Sign in or Register
  |  

Lung Cancer Overview - Signaling Pathway. Diagnostics Marker. Targeted Therapy and Clinical Trials.

Lung Cancer Signaling Pathway

Fig.1 Lung cancer signaling pathway. Targeted agents (listed in orange boxes) include those in clinical use (colored in green) and those in preclinical or early phase development (colored in red) for the treatment of advanced stage lung cancer.

An Introduction to Lung Cancer

Lung cancer (LC) has become the leading cause of cancer death in many industrialized countries claiming more than 160000 and 50000 lives annually in the United States and Japan, respectively. The majority of lung cancers, 85% of non-small-cell lung cancer and 98% of small cell lung carcinoma, arise in smokers. Carcinogens from tobacco smoke target both the central and peripheral compartments. Among the 20 carcinogens that are present in tobacco smoke and strongly associated with lung cancer development, the best known are polycyclic aromatic hydrocarbons and nicotine-derived nitroso-aminoketone, which lead to genetic mutations through DNA adduct formation. Adduct formation is caused by metabolic activation of these carcinogens by P450 cytochromes, enzymes encoded by the CYP family of genes, and glutathione S-transferases (GSTs). Significant advances in lung cancer biology may lead to customised therapy based on targeting specific genes and pathways. The main signalling pathways that could provide roadmaps for therapy include the following: RTK pathways, integrin-mediated pathways, growth inhibitory pathways. These networks result in, amongst others, proliferation, evasion of apoptosis and angiogenesis. The genetic and epigenetic pathways involved in lung tumorigenesis differ between smokers and nonsmokers, and are tools for cancer diagnosis, prognosis, clinical follow-up and targeted therapies.

1 Main Signaling Pathways in Breast Cancer Therapy

1.1 RTK signaling cascade

Whereas receptor tyrosine kinases (RTKs) activity in normal resting cells is tightly regulated, mutations or deregulated expression might cause them to function as potent oncogenes. Ligands, such as EGF, VEGF, HGF or others, bind to the homo- and heterodimer kinase domain , resulting in activation and receptor transphosphorylation. This creates docking sites for the adaptor proteins, Grb2 and Sos, which recruit Ras and phosphatidylinositol 3-kinase (PI3K), leading to the formation of two major signalling pathway branches, Ras/MAPK and PI3K/Akt and PLC-PKC pathways. The PI3K-AKT signaling phosphorylates and inhibits several apoptosis-inducing genes. NF-kB is convergently activated by several distinct stimuli including growth factors. So the activation of the RTK pathway can thus have noteworthy downstream effects on angiogenesis, evasion of apoptosis, cell growth.

1.2 Integrin-mediated signaling cascade

Integrins (ITGA/ITGB) are cell adhesion receptors that allow a cell to interact with extracellular matrix (ECM) in the local environment. The affinity with which integrins bind to ligands is highly dynamically regulated, between low affinity (suppressed) and high affinity (activated) states. Engagement and cross-linking integrins stimulates multiple intracellular signalling pathways, including those mediated by Ras, phosphoinositide 3-kinase (PI3K). NF-kB is activated by extracellular matrix attachment. These signalling cascades promote cell growth and mitogenesis.

1.3 Growth inhibitory signaling cascade

p53 is a sensor of cell stress, such as DNA damage and oncogenic stimuli, and functions as a transcription factor. Its target genes play roles in the control of the G1 arrest pathway, cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. CDKs regulate the cell's progression through the phases of the cell cycle by modulating the activity of key substrates. Downstream targets of CDKs include transcription factor E2F and its regulator Rb. In addition,susceptibility to apoptosis (Bax/Bcl-2), and control of the tumour necrosis factor receptor-like apoptosis inducing ligand (TRAIL) receptor 5 (DR5), Fas. It also enters into a DNA repair protein complex with proliferation cell nuclear antigen (PCNA).

2 Lung cancer diagnosis

2.1 Molecular Markers for Lung Cancer

Molecular diagnostics-guided targeted therapies have become a standard treatment for patients with lung cancer. Here, we grouped molecular biomarkers into three categories-mutations, gene rearrangements, and amplifications.

Mutations including EGFR, KRAS, BRAF, HER2, and MET. Activating somatic mutations including point substitution, small insertion, and in-frame deletion are major oncogenic drivers in lung cancer. The discovery of activating EGFR mutations and their close relation with the response to EGFR TKIs opened the new era of precision medicine. A variety of methods can be used for detecting mutations including direct sequencing, real-time polymerase chain reaction (PCR), and commercial kits. Gene rearrangements including ALK, ROS1, RET, NTRK1, NRG1, and FGFR, The presence of an ALK rearrangement and ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement in lung cancer has become the best predictor of response to crizotinib. Several methods are currently available for assessing gene rearrangement, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse-transcriptase polymerase chain reaction (RT-PCR), and NGS. Amplifications including FGFR1, EGFR, MET, and HER2, gene amplification is an important mechanism for oncogene activation. HER2-targeting therapy has been implemented in breast and gastric cancer on the basis of molecular testing for HER2. Amplifications of several genes have been studied in lung cancer. Several methods can be used for detection of gene amplifications. FISH using a locus-specific intensifier (LSI) gene and a chromosome-specific centromere (CEP) probe is a standard method for the detection of gene amplifications. Although the FISH assay requires technical expertise and experience for interpretation, this method has the advantage of being able to evaluate gene amplification by selecting only cancer cells.

2.2 Protein Markers for Lung Cancer

Chest radiography and computer tomography are the most commonly used methods for lung cancer diagnosis. However, as they can only identify visible and irreversible changes in lung, there is a need for additional methods for early diagnosis. In order to overcome this challenge, it is essential to discover novel, highly sensitive, and specific biomarker. Therefore, accurate identification of the histological type of cancer and respective protein biomarkers is crucial for adequate therapy. Proteins are the most suitable biomarkers for lung cancer diagnosis because of their involvement in cellular processes. Unfortunately, a uniform serum biomarker composition capable of distinguishing lung cancer types is yet to be discovered. Here, we discuss the recent advances in conventional and prospective aptamer based strategies for biomarker discovery.

Panels of various biomarkers have been recently applied and are becoming more popular as this technique improves early lung cancer detection. We suggest the use of a panel consisting of eight tumor-associated biomarkers-CEA, CYFRA21-1, ProGRP, CEA, PSF3, MUC, SCCA, and SST-allow us to differentiate between each histological type of lung cancer and to define the metastasis rate. In addition to conventional biomarker discovery methods, aptamer-based detection of several lung cancer biomarkers, such as LMN and VIM, DEF, and TUB, could be helpful for accurate diagnostics. An important clinical method often used for diagnosis of tumor biomarkers is immunohistochemistry; usually, hematoxilin and eosin staining is sufficient for diagnosis. Immunostaining is based on histological identification of tumor biomarkers and abnormal blood vessels by specific agents such as antibodies, but this method has some limitations such as: relatively high cost, difficulties in quantifying results. Cancer-related proteins can be detected using various sensors, most of them rely on antibody-antigen interaction in a sandwich-like system that requires two different types of antibodies for target identification.

3 Targeted therapy for lung cancer

The numerous molecular mechanisms implicated in the pathogenesis of lung cancer present exciting avenues for target-specific approaches to therapy. Major components of cell signaling pathways, such as the receptor tyrosine kinases (RTKs), protein kinase C (PKC), and the ras/mitogen-activated protein kinase (MAPK) systems, are altered in lung cancer cells by oncogenes through overexpression or mutation, leading to dysregulated cell signaling and cell proliferation. Here, we summarize potentially viable targets and new agents that have been developed and employed in recent, ongoing and future clinical trials to attempt to improve clinical outcomes in this disease (Table1-11).

3.1 Lung cancer therapy for RTK pathway

RTKs comprise the largest family of dominant oncogenes.Targeting EGFR: Cetuximab and Panitumumab competitively inhibit activation of the EGFRTK, causing cell cycle arrest in G1. ZD1839, CI-1033, and OSI774, as EGFR tyrosine kinase inhibitors, are undergoing various phases of clinical testing. Targeting HER-2: Trastuzumab cause growth arrest in the G0-G1 phase of the cell cycle. Antibodies elicited by the chimeric peptide MVF-HER-2 had antitumor activity in vitro and prevented tumor development in vivo. Targeting VEGFR: Bevacizumab is a mAB targeting the VEGF-A receptor. DC101 is a mAB that specifically binds murine VEGFR-2. Cediranib is highly potent inhibitor of VEGFR-1, -2 and -3 tyrosine kinases. Aflibercept binding to VEGFA and B, thereby preventing binding to their cell receptors. It has demonstrated inhibition of tumor growth and metastasis in vivo. Targeting c-Met: Cabozantinib, a multi-targeted c-Met inhibitor; Capmatinib is a selective c-Met inhibitor. Targeting PKC: many kinase inhibitors that act by blocking the catalytic site are not highly specific and may act as inhibitors of PKC, such as Staurosporine, Bryostatin. Targeting ras/MAPK pathway: ISIS 2503 reduces H-ras mRNA expression through Rnase H-mediated cleavage of the hybridized H-ras mRNA. BAY 43-9006 is a potent oral selective inhibitor of Raf-1 and the first in its class to enter clinical trials. PD-184352 is an active difluorobenzamide that nanomolar inhibition of MEK activation. CCI-779 inhibits mTOR and abrogate the uncontrolled proliferation of malignant cells.

Table 1 Clinical trials of EGFR mAB Cetuximab

Nct id Status Lead sponsor Study first posted
NCT02716311 Recruiting Intergroupe Francophone de Cancerologie Thoracique March 23, 2016
NCT02438722 Recruiting Southwest Oncology Group May 8, 2015
NCT02845856 Recruiting Fuda Cancer Hospital, Guangzhou July 27, 2016
NCT00533949 Active, not recruiting Radiation Therapy Oncology Group September 24, 2007
NCT01059188 Active, not recruiting Swiss Group for Clinical Cancer Research January 29, 2010
NCT00946712 Active, not recruiting Southwest Oncology Group July 27, 2009
NCT01416688 Active, not recruiting Southwest Oncology Group August 15, 2011
NCT01726309 Recruiting Cancer Trials Ireland November 14, 2012
NCT03319459 Recruiting Fate Therapeutics October 24, 2017
NCT02496663 Recruiting National Cancer Institute (NCI) July 14, 2015

Table 2 Clinical trials of EGFR mAB Panitumumab

Nct id Status Lead sponsor Study first posted
NCT00979212 Active, not recruiting Radiation Therapy Oncology Group September 17, 2009
NCT03582124 Recruiting Eben Rosenthal July 10, 2018
NCT01061788 Active, not recruiting Jeffrey Clarke February 3, 2010
NCT01416688 Active, not recruiting Southwest Oncology Group August 15, 2011
NCT01726309 Recruiting Cancer Trials Ireland November 14, 2012

Table 3 Clinical trials of EGFR inhibitor ZD1839

Nct id Status Lead sponsor Study first posted
NCT03292133 Recruiting Massachusetts General Hospital September 25, 2017
NCT03122717 Recruiting Dana-Farber Cancer Institute April 21, 2017
NCT02804776 Recruiting National Cancer Centre, Singapore June 17, 2016
NCT03399669 Active, not recruiting Samsung Medical Center January 16, 2018
NCT03599518 Not yet recruiting Daiichi Sankyo Co., Ltd. July 25, 2018
NCT03264794 Not yet recruiting Jiangsu Famous Medical Technology Co., Ltd. August 29, 2017
NCT01570296 Active, not recruiting National Cancer Centre, Singapore April 4, 2012
NCT02151721 Active, not recruiting Kanazawa University May 30, 2014
NCT03381430 Not yet recruiting Qilu Pharmaceutical Co., Ltd. December 22, 2017
NCT02347839 Recruiting Sun Yat-sen University January 27, 2015
NCT01405079 Active, not recruiting Guangdong Association of Clinical Trials July 29, 2011
NCT01982955 Active, not recruiting Merck KGaA November 13, 2013
NCT02374645 Active, not recruiting Hutchison Medipharma Limited March 2, 2015
NCT03457337 Not yet recruiting Henan Cancer Hospital March 7, 2018
NCT03602027 Not yet recruiting Second Affiliated Hospital of Nanchang University July 26, 2018
NCT01951469 Recruiting Sun Yat-sen University September 26, 2013
NCT01544179 Active, not recruiting AstraZeneca March 5, 2012
NCT01610336 Active, not recruiting Novartis Pharmaceuticals June 4, 2012
NCT02296125 Active, not recruiting AstraZeneca November 20, 2014
NCT03374280 Recruiting Guangzhou Medical University December 15, 2017
NCT01933347 Active, not recruiting Guangdong Association of Clinical Trials September 2, 2013
NCT02824458 Recruiting Sun Yat-sen University July 6, 2016
NCT02518802 Recruiting Tang-Du Hospital August 10, 2015
NCT02976116 Active, not recruiting Hutchison Medipharma Limited November 29, 2016
NCT03267654 Not yet recruiting Qilu Pharmaceutical Co., Ltd. August 30, 2017
NCT03050411 Recruiting Peking University Third Hospital February 10, 2017
NCT01774721 Active, not recruiting SFJ Pharmaceuticals, Inc. January 24, 2013
NCT02416739 Recruiting Il Yeong Park, Ph.D. April 15, 2015
NCT03123484 Not yet recruiting China Medical University, China April 21, 2017
NCT01466660 Active, not recruiting Boehringer Ingelheim November 8, 2011
NCT02930954 Not yet recruiting Caicun Zhou October 12, 2016
NCT02088112 Active, not recruiting MedImmune LLC March 14, 2014
NCT01994057 Recruiting Sun Yat-sen University November 25, 2013
NCT03486496 Not yet recruiting Fujian Cancer Hospital April 3, 2018
NCT01556191 Active, not recruiting Intergroupe Francophone de Cancerologie Thoracique March 16, 2012
NCT02714010 Recruiting Sun Yat-sen University March 21, 2016
NCT02411448 Recruiting Eli Lilly and Company April 8, 2015
NCT03119519 Recruiting Southern Medical University, China April 18, 2017
NCT01965275 Recruiting Anhui Medical University October 18, 2013
NCT03595644 Not yet recruiting Tongji Hospital July 23, 2018
NCT03461185 Not yet recruiting Xinqiao Hospital of Chongqing March 9, 2018
NCT02893332 Recruiting Sichuan Provincial People's Hospital September 8, 2016
NCT02157883 Active, not recruiting AstraZeneca June 6, 2014
NCT02745691 Recruiting University Hospital Regensburg April 20, 2016
NCT02039674 Active, not recruiting Merck Sharp & Dohme Corp. January 17, 2014
NCT03002844 Not yet recruiting Shanghai Pulmonary Hospital, Shanghai, China December 26, 2016
NCT02788058 Not yet recruiting First People's Hospital of Hangzhou June 2, 2016
NCT02906163 Not yet recruiting SciClone Pharmaceuticals September 19, 2016
NCT03333343 Recruiting Novartis Pharmaceuticals November 6, 2017
NCT03341494 Recruiting Fujian Cancer Hospital November 14, 2017
NCT03382795 Recruiting Korea University Guro Hospital December 26, 2017
NCT02716311 Recruiting Intergroupe Francophone de Cancerologie Thoracique March 23, 2016
NCT02951637 Not yet recruiting Shanghai Chest Hospital November 1, 2016
NCT02804100 Recruiting Wenzhou Medical University June 17, 2016
NCT03399487 Not yet recruiting Yonsei University January 16, 2018
NCT02954523 Recruiting Giuseppe Giaccone November 3, 2016
NCT01967095 Active, not recruiting Memorial Sloan Kettering Cancer Center October 22, 2013
NCT03424759 Active, not recruiting Samsung Medical Center February 7, 2018
NCT02759835 Recruiting National Cancer Institute (NCI) May 3, 2016
NCT03258671 Not yet recruiting LuBing August 23, 2017
NCT03389256 Not yet recruiting Sichuan Cancer Hospital and Research Institute January 3, 2018
NCT03151161 Not yet recruiting Sun Yat-sen University May 12, 2017
NCT01963195 Recruiting Anhui Medical University October 16, 2013
NCT03071705 Recruiting Instituto Nacional de Cancerologia de Mexico March 7, 2017
NCT02701231 Recruiting Chinese PLA General Hospital March 8, 2016
NCT02736513 Recruiting Rabin Medical Center April 13, 2016
NCT02787447 Recruiting First People's Hospital of Hangzhou June 1, 2016
NCT02778893 Recruiting Henan Provincial Hospital May 20, 2016
NCT03090815 Recruiting The University of Hong Kong March 27, 2017
NCT02805530 Recruiting Instituto Nacional de Cancerologia de Mexico June 20, 2016
NCT02847377 Recruiting Centre Georges Francois Leclerc July 28, 2016

According to statistics, a total of 71 ZD1839 projects targeting lung cancer EGFR are currently in clinical stage, of which 33 are recruiting and 38 are not recruiting.

Table 4 Clinical trials of EGFR inhibitor OSI774

Nct id Status Lead sponsor Study first posted
NCT01967095 Active, not recruiting Memorial Sloan Kettering Cancer Center October 22, 2013
NCT01487265 Active, not recruiting SCRI Development Innovations, LLC December 7, 2011
NCT00254384 Active, not recruiting M.D. Anderson Cancer Center November 16, 2005
NCT01455389 Recruiting Genprex, Inc. October 20, 2011
NCT01911507 Recruiting University of California, Davis July 30, 2013
NCT02770014 Active, not recruiting Dana-Farber Cancer Institute May 12, 2016
NCT02424617 Recruiting BerGenBio ASA April 23, 2015
NCT00563784 Active, not recruiting M.D. Anderson Cancer Center November 26, 2007
NCT02013219 Active, not recruiting Hoffmann-La Roche December 17, 2013
NCT02468661 Recruiting Novartis Pharmaceuticals June 11, 2015
NCT01562028 Active, not recruiting European Thoracic Oncology Platform March 23, 2012
NCT00871923 Active, not recruiting M.D. Anderson Cancer Center March 30, 2009
NCT00100854 Active, not recruiting Translational Oncology Research International January 7, 2005
NCT00130728 Active, not recruiting Genentech, Inc. August 16, 2005
NCT01407822 Recruiting Guangdong Association of Clinical Trials August 2, 2011
NCT02633189 Recruiting National Cancer Institute, Naples December 17, 2015
NCT02991651 Recruiting Io Therapeutics December 13, 2016
NCT03126799 Recruiting National Cancer Center, Korea April 24, 2017
NCT01859026 Recruiting H. Lee Moffitt Cancer Center and Research Institute May 21, 2013
NCT02535338 Active, not recruiting National Cancer Institute (NCI) August 28, 2015
NCT03074864 Active, not recruiting Guangdong General Hospital March 9, 2017
NCT02926638 Active, not recruiting Southwest Oncology Group October 6, 2016
NCT01708954 Active, not recruiting National Cancer Institute (NCI) October 17, 2012
NCT01714908 Active, not recruiting Jinming Yu October 26, 2012
NCT01532089 Active, not recruiting Academic and Community Cancer Research United February 14, 2012
NCT00436332 Active, not recruiting Southwest Oncology Group February 19, 2007
NCT02411448 Recruiting Eli Lilly and Company April 8, 2015
NCT02296125 Active, not recruiting AstraZeneca November 20, 2014
NCT01454102 Active, not recruiting Bristol-Myers Squibb October 18, 2011
NCT02193282 Recruiting National Cancer Institute (NCI) July 17, 2014
NCT02904850 Recruiting University Hospital, Strasbourg, France September 19, 2016
NCT01259089 Active, not recruiting Northwestern University December 13, 2010
NCT01248247 Active, not recruiting M.D. Anderson Cancer Center November 25, 2010
NCT02152631 Active, not recruiting Eli Lilly and Company June 2, 2014
NCT02364609 Recruiting University of California, Davis February 18, 2015
NCT01573702 Active, not recruiting UNC Lineberger Comprehensive Cancer Center April 9, 2012
NCT02655536 Recruiting National Taiwan University Hospital January 14, 2016
NCT00977470 Active, not recruiting Massachusetts General Hospital September 15, 2009
NCT00708448 Active, not recruiting University of Utah July 2, 2008
NCT03460678 Recruiting Hikma Pharmaceuticals LLC March 9, 2018
NCT03123484 Not yet recruiting China Medical University, China April 21, 2017
NCT02416739 Recruiting Il Yeong Park, Ph.D. April 15, 2015
NCT02704767 Not yet recruiting The First Affiliated Hospital of Kunming Medical College March 10, 2016
NCT01897480 Active, not recruiting Eli Lilly and Company July 12, 2013
NCT01556191 Active, not recruiting Intergroupe Francophone de Cancerologie Thoracique March 16, 2012
NCT01683175 Active, not recruiting Tianjin Medical University Cancer Institute and Hospital September 11, 2012
NCT02431169 Recruiting Washington University School of Medicine April 30, 2015
NCT00126581 Active, not recruiting National Cancer Institute (NCI) August 4, 2005
NCT01994057 Recruiting Sun Yat-sen University November 25, 2013
NCT03050411 Recruiting Peking University Third Hospital February 10, 2017
NCT03076164 Recruiting Memorial Sloan Kettering Cancer Center March 10, 2017
NCT01416688 Active, not recruiting Southwest Oncology Group August 15, 2011
NCT03119519 Recruiting Southern Medical University, China April 18, 2017
NCT01965275 Recruiting Anhui Medical University October 18, 2013
NCT02352948 Active, not recruiting AstraZeneca February 2, 2015
NCT02284633 Recruiting Aarhus University Hospital November 6, 2014
NCT03595644 Not yet recruiting Tongji Hospital July 23, 2018
NCT02893332 Recruiting Sichuan Provincial People's Hospital September 8, 2016
NCT03461185 Not yet recruiting Xinqiao Hospital of Chongqing March 9, 2018
NCT02714010 Recruiting Sun Yat-sen University March 21, 2016
NCT02714530 Recruiting Oslo University Hospital March 21, 2016
NCT02140333 Recruiting The First Affiliated Hospital of Guangzhou Medical University May 16, 2014
NCT02157883 Active, not recruiting AstraZeneca June 6, 2014
NCT02039674 Active, not recruiting Merck Sharp & Dohme Corp. January 17, 2014
NCT02117024 Active, not recruiting Heat Biologics April 17, 2014
NCT02745691 Recruiting University Hospital Regensburg April 20, 2016
NCT02788058 Not yet recruiting First People's Hospital of Hangzhou June 2, 2016
NCT01610336 Active, not recruiting Novartis Pharmaceuticals June 4, 2012
NCT01306045 Recruiting National Cancer Institute (NCI) March 1, 2011
NCT02906163 Not yet recruiting SciClone Pharmaceuticals September 19, 2016
NCT02716311 Recruiting Intergroupe Francophone de Cancerologie Thoracique March 23, 2016
NCT03399669 Active, not recruiting Samsung Medical Center January 16, 2018
NCT02194738 Recruiting National Cancer Institute (NCI) July 18, 2014
NCT03382795 Recruiting Korea University Guro Hospital December 26, 2017
NCT02954523 Recruiting Giuseppe Giaccone November 3, 2016
NCT03264794 Not yet recruiting Jiangsu Famous Medical Technology Co., Ltd. August 29, 2017
NCT02507518 Recruiting Centre Henri Becquerel July 24, 2015
NCT02399566 Not yet recruiting Hunan Province Tumor Hospital March 26, 2015
NCT02705820 Recruiting Bank of Cyprus Oncology Centre March 11, 2016
NCT02117167 Recruiting UNICANCER April 17, 2014
NCT02154490 Recruiting Southwest Oncology Group June 3, 2014
NCT03399487 Not yet recruiting Yonsei University January 16, 2018
NCT01570296 Active, not recruiting National Cancer Centre, Singapore April 4, 2012
NCT02314364 Recruiting Massachusetts General Hospital December 11, 2014
NCT03497767 Not yet recruiting Trans-Tasman Radiation Oncology Group (TROG) April 13, 2018
NCT02574078 Active, not recruiting Bristol-Myers Squibb October 12, 2015
NCT03424759 Active, not recruiting Samsung Medical Center February 7, 2018
NCT02759835 Recruiting National Cancer Institute (NCI) May 3, 2016
NCT02045446 Active, not recruiting University of Texas Southwestern Medical Center January 24, 2014
NCT03151161 Not yet recruiting Sun Yat-sen University May 12, 2017
NCT01725165 Active, not recruiting M.D. Anderson Cancer Center November 12, 2012
NCT03389256 Not yet recruiting Sichuan Cancer Hospital and Research Institute January 3, 2018
NCT01963195 Recruiting Anhui Medical University October 16, 2013
NCT03071705 Recruiting Instituto Nacional de Cancerologia de Mexico March 7, 2017
NCT02701231 Recruiting Chinese PLA General Hospital March 8, 2016
NCT02736513 Recruiting Rabin Medical Center April 13, 2016
NCT02787447 Recruiting First People's Hospital of Hangzhou June 1, 2016
NCT03090815 Recruiting The University of Hong Kong March 27, 2017
NCT02891733 Recruiting Groupe Hospitalier Paris Saint Joseph September 7, 2016
NCT01470716 Recruiting National Cancer Center, Korea November 11, 2011
NCT00600496 Active, not recruiting AstraZeneca January 25, 2008
NCT02805530 Recruiting Instituto Nacional de Cancerologia de Mexico June 20, 2016
NCT02071862 Active, not recruiting Calithera Biosciences, Inc February 26, 2014
NCT02847377 Recruiting Centre Georges Francois Leclerc July 28, 2016

According to statistics, a total of 104 OSI774 projects targeting lung cancer EGFR are currently in clinical stage, of which 49 are recruiting and 55 are not recruiting.

Table 5 Clinical trials of HER2 mAB Trastuzumab

Nct id Status Lead sponsor Study first posted
NCT02289833 Active, not recruiting Hoffmann-La Roche November 13, 2014
NCT03505710 Recruiting Daiichi Sankyo, Inc. April 23, 2018
NCT02314481 Recruiting University College, London December 11, 2014
NCT02675829 Recruiting Memorial Sloan Kettering Cancer Center February 5, 2016
NCT03319459 Recruiting Fate Therapeutics October 24, 2017
NCT02393248 Recruiting Incyte Corporation March 19, 2015
NCT02465060 Recruiting National Cancer Institute (NCI) June 8, 2015
NCT03235427 Recruiting Northwell Health August 1, 2017
NCT02452554 Active, not recruiting Children's Oncology Group May 22, 2015

Table 6 Clinical trials of VEGFR mAB Bevacizumab

Nct id Status Lead sponsor Study first posted
NCT02521051 Recruiting Massachusetts General Hospital August 13, 2015
NCT02803203 Recruiting Memorial Sloan Kettering Cancer Center June 16, 2016
NCT01980472 Active, not recruiting Grupo de Investigación y Divulgación Oncológica November 11, 2013
NCT03196986 Recruiting Beijing Mabworks Biotech Co., Ltd. June 23, 2017
NCT00234052 Active, not recruiting Northwestern University October 6, 2005
NCT01562028 Active, not recruiting European Thoracic Oncology Platform March 23, 2012
NCT02633189 Recruiting National Cancer Institute, Naples December 17, 2015
NCT02754882 Active, not recruiting Samsung Bioepis Co., Ltd. April 28, 2016
NCT03533127 Recruiting Luye Pharma Group Ltd. May 22, 2018
NCT00130728 Active, not recruiting Genentech, Inc. August 16, 2005
NCT01891708 Recruiting Li Liu July 3, 2013
NCT03240549 Not yet recruiting Beijing Hospital August 7, 2017
NCT01107626 Active, not recruiting Eastern Cooperative Oncology Group April 21, 2010
NCT03296163 Recruiting mAbxience S.A September 28, 2017
NCT03616691 Not yet recruiting Samsung Medical Center August 6, 2018
NCT00828009 Active, not recruiting Eastern Cooperative Oncology Group January 23, 2009
NCT02200354 Recruiting Kobe City General Hospital July 25, 2014
NCT01951482 Recruiting Sun Yat-sen University September 26, 2013
NCT02681549 Recruiting Yale University February 12, 2016
NCT02429843 Active, not recruiting University of Alabama at Birmingham April 29, 2015
NCT01454102 Active, not recruiting Bristol-Myers Squibb October 18, 2011
NCT03126799 Recruiting National Cancer Center, Korea April 24, 2017
NCT01532089 Active, not recruiting Academic and Community Cancer Research United February 14, 2012
NCT00324805 Active, not recruiting National Cancer Institute (NCI) May 11, 2006
NCT00436332 Active, not recruiting Southwest Oncology Group February 19, 2007
NCT00948675 Active, not recruiting Eli Lilly and Company July 29, 2009
NCT03390686 Not yet recruiting Prestige Biopharma Pte Ltd January 4, 2018
NCT00946712 Active, not recruiting Southwest Oncology Group July 27, 2009
NCT00334815 Active, not recruiting National Cancer Institute (NCI) June 8, 2006
NCT02942043 Recruiting Beijing Cancer Hospital October 21, 2016
NCT02655536 Recruiting National Taiwan University Hospital January 14, 2016
NCT02971501 Recruiting National Cancer Institute (NCI) November 23, 2016
NCT03133546 Recruiting European Thoracic Oncology Platform April 28, 2017
NCT02507518 Recruiting Centre Henri Becquerel July 24, 2015
NCT00708448 Active, not recruiting University of Utah July 2, 2008
NCT02366143 Active, not recruiting Hoffmann-La Roche February 19, 2015
NCT03117049 Recruiting Ono Pharmaceutical Co. Ltd April 17, 2017
NCT02743923 Recruiting The Netherlands Cancer Institute April 19, 2016
NCT02162537 Recruiting Centre Hospitalier Intercommunal Creteil June 12, 2014
NCT03195569 Recruiting Qilu Pharmaceutical Co., Ltd. June 22, 2017
NCT03169335 Recruiting Qilu Pharmaceutical Co., Ltd. May 30, 2017
NCT02745691 Recruiting University Hospital Regensburg April 20, 2016
NCT03169738 Not yet recruiting NantKwest, Inc. May 30, 2017
NCT02930954 Not yet recruiting Caicun Zhou October 12, 2016
NCT03329911 Recruiting Bio-Thera Solutions November 6, 2017
NCT02039674 Active, not recruiting Merck Sharp & Dohme Corp. January 17, 2014
NCT02946359 Recruiting Chinese PLA General Hospital October 27, 2016
NCT02045446 Active, not recruiting University of Texas Southwestern Medical Center January 24, 2014
NCT02810457 Active, not recruiting Centus Biotherapeutics Limited June 23, 2016
NCT01725165 Active, not recruiting M.D. Anderson Cancer Center November 12, 2012
NCT02574078 Active, not recruiting Bristol-Myers Squibb October 12, 2015
NCT01578551 Active, not recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins April 17, 2012
NCT02701231 Recruiting Chinese PLA General Hospital March 8, 2016
NCT02272413 Active, not recruiting Boehringer Ingelheim October 23, 2014
NCT01803282 Active, not recruiting Gilead Sciences March 4, 2013
NCT02120807 Active, not recruiting Memorial Sloan Kettering Cancer Center April 23, 2014
NCT01327612 Active, not recruiting Amgen April 1, 2011
NCT02734004 Recruiting AstraZeneca April 12, 2016

According to statistics, a total of 58 Bevacizumab projects targeting lung cancer VEGFR are currently in clinical stage, of which 26 are recruiting and 32 are not recruiting.

Table 7 Clinical trials of VEGFR inhibitor Cediranib

Nct id Status Lead sponsor Study first posted
NCT02498613 Recruiting National Cancer Institute (NCI) July 15, 2015
NCT01064648 Active, not recruiting National Cancer Institute (NCI) February 8, 2010
NCT02484404 Recruiting National Cancer Institute (NCI) June 29, 2015
NCT02893917 Recruiting National Cancer Institute (NCI) September 9, 2016

Table 8 Clinical trials of c-Met inhibitor Cabozantinib

Nct id Status Lead sponsor Study first posted
NCT01639508 Recruiting Memorial Sloan Kettering Cancer Center July 12, 2012
NCT02132598 Recruiting Liza Villaruz, MD May 7, 2014
NCT01708954 Active, not recruiting National Cancer Institute (NCI) October 17, 2012
NCT03468985 Recruiting National Cancer Institute (NCI) March 19, 2018
NCT01588821 Active, not recruiting Massachusetts General Hospital May 1, 2012
NCT03170960 Recruiting Exelixis May 31, 2017
NCT02795156 Recruiting SCRI Development Innovations, LLC June 9, 2016
NCT02071862 Active, not recruiting Calithera Biosciences, Inc February 26, 2014

Table 9 Clinical trials of c-Met inhibitor Capmatinib

Nct id Status Lead sponsor Study first posted
NCT01911507 Recruiting University of California, Davis July 30, 2013
NCT02468661 Recruiting Novartis Pharmaceuticals June 11, 2015
NCT02335944 Recruiting Novartis Pharmaceuticals January 12, 2015
NCT02323126 Recruiting Novartis Pharmaceuticals December 23, 2014
NCT02276027 Active, not recruiting Novartis Pharmaceuticals October 27, 2014
NCT01610336 Active, not recruiting Novartis Pharmaceuticals June 4, 2012
NCT02750215 Recruiting Massachusetts General Hospital April 25, 2016
NCT02414139 Recruiting Novartis Pharmaceuticals April 10, 2015
NCT03333343 Recruiting Novartis Pharmaceuticals November 6, 2017

Table 10 Clinical trials of Raf inhibitor BAY 43-9006

Nct id Status Lead sponsor Study first posted
NCT00954278 Active, not recruiting University of Wisconsin, Madison August 7, 2009
NCT01248247 Active, not recruiting M.D. Anderson Cancer Center November 25, 2010
NCT02847377 Recruiting Centre Georges Francois Leclerc July 28, 2016

Table 11 Clinical trials of mTOR inhibitor CCI-779

Nct id Status Lead sponsor Study first posted
NCT02321501 Recruiting M.D. Anderson Cancer Center December 22, 2014
NCT01563354 Active, not recruiting Novartis Pharmaceuticals March 27, 2012
NCT01061788 Active, not recruiting Jeffrey Clarke February 3, 2010
NCT03348670 Active, not recruiting Han Xu, M.D., Ph.D., Sponsor-Investigator-Monitor, IRB Chair November 21, 2017
NCT02890069 Recruiting Novartis Pharmaceuticals September 7, 2016
NCT03033186 Recruiting Maastricht University Medical Center January 26, 2017
NCT03065062 Recruiting Dana-Farber Cancer Institute February 27, 2017
NCT03217669 Recruiting Chao Huang July 14, 2017
NCT01737502 Recruiting Mayo Clinic November 29, 2012
NCT02583542 Recruiting Queen Mary University of London October 22, 2015
NCT02071862 Active, not recruiting Calithera Biosciences, Inc February 26, 2014
NCT00600496 Active, not recruiting AstraZeneca January 25, 2008
NCT01524783 Active, not recruiting Novartis Pharmaceuticals February 2, 2012
NCT02145559 Active, not recruiting University of Chicago May 23, 2014

According to statistics, a total of 14 CCI-779 projects targeting lung cancer VEGFR are currently in clinical stage, of which 7 are recruiting and 7 are not recruiting.

3.2 Lung cancer therapy for integrin-mediated pathway

Matrix metalloproteinases (MMPs) are a family of enzymes responsible for remodeling of the extracellular matrix in processes of growth and morphogenesis for which they have been implicated in metastasis and angiogenesis. Targeting EMC: BMS-275291 is an orally bioavailable, nonpeptidic MMPI that exhibits antiangiogenic effects. Tetracycline inhibit collagenase activity through zincing chelation at the MMP active site, downregulation, inhibition of oxidative activation. Targeting integrins: LM609 monoclonal antibody, directed against integrin,  intervene the angiogenic process.

3.3 Lung cancer therapy for growth inhibitory pathway

The human p53 protein is a tumor suppressor nuclear phosphoprotein, once p53 genes are deleted or mutated, cells become susceptible to DNA damage and dysregulated cell growth. Targeting p53: ONYX-015 is an attenuated, replicationselective adenovirus that replicate in tumor cells lacking functional p53, with consequent tumor cell lysis. Targeting CDK: Flavopiridol exhibits potent antiproliferative and antitumor activity by selectively inhibiting the activity of cdk1, cdk2, cdk4, and cdk7 with subsequent cell cycle arrest at the G1/S and G2/M boundaries as well as downregulation of cyclin D1.

References:

  1. Dy G K, Adjei A A. Novel targets for lung cancer therapy: part I[J]. Journal of clinical oncology, 2002, 20(13):3016-3028.
  2. Dy G K, Adjei A A. Novel targets for lung cancer therapy: part II[J]. Journal of clinical oncology, 2002, 20(13): 3016-3028.
  3. Brambilla E, Gazdar A. Pathogenesis of lung cancer signalling pathways: roadmap for therapies[J]. European Respiratory Journal, 2009, 33(6):1485-1497.
  4. Shim H S.; et al. Molecular Testing of Lung Cancers[J]. Journal of pathology and translational medicine, 2017, 51(3): 242.
  5. Zamay T N.; et al. Current and prospective protein biomarkers of lung cancer[J]. Cancers, 2017, 9(11): 155.
  6. Yuan X.; et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application[J]. Journal of hematology & oncology, 2014, 7(1): 87.
  7. Osada H, Takahashi T. Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer[J]. Oncogene, 2002, 21(48): 7421.
  8. Dholaria B.; et al. Emerging therapeutic agents for lung cancer[J]. Journal of hematology & oncology, 2016, 9(1): 138.
For research use only. Not intended for any clinical use.