Advances In Targeted Therapy Research Articles

METB-06. PEDIATRIC BRAIN TUMOURS: A SINGLE INSTITUTIONAL EXPERIENCE OF NEXT GENERATION SEQUENCING-BASED TARGETED PANEL EVALUATION

Abstract BACKGROUND Pediatric brain tumours (pBT) are molecularly diverse and with the advent of targeted-therapies it is important to decipher molecularly. METHODS Single institutional non-consecutive pBT (<18 years) cohort include – a. high-grade glial tumour (HGG; H3-wildtype, IDH1/2-wildtype, immunohistochemically MMR-protein-proficient, negative for NTRK/ALK-rearrangements by FISH in <3 years), b. high-grade CNS neuroepithelial tumour, NOS (cNET), c & d. pilocytic astrocytoma (LGG-PCA), and low-grade glial/glioneuronal tumour LGG-LGGNT), histologically not typical of PCA nor any defined entity that were negative for BRAFV600mutations, KIAA1549- BRAF (16-9, 15-9, & 16-10) fusions, e. low-grade glial tumour with diffuse architecture (LGG-DLGG) that were negative for IDH1R132/IDH2R172-mutations. These were evaluated for NGS-based-panel (42 genes, 137 RNA fusions, and 24 genes for amplification – STS-plus-panel Sophia Genetics). RESULTS 41 cases (HGG: 12, cNET:2, LGG-PCA: 10 & 1, LGG-LGGNT: 13 & LGG-DLGG: 3) formed the study-cohort. a. HGG: 5 were <3 years (supratentorial [ST]: 3; posterior-3rd-ventricular [p3v]: 1 & posterior-fossa [PF]: 1), 2 showed mutations in TP53-exons 5 & 6 respectively, one ST case showed SND1-AKT2 (9:7) fusion. Of 6-18 years (all ST location), 3 showed TP53-mutations, one showed PDGFA & KIT-amplification with SF3B1-mutation and one showed BRAFV600E-mutation. b. cNET: BRAFV600E and TP53-mutation was observed in each of the case respectively. c. LGG-PCA: one case showed FAM131B-BRAF (2:9) fusion. One KIAA1549- BRAF (15-9) fusion case was evaluated as it progressed, showed additional TP53-mutation. d. LGG-LGGNT: one (4/F; PF location) showed EGFR-gains with TERT-promoter (C228T) mutation (like adult-type glioma), one showed NF1-exon 12 mutation with KIAA1549-RAD51 (18:4) fusion, one showed CDKN2A-exon 2 mutation and one (midbrain) case showed BRAFV600E-mutation. e. LGG-DLGG: one (11/M, occipital-SOL) showed KEAP1-exon 5 mutation with KIAA1549- BRAF (15:9) fusion. CONCLUSIONS TP53-mutations is common in HGG, infantile HGG can show non-ALK/NTRK fusions. LGG can show non-BRAF/KIAA1549-fusions, rarely can show KEAP1 mutations and adult-type-like alterations. Target-panel NGS-based assay can help to molecularly decipher to a certain extent, especially for instituting targeted-therapies.

Advances in Targeted Therapies (ATT) What's cooking in the academic's kitchen? 3TR (IMI)

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Inhibition of murine colorectal cancer metastasis by targeting M2-TAM through STAT3/NF-kB/AKT signaling using macrophage 1-derived extracellular vesicles loaded with oxaliplatin, retinoic acid, and Libidibia ferrea

Colorectal cancer is still unmanageable despite advances in target therapy. However, extracellular vesicles (EVs) have shown potential in nanomedicine as drug delivery systems, especially for modulating the immune cells in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), alone or in combination (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines and prevent metastasis in mice of allograft and peritoneal colorectal cancer models. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or particularly M1EV4 downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastasis in the peritoneum, liver, and lungs. STAT3, NF-kB, and AKT were the major genes downregulated by of M1EV systems. Tumor-associated macrophages (TAMs) shifted from an M2 phenotype (CD163) to an M1 phenotype (CD68) reducing levels of IL-10, TGF-β and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR1, survivin, vimentin, and PD-L1 after treatment with systems of M1EVs. The study shows that EVs from M1 antitumor macrophages can transport drugs and enhance their immunomodulatory and antitumor activity by modulating pathways associated with cell proliferation, migration, survival, and drug resistance.

Role of Microribonucleic acid in the Carcinogenesis of Non-Small-Cell Lung Cancer

INTRODUCTION: Lung cancer is the most common malignant neoplasm. Despite advances in target therapy, immunotherapy, and chemotherapy, non-small cell lung cancer remains the major cause of cancer-related death worldwide. Tumor development is a complex process that depends on the influence of environmental factors and genetic predisposition. Although oncogenic factors have received much attention, the main mechanisms for oncogenesis are still poorly understood. Thus, studying the oncogenic mechanisms, including those with the involvement of microribonucleic acid (microRNA), is important for the diagnostics and treatment of malignant neoplasms. MicroRNA (miRNA) belong to the class of small non-coding ribonucleic acids that are involved in various cellular biological processes, including epithelialmesenchymal transition, apoptosis, proliferation, invasion, and metastatic dissemination of cancer cells. Recent publications show that the course of the oncological disease can be predicted by evaluating the expressions of some miRNAs. Therefore, miRNAs serve as promising diagnostic and therapeutic targets in oncological diseases.
 CONCLUSION: This review summarizes data on the role in carcinogenesis and prognostic significance of several miRNA (i.e., miRNA-128, -4500, -222, -224, -124, -125b, -127, -129-2, -137, and -375) in non-small cell lung cancer.

FLUORO-CT GUIDED BIOPSY OF LUNG NODULES: A STEP BY STEP REVISION.

Transthoracic biopsies under fluoro-computer tomography (CT) guidance play an important role on the diagnosis and management of lung nodules, permitting histological examination and differentiation between benign and malignant lesions(1). Furthermore, with recent advances in target therapy, it is increasingly necessary to obtain tumor tissue for the analysis of molecular fingerprints allowing personalized treatment(1). Although many studies report low complication rates for this procedure, they are not negligible, urging the need for a structured and reproducible guide to reduce technique-related complications(1,2).

Neurokinin-1 receptor promotes non-small cell lung cancer progression through transactivation of EGFR

Despite the great advances in target therapy, lung cancer remains the top cause of cancer-related death worldwide. G protein-coupled receptor neurokinin-1 (NK1R) is shown to play multiple roles in various cancers; however, the pathological roles and clinical implication in lung cancer are unclarified. Here we identified NK1R as a significantly upregulated GPCR in the transcriptome and tissue array of human lung cancer samples, associated with advanced clinical stages and poor prognosis. Notably, NK1R is co-expressed with epidermal growth factor receptor (EGFR) in NSCLC patients’ tissues and co-localized in the tumor cells. NK1R can crosstalk with EGFR by interacting with EGFR, transactivating EGFR phosphorylation and regulating the intracellular signaling of ERK1/2 and Akt. Activation of NK1R promotes the proliferation, colony formation, EMT, MMP2/14 expression, and migration of lung cancer cells. The inhibition of NK1R by selective antagonist aprepitant repressed cell proliferation and migration in vitro. Knockdown of NK1R significantly slowed down the tumor growth in nude mice. The sensitivity of lung cancer cells to gefitinib/osimertinib is highly increased in the presence of the selective NK1R antagonist aprepitant. Our data suggest that NK1R plays an important role in lung cancer development through EGFR signaling and the crosstalk between NK1R and EGFR may provide a potential therapeutic target for lung cancer treatment.

Current status and future perspectives of liquid biopsy in non-small cell lung cancer.

With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.

New advances in targeted therapy and immunotherapy of acute myelogenous leukemia

Acute myelogenous leukemia (AML) is a highly heterogeneous malignant hematologic disease, and it is mainly treated with traditional chemotherapy, but the efficacy is limited and the patients with worse performance status and comorbidities can not be treated with chemotherapy. Gene changes play an important role in the diagnosis and prognosis of AML, and these gene changes also provide targets for molecular targeted therapy. Meanwhlie, immunotherapy has achieved certain curative effects in AML and has a promising prospect. In this review, targeted therapy and immunotherapy of AML reported in 61st American Society of Hematology (ASH) Annual Meeting are summarized. Key words: Leukemia, myelogenous, acute; Immunotherapy; Gene change; Molecular targeted therapy

Clinical Experience With 75-mg Dose of Erlotinib for Mutated Metastatic EGFR Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide, although important advances in target therapy have been developed in the past few years. Erlotinib is a reversible epidermal growth factor receptor (EGFR) inhibitor, which was approved at its maximum tolerated dose of 150 mg/d determined from the initial phase I study. Studies suggest that the optimal biological dose of erlotinib should be lower and dependent on different variables. We aimed to evaluate the response rates and toxicity with 75 mg/d dose of erlotinib in South American patients. We performed a retrospective review of 18 patients with histologically proven (+) EGFR (+) mutation metastatic NSCLC (mNSCLC) treated with 75 mg/d erlotinib as starting dose. Clinical information, including toxicity grade 1-4, drug discontinuation, clinical evolution and radiological evaluation, and overall survival (OS), was revised. Patients received 75 mg/d of erlotinib as starting dose. Sixteen (89%) patients were treated in first-line treatment and 2 (11%) in second-line treatment. Mean age was 62 years (range 36-89 years), and 50% patients were female. Sixteen percent of the patients had brain metastases at first diagnosis. All patients had mutation positive EGFR, 12 (66%) had Del19 and 6 (34%) exon 21 mutation. Median progression-free survival was 17 months and OS 23 months. The main grade 1-2 toxicities were rash (44%) and diarrhea (22%). No grade 3-4 toxicity and no cases of drug discontinuation were reported. In South American population with mutated mNSCLC, a dose of 75 mg/d of erlotinib was well tolerated. This dose resulted in comparable benefits in progression-free survival and OS when compared to those reported in the literature with the standard dose. More studies are needed to explore the use of adjusted doses of biological agents in different ethnic backgrounds.

Impacts of EGFR-mutation status and EGFR-TKI on the efficacy of stereotactic radiosurgery for brain metastases from non-small cell lung adenocarcinoma: A retrospective analysis of 133 consecutive patients

ObjectivesRecent advances in target therapies have prolonged overall survival (OS) for patients with epidermal growth factor receptor (EGFR)-mutant lung cancer. The impact of EGFR mutations on stereotactic radiosurgery (SRS) for brain metastases (BM) has yet to be determined. The present study sought to evaluate the efficacy and limitations of SRS, administered with EGFR-tyrosine kinase inhibitors (TKI), for BM from EGFR-mutant lung adenocarcinoma. Materials and methodsThis retrospective observational study analyzed data from patients with BM arising from EGFR-mutant lung adenocarcinoma who received upfront Gamma Knife SRS between December 2010 and April 2016. OS and distant and local intracranial disease control rates were calculated. The prognostic factors for each event were also determined. ResultsOne hundred thirty-three consecutive patients (47 males/86 females) were eligible. The median age was 69 years, and the median Karnofsky performance status (KPS) was 90. Sixty-six patients (50%) had no history of EGFR-TKI use at the time of SRS. EGFR-TKI were administered to 85% of EGFR-TKI naïve patients after SRS. One- and 2-year OS rates were 74% and 52%, respectively. One- and 2-year distant BM recurrence rates (per patient) after SRS were 34% and 53%, respectively. One- and 2-year rates of local tumor control (per lesion) were 97% and 95%, respectively. Multivariate proportional hazards analyses showed that being EGFR-TKI naïve was associated with longer OS (HR: 0.42, P < 0.001), a lower distant intracranial recurrence rate (HR: 0.61, P = 0.037) and a higher local tumor control rate (HR: 0.28, P = 0.001). ConclusionsThe present study demonstrated the upfront SRS strategy to offer a minimally invasive and effective treatment option for EGFR-mutant lung adenocarcinoma patients with limited BM. EGFR-TKI naïve patients were found to be a distinct subgroup for which a longer survival time and durable intracranial disease control can be expected.

Advances in targeted therapy for childhood acute myeloid leukemia

At present, acute myeloid leukemia (AML) accounts for about 15%-20% of childhood acute leukemia. Although overall survival rate is increasing with the help of risk stratification, stratification of chemotherapy, and supportive treatment, conventional pharmacotherapy still has a limited clinical effect and certain limitations in improving remission rate in previously untreated patients and reducing recurrence after remission. With the development of precision medicine, the mechanisms of targeted therapy, including abnormal activation of AML-related signaling pathways and epigenetic modification, have been found in recent years. Molecular-targeted drugs can therefore act on specific receptors and target genes to improve clinical effect and the prognosis of AML patients.

Advances in target therapy in lung cancer.

Herein, we have reviewed and analysed recent literature, published in 2013 and early 2014, in the context of pre-existing data. Considered target therapies were tyrosine kinase inhibitors of active epidermal growth factor receptor mutations (e.g. erlotinib, gefinitib and afatinib), anaplastic lymphoma kinase rearrangements (e.g. crizotinib) or angiogenesis (drugs under development), or monoclonal antibodies against vascular endothelial growth factor (e.g. bevacizumab) or epidermal growth factor receptors (e.g. cetuximab). The therapeutic project has to consider tyrosine kinase inhibitors in the case of nonsmall cell lung cancer with active epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangement. However, these drugs should not be used in the absence of the targeted genetic abnormalities.

Gastroenteropancreatic neuroendocrine tumors. Where are we now?

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are tumors derived from neuroendocrine cells thatcan occur anywhere along the gastrointestinal tract. Due totheir particular features, GEP-NETs are among the mostcomplex tumors to diagnose and treat. For instance,symptoms vary according to the type of GEP-NET, andtherefore they are easily mistaken for other conditions.Although the general idea is that GEP-NETs are raretumors, the most recent data from the US SurveillanceEpidemiology and End Results show an impressiveincrease of more than 400% in the incidence of this diseaseover a period of 29 years, rising from 1.09 per 100,000population in 1973 to 5.25 per 100,000 population in 2004[1]. Only in the last year, their incidence increase from 3.00to 5.25 per 100,000. In fact, GEP-NETs are more prevalentthan many other tumors of the gastrointestinal tract,including stomach and pancreatic carcinomas combined.Survival of patients with GEP-NETs depends greatly onstage and histology. For example, patients with well andmoderately well-differentiated distant metastases have a 5-yearsurvivalprobabilityof35%;conversely,inpatientswithpoorlydifferentiateddistantmetastases,the5-yearsurvivalprobabilitydrops to only 4% [ 1]. The mere observation of these figurescalls our attention to the importance of an early diagnosis, andtumor classification and staging of patients in whom a GEP-NET is suspected, as well as to the need for ongoingmodifications in the therapeutic approach.Interestingly, in parallel to changes in the epidemiologyof GEP-NET, there have been substantial advances intreatment, such as the use of peptide receptor radiotherapy,and more recently, antiangiogenic agents (bevacizumab,everolimus, sunitinib), which have echoed on the prognosisof many patients with this disease. As shown by the resultsof the RADIANT trials, with the advent of targetedtherapies, we may be on the verge of a paradigm shift inthe treatment of advanced GEP-NETs.The Spanish Group of Neuroendocrine Tumors(GETNE), aware of the interest this disease has raised dueto its increasing incidence and significant advances intreatment, considered it would be of relevance to publishthe contents from the“V GETNE Symposium on GEP-NETs” held in September 2009 in the city of Madrid(Spain). In this Special Issue, the updated contents of thissymposium are reported. The purpose is to provide ageneral overview of the current state of knowledge of GEP-NETs regarding diagnosis and innovations in therapy.Reference

Advances in Target Therapy for Lung Cancer

Recent progress in molecular biology has shown that cancer cells acquire common phenotypes such as self-sufficiency of growth signals, resistance to anti-proliferative and apoptotic signals through the accumulation of genetic and epigenetic changes. Recently developed anticancer drugs target these molecular mechanisms and good results have been reported for various cancer types. In lung cancer, tyrosine kinase inhibitors specific for the epidermal growth factor receptor such as gefitinib and erlotinib have changed clinical practice dramatically. About half of the Japanese patients with lung cancers harbor an activating mutation of the epidermal growth factor receptor gene and they are very sensitive to epidermal growth factor receptor tyrosine kinase inhibitors. Progression-free survival of such patients is approximately 10 months when treated with gefitinib, whereas the survival for those treated with platinum doublet therapy is approximately 6 months. Target therapies against echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion protein or a mutated ERBB2 (v-ERB-B avian erythroblastic leukemia viral oncogene homologue 2) present in approximately 5% and approximately 3% of the Japanese patients with adenocarcinomas, respectively, are currently under development. Addition of an anti-epidermal growth factor receptor antibody, cetuximab, or anti-vascular endothelial growth factor antibody, bevacizumab, to platinum doublet therapy significantly but modestly prolonged the survival in recent clinical trials. However, clinical development of small molecule multi-kinase inhibitors including those targeting vascular endothelial growth factor receptors, such as vandetanib, sunitinib and sorafenib, has not been very successful. Through these collaborations among clinicians, basic researchers and pharmaceutical companies, it should be possible to individualize lung cancer treatment to turn this fatal disease into a chronic disorder and, eventually, to cure it.