scholarly journals The Molecular and Microenvironmental Landscape of Glioblastomas: Implications for the Novel Treatment Choices

2020 ◽  
Vol 14 ◽  
Author(s):  
Federica Di Cintio ◽  
Michele Dal Bo ◽  
Lorena Baboci ◽  
Elena De Mattia ◽  
Maurizio Polano ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Alkylating Agents ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Types ◽  
Molecular Signature ◽  
Central Nervous System Tumor ◽  
Cell Lung Carcinoma

Glioblastoma (GBM) is the most frequent and aggressive primary central nervous system tumor. Surgery followed by radiotherapy and chemotherapy with alkylating agents constitutes standard first-line treatment of GBM. Complete resection of the GBM tumors is generally not possible given its high invasive features. Although this combination therapy can prolong survival, the prognosis is still poor due to several factors including chemoresistance. In recent years, a comprehensive characterization of the GBM-associated molecular signature has been performed. This has allowed the possibility to introduce a more personalized therapeutic approach for GBM, in which novel targeted therapies, including those employing tyrosine kinase inhibitors (TKIs), could be employed. The GBM tumor microenvironment (TME) exerts a key role in GBM tumor progression, in particular by providing an immunosuppressive state with low numbers of tumor-infiltrating lymphocytes (TILs) and other immune effector cell types that contributes to tumor proliferation and growth. The use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers as well as promising results have been shown for the use of these antibodies in untreated brain metastases from melanoma and from non-small cell lung carcinoma (NSCLC). Consequently, the use of PD-1/PD-L1 inhibitors has also been proposed in several clinical trials for the treatment of GBM. In the present review, we will outline the main GBM molecular and TME aspects providing also the grounds for novel targeted therapies and immunotherapies using ICIs for GBM.

scholarly journals PD-1/PD-L1-negative tracheal mucoepidermoid carcinoma: A case report and systematic review of the literature

2021 ◽  
Author(s):  
Ying Ying Liu ◽  
Jian Guo ◽  
Ji Chen ◽  
Hai Xia Li ◽  
Zeng Tao Wang ◽  
...  
Keyword(s):  
Mucoepidermoid Carcinoma ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Cell Types ◽  
Intermediate Cell ◽  
Sleeve Lobectomy ◽  
Cell Lung Carcinoma ◽  
Segmental Bronchus ◽  
Intermediate Cells ◽  
Chinese Male

Abstract Background: Tracheal mucoepidermoid carcinoma is a rare form of non-small cell lung carcinoma and is defined as a tumor characterized by a combination of squamous, mucus-secreting, and intermediate cell types. This carcinoma is usually located in the lobar or segmental bronchus. Currently, surgery is the preferred treatment for this disease, which includes pneumonectomy, lobectomy, and sleeve lobectomy. Case presentation: A 50-year-old Chinese male presented with cough, shortness of breath and hemoptysis, and the effect of antibiotic therapy was not good. Subsequently, the airway occupied lesion was found by chest CT, and he was transferred to our hospital for surgical resection. Histologically, the tumor contained squamous epidermal cells, mucoepidermoid cells and intermediate cells. Immunohistochemistrically, the tumor cells were positive for p63, CK5/6, CK7 and Ki67. However, the tumor is generally negative for TTF-1 and neuroendocrine markers. The patient had no recurrence 15 months after the surgery.Conclusions: We report a rare case of mucoepidermoid carcinoma in the distal trachea in which the surgery was difficult and could not be performed like a traditional pulmonary resection. We first provide a comprehensive description of airway management and anesthesia intubation. After surgery, we reviewed the literature and found that PD-1/PD-L1 detection had never been reported in tracheal mucoepidermoid carcinoma. Therefore, we studied the PD-1/PD-L1 pathway in this patient, and the results were negative, which may indicate that potential adjuvant therapy with immune checkpoint inhibitors (ICIs) is not useful in this case.

scholarly journals PD-1/PD-L1-negative tracheal mucoepidermoid carcinoma: A case report and systematic review of the literature

2022 ◽  
pp. 260
Author(s):  
Keyword(s):  
Mucoepidermoid Carcinoma ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Cell Types ◽  
Intermediate Cell ◽  
Sleeve Lobectomy ◽  
Cell Lung Carcinoma ◽  
Segmental Bronchus ◽  
Intermediate Cells ◽  
Chinese Male

Background: Tracheal mucoepidermoid carcinoma is a rare form of non-small cell lung carcinoma and is defined as a tumor characterized by a combination of squamous, mucus-secreting, and intermediate cell types. This carcinoma is usually located in the lobar or segmental bronchus. Currently, surgery is the preferred treatment for this disease, which includes pneumonectomy, lobectomy, and sleeve lobectomy. Case presentation: A 50-year-old Chinese male presented with cough, shortness of breath and hemoptysis, and the effect of antibiotic therapy was not good. Subsequently, the airway occupied lesion was found by chest CT, and he was transferred to our hospital for surgical resection. Histologically, the tumor contained squamous epidermal cells, mucoepidermoid cells and intermediate cells. Immunohistochemistrically, the tumor cells were positive for p63, CK5/6, CK7 and Ki67. However, the tumor is generally negative for TTF-1 and neuroendocrine markers. The patient had no recurrence 15 months after the surgery. Conclusions: We report a rare case of mucoepidermoid carcinoma in the distal trachea in which the surgery was difficult and could not be performed like a traditional pulmonary resection. We first provide a comprehensive description of airway management and anesthesia intubation. After surgery, we reviewed the literature and found that PD-1/PD-L1 detection had never been reported in tracheal mucoepidermoid carcinoma. Therefore, we studied the PD-1/PD-L1 pathway in this patient, and the results were negative, which may indicate that potential adjuvant therapy with immune checkpoint inhibitors (ICIs) is not useful in this case.

scholarly journals Heart Failure With Targeted Cancer Therapies

2021 ◽  
Vol 128 (10) ◽  
pp. 1576-1593
Author(s):  
Virginia S. Hahn ◽  
Kathleen W. Zhang ◽  
Lova Sun ◽  
Vivek Narayan ◽  
Daniel J. Lenihan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Proteasome Inhibitors ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Term Treatment ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Therapies

Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.

scholarly journals Blood–Brain Barrier in Brain Tumors: Biology and Clinical Relevance

2021 ◽  
Vol 22 (23) ◽  
pp. 12654
Author(s):  
Francesca Mo ◽  
Alessia Pellerino ◽  
Riccardo Soffietti ◽  
Roberta Rudà
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Phase 1 ◽  
Brain Barrier ◽  
Convection Enhanced Delivery ◽  
Cell Lung Carcinoma ◽  
Blood Brain

The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1–2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing.

scholarly journals Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5632
Author(s):  
Mariam Elshiaty ◽  
Hannah Schindler ◽  
Petros Christopoulos
Keyword(s):  
Kinase Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Phase 1 ◽  
Survival Rates ◽  
Cell Receptor ◽  
Therapeutic Success ◽  
Cell Lung Carcinoma ◽  
Anticancer Efficacy ◽  
Cell Therapies ◽  
Recent Phase

Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.

scholarly journals Trichostatin A downregulates bromodomain and extra-terminal proteins to suppress osimertinib resistant non-small cell lung carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuting Meng ◽  
Xixi Qian ◽  
Li Zhao ◽  
Nan Li ◽  
Shengjie Wu ◽  
...  
Keyword(s):  
Trichostatin A ◽  
Small Cell Lung Carcinoma ◽  
Cell Types ◽  
Inhibitory Effects ◽  
Cell Lung Carcinoma ◽  
Growth Inhibitory ◽  
Terminal Proteins ◽  
P Cells

Abstract Background The third-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown significant therapeutic effects on patients with non-small cell lung carcinoma (NSCLC) who carry active EGFR mutations, as well as those who have developed acquired resistance to the first-generation of EGFR-TKIs due to the T790M mutation. However, most patients develop drug resistance after 8–10 months of treatment. Currently, the mechanism has not been well clarified, and new therapeutic strategies are urgently needed. Methods Osimertinib resistant cell lines were established by culturing sensitive cells in chronically increasing doses of osimertinib. The anticancer effect of reagents was examined both in vitro and in vivo using the sulforhodamine B assay and a xenograft mouse model. The molecular signals were detected by western blotting. The combination effect was analyzed using CompuSyn software. Results We found that bromodomain and extra-terminal proteins (BETs) were upregulated in osimertinib resistant (H1975-OR) cells compared with those in the paired parental cells (H1975-P), and that knockdown of BETs significantly inhibited the growth of H1975-OR cells. The BET inhibitor JQ1 also exhibited stronger growth-inhibitory effects on H1975-OR cells and a greater expression of BETs and the downstream effector c-Myc than were observed in H1975-P cells. The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) showed stronger growth suppression in H1975-OR cells than in H1975-P cells, but vorinostat, another HDAC inhibitor, showed equal inhibitory efficacy in both cell types. Consistently, downregulation of BET and c-Myc expression was greater with TSA than with vorinostat. TSA restrained the growth of H1975-OR and H1975-P xenograft tumors. The combination of TSA and JQ1 showed synergistic growth-inhibitory effects in parallel with decreased BET and c-Myc expression in both H1975-OR and H1975-P cells and in xenograft nude mouse models. BETs were not upregulated in osimertinib resistant HCC827 cells compared with parental cells, while TSA and vorinostat exhibited equal inhibitory effects on both cell types. Conclusion Upregulation of BETs contributed to the osimertinib resistance of H1975 cells. TSA downregulated BET expression and enhanced the growth inhibitory effect of JQ1 both in vitro and in vivo. Our findings provided new strategies for the treatment of osimertinib resistance.

scholarly journals iNOS Expression by Tumor-Infiltrating Lymphocytes, PD-L1 and Prognosis in Non-Small-Cell Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3276
Author(s):  
Alexandra Giatromanolaki ◽  
Avgi Tsolou ◽  
Eleftheria Daridou ◽  
Maria Kouroupi ◽  
Katerina Chlichlia ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Small Cell Lung Carcinoma ◽  
Expression Patterns ◽  
Tumor Infiltrating Lymphocytes ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tissue Samples ◽  
Cell Lung Carcinoma ◽  
Infiltrating Lymphocytes

Background: Inducible Nitric Oxygen Synthase (iNOS) promotes the generation of NO in tissues. Its role in tumor progression and immune response is unclear. Methods: The immunohistochemical expression patterns of iNOS were studied in a series of 98 tissue samples of non-small-cell lung carcinoma (NSCLC), in parallel with the expression of hypoxia and anaerobic metabolism markers, PD-L1 and tumor-infiltrating lymphocytes (TILs). Results: iNOS is expressed by cancer cells in 19/98 (19.4%), while extensive expression by cancer-associated fibroblasts occurs in 8/98 (8.2%) cases. None of these patterns relate to stage or prognosis. Extensive infiltration of the tumor stroma by iNOS-expressing TILs (iNOS+TILs) occurs in 47/98 (48%) cases. This is related to low Hypoxia-Inducible Factor 1α (HIF1α), high PD-L1 expression and a better overall survival (p = 0.002). Expression of PD-L1, however, mitigates the beneficial effect of the presence of iNOS+TIL. Conclusions: Extensive expression of iNOS by TILs occurs in approximately 50% of NSCLCs, and this is significantly related to an improved overall survival. This brings forward the role of iNOS in anti-neoplastic lymphocyte biology, supporting iNOS+TILs as a putative marker of immune response. The value of this biomarker as a predictive and treatment-guiding tool for tumor immunotherapy demands further investigation.

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