scholarly journals Developmental Insights into Lung Cancer

2021 ◽  
Vol 5 (1) ◽  
pp. 351-369
Author(s):  
Tushar J. Desai
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Immune Checkpoint Blockade ◽  
Genomic Profiling ◽  
Limited Efficacy ◽  
Cancer Initiation ◽  
The Face ◽  
Mouse Genetic

Lung cancer continues to be the number one cancer killer. Despite a surge of therapeutic advances in recent years, lung cancer remains fatal when it presents at a stage too advanced for surgical resection. In part, this is due to the disappointing reality of inevitable drug resistance in the face of highly effective, mutation-specific chemotherapy and the limited efficacy of immune checkpoint blockade. Yet, with the increasing application and integration of diverse genomic profiling approaches and the advent of high-content single-cell technologies, the mechanisms of lung cancer initiation, evolution, spread, and resistance are being unraveled at unprecedented resolution. Increasingly sophisticated mouse genetic, xenotransplantation, and ex vivo assays are also enabling functional validation and empiric screening of new therapeutic candidates. In this review, I highlight recent insights into the genetic, cellular, and molecular mechanisms of lung cancer and relate them to the normal biology of the developing and mature lung.

scholarly journals Actinomycin D and Telmisartan Combination Targets Lung Cancer Stem Cells Through the Wnt/Beta Catenin Pathway

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryan Green ◽  
Mark Howell ◽  
Roukiah Khalil ◽  
Rajesh Nair ◽  
Jiyu Yan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Actinomycin D ◽  
Inner Core ◽  
Ex Vivo ◽  
Beta Catenin ◽  
Novel Treatments

AbstractThe failure of lung cancer treatments has been attributed mostly to the development of drug resistance, however the underlying cellular and molecular mechanisms are poorly understood. Cancer initiating stem cells (CSCs), present in tumors in a small percentage, play critical roles in the development of drug resistance, metastasis, and cancer relapse. Hence, novel treatments targeting both bulk cancer cells and CSCs are under intense investigation. Herein, we report that lung cancer cells grown on a 3D fibrous scaffold form tumoroids that resemble in vivo tumors, expand CSCs, and provide a platform to identify anti-CSC drugs. The screening of an NCI library of FDA-approved drugs using tumoroid cultures led to identification of Actinomycin D (AD) as a top CSC inhibitor. Since CSCs are mostly resident in the tumor’s inner core, AD was combined with an angiotensin receptor antagonist, Telmisartan (TS), which is known to increase drug permeability in tumors and was shown to have anti-CSC activity. Our results showed that AD + TS administered intra-tumorally was significantly more effective than either drug alone in both syngeneic and xenograft mouse models. The results of mechanistic studies revealed that CSC expansion in tumoroids was associated with activation of β catenin signaling and that AD + TS treatment reduced active β catenin levels in tumors. Together, these results establish the utility of the tumoroid culture system to expand CSCs ex vivo for targeted drug screening, to identify promising novel treatments with both anti-CSC and anti-cancer effects, and to individualize treatments for metastatic drug resistant lung cancer patients.

scholarly journals Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1247 ◽  
Author(s):  
David G.J. Cucchi ◽  
Costa Bachas ◽  
Marry M. van den Heuvel-Eibrink ◽  
Susan T.C.J.M. Arentsen-Peters ◽  
Zinia J. Kwidama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Drug Response ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Leukemic Cells ◽  
Treatment Optimization ◽  
Pediatric Aml

Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. To assess which genes and pathways are implicated in tumor drug resistance, we correlated ex vivo drug response data to genome-wide gene expression profiles of 73 primary pediatric AML samples obtained at initial diagnosis. Ex vivo response of primary AML blasts towards cytarabine (Ara C), daunorubicin (DNR), etoposide (VP16), and cladribine (2-CdA) was associated with the expression of 101, 345, 206, and 599 genes, respectively (p < 0.001, FDR 0.004–0.416). Microarray based expression of multiple genes was technically validated using qRT-PCR for a selection of genes. Moreover, expression levels of BRE, HIF1A, and CLEC7A were confirmed to be significantly (p < 0.05) associated with ex vivo drug response in an independent set of 48 primary pediatric AML patients. We present unique data that addresses transcriptomic analyses of the mechanisms underlying ex vivo drug response of primary tumor samples. Our data suggest that distinct gene expression profiles are associated with ex vivo drug response, and may confer a priori drug resistance in leukemic cells. The described associations represent a fundament for the development of interventions to overcome drug resistance in AML, and maximize the benefits of current chemotherapy for sensitive patients.

Abstract 873: Molecular mechanisms of non-small cell lung cancer growth and drug resistance

2019 ◽  
Author(s):  
SK Kayum Alam ◽  
Matteo Astone ◽  
Ping Liu ◽  
Li Wang ◽  
Abbygail M. Coyle ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Small Cell ◽  
Cancer Growth ◽  
Small Cell Lung

Abstract 873: Molecular mechanisms of non-small cell lung cancer growth and drug resistance

2019 ◽  
Author(s):  
SK Kayum Alam ◽  
Matteo Astone ◽  
Ping Liu ◽  
Li Wang ◽  
Abbygail M. Coyle ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Small Cell ◽  
Cancer Growth ◽  
Small Cell Lung

scholarly journals Nanomedicine Strategies for Management of Drug Resistance in Lung Cancer

2022 ◽  
Author(s):  
Mohamed Haider ◽  
Amr El Sherbeny ◽  
Valeria Pittalà ◽  
Antonino N. Fallica ◽  
Maha Ali Alghamdi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Therapeutic Agents ◽  
Future Directions ◽  
Significant Challenge ◽  
Cancer Occurrence ◽  
Complex Process ◽  
Anticancer Treatment ◽  
Therapeutic Alternatives

Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer; presents novel nanomedicine therapeutics aimed to improve the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for clinical application of nanomedicine in management of LC resistance.

scholarly journals Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis.

2020 ◽  
Author(s):  
Neal Shah ◽  
Zhongwei Liu ◽  
Rachel M. Tallman ◽  
Afroz Mohammad ◽  
Samuel A Sprowls ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Lung Cancer Cells ◽  
Cardiac Ventricle

Abstract Background Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. Methods Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis. Results A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a significantly decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50>2.5 µM at 48hrs and 0.1 µM at 72hrs) compared with parental PC-9 (IC50: 0.75 µM at 48hrs and 0.027 µM at 72hrs). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither T790 mutation nor amplifications of MET and HER2 compared with parental PC-9. Conclusion Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

scholarly journals Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis.

2020 ◽  
Author(s):  
Neal Shah ◽  
Zhongwei Liu ◽  
Rachel M. Tallman ◽  
Afroz Mohammad ◽  
Samuel A Sprowls ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Lung Cancer Cells ◽  
Cardiac Ventricle

Abstract Background Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. Methods Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis. Results A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a significantly decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50>2.5 µM at 48hrs and 0.1 µM at 72hrs) compared with parental PC-9 (IC50: 0.75 µM at 48hrs and 0.027 µM at 72hrs). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither T790 mutation nor amplifications of MET and HER2 compared with parental PC-9. Conclusion Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

scholarly journals Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Kasey R. Cargill ◽  
William L. Hasken ◽  
Carl M. Gay ◽  
Lauren A. Byers
Keyword(s):  
Lung Cancer ◽  
Alternative Energy ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Lung Cancers ◽  
Limited Efficacy ◽  
Cancer Models ◽  
Cancer Initiation ◽  
Metabolic Heterogeneity ◽  
The Warburg Effect

Metabolic reprogramming is a hallmark of cancer initiation, progression, and relapse. From the initial observation that cancer cells preferentially ferment glucose to lactate, termed the Warburg effect, to emerging evidence indicating that metabolic heterogeneity and mitochondrial metabolism are also important for tumor growth, the complex mechanisms driving cancer metabolism remain vastly unknown. These unique shifts in metabolism must be further investigated in order to identify unique therapeutic targets for individuals afflicted by this aggressive disease. Although novel therapies have been developed to target metabolic vulnerabilities in a variety of cancer models, only limited efficacy has been achieved. In particular, lung cancer metabolism has remained relatively understudied and underutilized for the advancement of therapeutic strategies, however recent evidence suggests that lung cancers have unique metabolic preferences of their own. This review aims to provide an overview of essential metabolic mechanisms and potential therapeutic agents in order to increase evidence of targeted metabolic inhibition for the treatment of lung cancer, where novel therapeutics are desperately needed.

scholarly journals Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis.

2019 ◽  
Author(s):  
Neal Shah ◽  
Zhongwei Liu ◽  
Rachel M. Tallman ◽  
Afroz Mohammad ◽  
Samuel A Sprowls ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Lung Cancer Cells ◽  
Cardiac Ventricle

Abstract Background Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. Methods Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis. Results A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a significantly decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50>2.5 µM at 48hrs and 0.1 µM at 72hrs) compared with parental PC-9 (IC50: 0.75 µM at 48hrs and 0.027 µM at 72hrs). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither T790 mutation nor amplifications of MET and HER2 compared with parental PC-9. Conclusion Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

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