of distant metastasis in patients with lung squamous cell carcinoma (LUSC) and adenocarcinoma. However, mechanisms underlying this phenomenon are unknown. Here we aimed to assess the mutational landscape of metastatic LUSC associated with isolated BCH.
Methods
The study included 10 (48 to 77 years old) patients with LUSC (T1-4N0-2M0) divided into three groups: 1) patients with isolated BCH and metastases; 2) patients with isolated BCH but without metastases; and 3) patients without premalignant bronchial lesions and metastases. Premalignant lesions were analyzed in hematoxylin and eosin-stained sections of formalin-fixed paraffin-embedded samples of small bronchi distant (3-5 cm) from the tumor. Tumor samples were sequenced on a NextSeq 500 (Illumina) using SureSelect XT Human All Exon v7 kit (Agilent).
Results
LUSC patients with BCH and metastases showed 1.6-times more mutations than cases without premalignant bronchial lesions and metastases. Interestingly, among patients with BCH, mutations were 1.8-times more in metastatic tumors than in non-metastatic tumors confirming that the presence of hyperplasia is not absolute for distant metastasis. Metastatic LUSC more often also harbored mutations in genes involved in cell-cell adhesion (CDH8, CDH9, ITGAL, SDK1, SDK2, et al.) and signal pathways of carcinogenesis (TP53, RB1, MMP1, MMP2, EGFR, et al.). Importantly, the most frequently mutated genes in metastatic tumors were TP53 (100% of cases) and PTPRT (75% of cases).
Conclusions
Taken together, our findings indicate that metastatic LUSC associated with isolated BCH shows a highly mutable phenotype.
Legal entity responsible for the study
Cancer Research Institute, Tomsk National Research Medical Center.
Funding
Russian Science Foundation, #20-75-10060.
Disclosure
All authors have declared no conflicts of interest.
27P - MiR-939-5p exhibits tumour suppressor activity and immune surveillance manipulation in triple-negative breast cancer (ID 277)
- Heba M. Nafea (Cairo, Egypt)
- Heba M. Nafea (Cairo, Egypt)
- Rana A. Youness (Cairo, Egypt)
- Khaled Abou-Aisha (Cairo, Egypt)
- MOHAMED ZAKARIA Gad (Cairo, Egypt)
Abstract
Background
MiRNAs have been thoroughly studied for their vast roles in oncology, however, recent immune-related miRNAs have been recognized as prospective modulators in the tumor immune surveillance process. The high immunogenicity of TNBC along with its stubbornness towards effective targeted therapy shifted therapeutic interests towards immunotherapy. Accordingly, a promising approach would be targeting the immune suppressive tumor microenvironment (TME). Such an approach could be manifested in a dual manner through blocking prominent checkpoint proteins and regulating Natural Killer (NK) cells and thus modifying the TME. MiR-939-5p is a scarcely explored miRNA especially in TNBC. Therefore, our aim is to identify the expression profile of miR-939-5p in BC tissues and the role it plays in tumor suppression as well as the immunomodulatory role on checkpoint proteins and NKG2D ligands in TNBC.
Methods
Breast biopsies were collected from 40 BC patients. MDA-MB-231 cells were cultured and transfected with different oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular viability, colony forming ability and migration were measured using MTT, colony forming and scratch assays, respectively.
Results
MiR-939-5p was down-regulated in TNBC tissues compared to normal tissues and other BC subtypes. Functionally, forced expression of miR-939-5p ensued a decline in cellular viability, colony forming ability and migration capacity of MDA-MB-231 cells thus highlighting miR-939-5p as a tumor suppressive miRNA in TNBC. Immunomodulation wise, miR-939-5p overexpression resulted in down-regulation of the checkpoint protein PD-L1 as well as upregulation of the shedded NKG2D ligands MICA/B in TNBC cells. Lastly, drastic repression of the immune inhibitory cytokines, TNF-α and IL-10 was detected upon miR-939-5p upregulation.
Conclusions
The present study categorized miR-939-5p as a tumor suppressing miRNA under expressed in TNBC patients and cell lines. Furthermore, it institutes the first major stride in unraveling the immunomodulatory role of miR-939-5p in advancing NK cells cytotoxicity and trimming TME in favor of TNBC eradication, thus proposing miR-939-5p as a novel therapeutic module in TNBC.
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.
Invited discussant of abstracts 34MO, 35MO and 36MO (ID 338)
- Matthew G. Krebs (Manchester, United Kingdom)
- Matthew G. Krebs (Manchester, United Kingdom)
Bugs as drugs: Using the microbiome to augment immunotherapy responses (ID 30)
- Lillian Siu (Toronto, ON, Canada)
- Lillian Siu (Toronto, ON, Canada)
Innovative strategies CAR-T in solid tumors (ID 159)
- Mark Cobbold (Charlestown, IN, United States of America)
- Mark Cobbold (Charlestown, IN, United States of America)
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.
Live Q&A (ID 325)
- Emiliano Calvo (Madrid, Spain)
- Lesley Seymour (Kingston, ON, Canada)
- E.G. Elisabeth De Vries (Groningen, AL, Netherlands)
- Pawel Sobczuk (Warsaw, Poland)
- Emiliano Calvo (Madrid, Spain)
- Lesley Seymour (Kingston, ON, Canada)
- E.G. Elisabeth De Vries (Groningen, AL, Netherlands)
- Pawel Sobczuk (Warsaw, Poland)
Gastrointestinal cancer organoids for forward and reverse translation (ID 20)
- Nicola Valeri (Sutton, United Kingdom)
- Nicola Valeri (Sutton, United Kingdom)
Age, gender and other cofounders in early phase studies (ID 66)
- Elena Garralda (Barcelona, Spain)
- Elena Garralda (Barcelona, Spain)
37MO - Concurrent mutations in STK11 and KEAP1 promote ferroptosis protection and SCD1 dependence in lung cancer (ID 252)
- Triparna Sen (New York, United States of America)
- Triparna Sen (New York, United States of America)
Abstract
Background
STK11 and KEAP1 loss are strongly co-associated (p<0.001) in lung adenocarcinoma (LUAD). Our team has found that in a 468-gene panel, co-occurrence of these two mutations is the strongest driver of poor outcome in LUADs, conferring resistance to both standard chemotherapy and immunotherapy, resulting in an average overall survival of less than 8 months from diagnosis. Little is known about the cooperativity and an in-depth understanding of the biological and functional consequences of STK11 and KEAP1 co-mutation is an urgent clinical need that is essential to identify effective therapeutic targets.
Methods
We sequentially profiled 1,235 patients with metastatic LUAD by next generation sequencing (MSK-IMPACT). We used CRISPR/Cas9 to create stable knockouts of STK11, KEAP1, or both genes, in three LUAD lines. We performed cell proliferation, bulk RNAsequencing. Furthermore, we performed CRISPR/Cas9 screens in isogenic in vitro models using a curated “druggable genome” sgRNA library that targets 1,463 genes.
Results
STK11/KEAP1 co-mutation predicts short overall survival in patients with LUAD. STK11/KEAP1 co-mutation promotes tumor cell proliferation and migration in vitro and significantly enhanced tumor growth in vivo. Bulk RNA sequencing demonstrated that STK11/KEAP1 co-mutant cells have higher expression of genes involved in ferroptosis protection and are resistant to ferroptosis inducing agents. CRISPR/Cas9 screen identified ferroptosis regulator SCD as an essential gene required for proliferation and survival of STK11/KEAP1 co-mutant cells. Genetic and pharmacological inhibition of SCD1 prevented the growth of STK11/KEAP1 co-mutant cells and sensitized these cells to ferroptosis induction. Finally, in vivo inhibition of SCD1 significantly delayed tumor growth in STK11/KEAP1 co-mutant LUAD.
Conclusions
This study describes, for the first time, ferroptosis evasion as a survival mechanism for STK11/KEAP1 mutant tumors. We identify SCD as an essential gene in STK11/KEAP1 co-mutant LUAD. SCD1 inhibition, either alone or in conjunction with agents targeting ferroptosis, represents a promising strategy to improve outcomes in this cohort of patients with limited therapeutic options and poor prognosis.
Legal entity responsible for the study
The author.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.