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

Colorectal Cancer Signaling Pathway

Fig.1 Colorectal 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 colorectal cancer.

An Introduction to Colorectal Cancer

Colorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). It appears that some individuals are more prone to colorectal cancer than others. It has been suggested that about 25% of colon cancer patients have some degree of familial background, and another 15% have a strong family history involving a first or second degree relative.1 Perhaps as many as 5% of colon cancers are caused by single-gene syndromes, most commonly familial adenomatous polyposis (FAP) or Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, or HNPCC. The common affected pathways include Wnt signaling, receptor tyrosine kinase (RTK) signaling, TGFβ and TNF-α signaling, which inducing cell growth, proliferation and differentiation. Here, we show the main signaling pathway of altered gene regulation and therapy in gastric cancer.

1 Main Signaling Pathways in Colorectal Cancer Therapy

1.1 Wnt signaling cascade

Wnt signaling pathway is activated by Wnt ligands bind to the lipoprotein receptor-related protein and the frizzled receptor, the cytosolic disheveled protein is activated, and it inhibits CTNNB1 phosphorylation and its consequent degradation. Thus, the protein accumulates in the cytosol and eventually translocates to the nucleus, where it binds to T-cellespecific transcription factor 7, and both participate in the activation of downstream target genes, such as c-Myc, promoting cell proliferation. Coloretal tumors showed the Wnt pathway was affected with inactivating mutations of APC and activating mutations of β-Catenin.

Therapy

1.2 RTK Signaling Cascade

An important group of signaling pathways involved in CRC is the group triggered by RTKs. These include the VEGFR, IGFR1, PI3K, EGFR, and MET pathways. RTKs are auto-phosphorylated upon ligand binding, which results in the activation of Ras and induction of serine/threonine kinase Raf. Raf phosphorylates MEK1/2 which in turn phosphorylate and activate Erk1/2, JNK1/2 and p38. PI3K is activated by RTK autophosphorylation and results in the activation of Akt which also induces mTOR within the mTORC1 complex. Akt is also regulated by mTORC2 complex. PLCγ activation leads to the activation of COX-2, promoting angiogenesis. These events play an essential role in proliferation, differentiation, survival and cell migration.

1.3 TGF-β Signaling Cascade

TGF-β signals through a heteromeric cell-surface complex of two types of transmembrane serine/threonine kinases, named ‘type I’ and ‘type II’ receptors.After ligand-induced activation of the receptor, Smad2 and/or Smad3 interact transiently with the TβRI receptor (RI), and then dissociate from the receptor to form a heterotrimeric complex comprising two receptor-activated Smads and Smad4. This complex then translocates into the nucleus, where it interacts at the promoter with transcription factors with sequence-specific DNA binding to regulate gene expression. Inactivation of TGF-β signaling in CRC also contributes to carcinogenesis. The increased proliferation results from the loss of the growth inhibition mediated by TGF-β.

1.4 TNF-α Signaling Cascade

Tumor necrosis factor alpha (TNF-α) activates both survival and proliferation pathways along with apoptotic pathways via TNFR. Upon binding of the homotrimer TNF-α, TNFR-1 trimerizes, and silencer of death domain protein is released. TNFR recruits the adaptor proteins receptor interacting protein (RIP), TNFR-associated factor (TRAF), and Fas-associated death domain (FADD). These adaptor proteins recruit key molecules that are responsible for further intracellular signaling. When TNFR signals apoptosis, FADD binds pro-caspase-8, which is subsequently activated. This activation initiates a protease cascade leading to apoptosis. Alternatively, the binding of TRAF initiates a pathway of phosphorylation steps resulting in the activation of NF-κB transcription factor via NIK and the IKK complex. The NF-κB induce transcription of antiapoptotic, proliferative, immunomodulatory, and inflammatory genes.

2  Colorectal Cancer Diagnosis

2.1 Molecular Markers for Colorectal Cancer

Rapidly growing insights into the molecular biology of colorectal cancer (CRC) and recent developments in gene sequencing and molecular diagnostics have led to high expectations for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, However, many markers investigated suffer from technical shortcomings, resulting from lack of quantitative techniques to capture the impact of the molecular alteration. This understanding has recently led to the more comprehensive approaches of global gene expression profiling or genome-wide analysis to determine prognostic and predictive signatures in tumors. Microsatellite instabilitypromising, KRAS hopefully become biological prognostic and/or predictive markers.

MSI reflects the presence of a defective mismatch repair mechanism and is characterized by somatic alterations in the size of simple repeat microsatellite nucleotide sequences common throughout the genome. As a consequence, genes containing simple repeat sequences, such as TGFβRII, EGFR, or BAX, are often mutated in these tumors. The prognostic significance of both KRAS mutations (by PCR) and p21 staining (by IHC) has been assessed in a multitude of studies, with conflicting results. The majority of reported studies show KRAS mutation as an adverse prognostic indicator, indicating the need for adjuvant therapy.Some investigations have shown that KRAS mutation is prognostic only in some stages of the disease or only when associated with specific mutation types (transition or transversion, specific codons), or when related to specific types of recurrence or in combination with other molecular abnormalities (p53 mutation).

2.2 Protein Markers for Colorectal Cancer

The existing diagnostic methods for colorectal cancer include fecal occult blood test, colonoscopy and carcinoembryonic antigen, but their sensitivity and accuracy is inadequate. Therefore, it is essential to identify novel serum biomarkers for CRC with high sensitivity and specificity.

Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) are high throughput techniques for the analysis of complex biological specimens with high sensitivity and specificity. SELDI-TOF-MS combined with ProteinChip technology has been used to identify novel biomarkers for CRC, breast cancer, thyroid cancer, endometriosis and other diseases. This technology can detect biomarkers in serum samples effectively, but it can only obtain the molecular weight data of biomarkers without protein sequences. In the present study, several technologies were combined to purify and identify a CRC-related protein.

3 Targeted therapy for colorectal cancer

Over the past years, the number of targeted agents used in various malignancies has increased dramatically. Currently there are seven FDA approved targeted agents in colorectal cancer with many more in development and in clinical trials (Table 1-11). These targeted agents fall under the broad classification of mAbs, fusion proteins and small molecule inhibitors.

3.1 Colorectal cancer therapy for Wnt pathway

A proposed strategy has been the development of inhibitors against molecules that do not constitute the central core of the pathway. Inhibition of the interaction between CTNNB1 and Creb-binding protein by the small molecule ICG 001, the Creb-binding

protein/CTNNB1 antagonist PRI-724 has been proposed for testing with chemotherapy and bevacizumab in patients with newly diagnosed metastatic colorectal cancer (mCRC).

3.2 Colorectal cancer therapy for RKT pathway

Among these molecules, VEGF is the most important regulator of the angiogenic process identified to date and has shown markedly increased expression in advanced colorectal tumors. Bevacizumab, Ramucirumab and Aflibercept are the anti-angiogenic agents available for therapy for mCRC that binds directly to all major isoforms of VEGF-A, forming a protein complex that prevents further binding to VEGF receptors. Cetuximab and Panitumumab block downstream signaling by binding to the EGFR’s extracellular domain, which prevents further ligand binding, sterically hinders dimerization with other RTKs and induces EGFR degradation. Onartuzumab and Rilotumumab are monoclonal antibodies developed against the extracellular domain of cMET and the hepatocyte growth factor, respectively. Buparlisib, BYL719, is an oral compound that specifically inhibits PI3K in the PI3K/AKT signaling pathway. MK-2206 binds to and inhibits the activity of AKT isoforms. Several clinical trials have been completed of mTOR inhibitors such as Everolimus or Temsirolimus, which are analogs of rapamycin. Trametinib binds to and inhibits the activity of MEK1/2.

Table 1 Clinical trials of VEGF mAB Bevacizumab

Nct id Status Lead sponsor Study first posted
NCT02394834 Active, not recruiting Takeda March 20, 2015
NCT00544700 Active, not recruiting Swiss Group for Clinical Cancer Research October 16, 2007
NCT02826837 Not yet recruiting Taiwan Leader Biotech Corp. July 11, 2016
NCT03288987 Active, not recruiting AryoGen Pharmed Co. September 20, 2017
NCT01321957 Active, not recruiting Martin-Luther-Universität Halle-Wittenberg March 24, 2011
NCT01531595 Recruiting Pia Osterlund February 13, 2012
NCT01622543 Active, not recruiting Canadian Cancer Trials Group June 19, 2012
NCT03401294 Not yet recruiting University of Saskatchewan January 17, 2018
NCT03475004 Not yet recruiting University of Colorado, Denver March 23, 2018
NCT01183494 Active, not recruiting University of Chicago August 17, 2010
NCT03126071 Recruiting Jiangsu Cancer Institute & Hospital April 24, 2017
NCT01718873 Active, not recruiting National Cancer Institute, Naples October 31, 2012
NCT02743221 Active, not recruiting Institut de Recherches Internationales Servier April 19, 2016
NCT00873275 Active, not recruiting City of Hope Medical Center April 1, 2009
NCT02591667 Recruiting Medical University of Vienna October 29, 2015
NCT02090101 Active, not recruiting Centre Georges Francois Leclerc March 18, 2014
NCT02226289 Recruiting Sixth Affiliated Hospital, Sun Yat-sen University August 27, 2014
NCT03451370 Recruiting Istituto Oncologico Veneto IRCCS March 1, 2018
NCT02350530 Recruiting Sun Yat-sen University January 29, 2015
NCT01858649 Recruiting Cliniques universitaires Saint-Luc- Université Catholique de Louvain May 21, 2013
NCT03176264 Recruiting Novartis Pharmaceuticals June 5, 2017
NCT02497157 Active, not recruiting Translational Research Center for Medical Innovation, Kobe, Hyogo, Japan July 14, 2015
NCT01532804 Active, not recruiting Institut du Cancer de Montpellier - Val d'Aurelle February 15, 2012
NCT03511183 Recruiting Harbin Medical University April 27, 2018
NCT01442649 Active, not recruiting UNICANCER September 28, 2011
NCT02086656 Active, not recruiting Fondazione IRCCS Istituto Nazionale dei Tumori, Milano March 13, 2014
NCT02487992 Active, not recruiting The First People's Hospital of Changzhou July 2, 2015
NCT03380689 Not yet recruiting Fujian Cancer Hospital December 21, 2017
NCT01274624 Active, not recruiting Oncolytics Biotech January 11, 2011
NCT01878422 Active, not recruiting Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori June 17, 2013
NCT02982694 Recruiting Vall d'Hebron Institute of Oncology December 5, 2016
NCT03439462 Recruiting Aadi, LLC February 20, 2018
NCT03286738 Recruiting Joong Bae Ahn September 18, 2017
NCT03271255 Not yet recruiting Shenzhen People's Hospital September 5, 2017
NCT02515734 Not yet recruiting Japan Clinical Cancer Research Organization August 5, 2015
NCT01079780 Active, not recruiting Pam Cogliano March 3, 2010
NCT02138617 Recruiting UNC Lineberger Comprehensive Cancer Center May 14, 2014
NCT03511963 Recruiting Shanghai Henlius Biotech April 30, 2018
NCT03396926 Recruiting University of California, San Francisco January 11, 2018
NCT02873195 Active, not recruiting Academic and Community Cancer Research United August 19, 2016
NCT00984048 Active, not recruiting Jewish General Hospital September 24, 2009
NCT00828672 Active, not recruiting Universitaire Ziekenhuizen Leuven January 26, 2009
NCT02331927 Recruiting University of Ulm January 6, 2015
NCT01206530 Active, not recruiting Abramson Cancer Center of the University of Pennsylvania September 22, 2010
NCT02256800 Recruiting Jaw-Yuan Wang, MD, PhD October 6, 2014
NCT01802645 Recruiting Technische Universität Dresden March 1, 2013
NCT02399410 Not yet recruiting University Hospital, Ghent March 26, 2015
NCT02096354 Active, not recruiting EpicentRx, Inc. March 26, 2014
NCT01814501 Recruiting John Hays March 20, 2013
NCT01996306 Active, not recruiting Epidemiological and Clinical Research Information Network November 27, 2013
NCT02244632 Recruiting Isofol Medical AB September 19, 2014
NCT03135652 Recruiting Wuhan Union Hospital, China May 1, 2017
NCT02753127 Recruiting Boston Biomedical, Inc April 27, 2016
NCT03428958 Not yet recruiting NuCana plc February 12, 2018
NCT01822444 Active, not recruiting Cancer Trials Ireland April 2, 2013
NCT03169777 Not yet recruiting NantKwest, Inc. May 30, 2017
NCT02563002 Active, not recruiting Merck Sharp & Dohme Corp. September 29, 2015
NCT03470350 Not yet recruiting The Netherlands Cancer Institute March 19, 2018
NCT01895257 Recruiting Universiteit Antwerpen July 10, 2013
NCT01963182 Recruiting Centre Jean Perrin October 16, 2013
NCT03251612 Recruiting Vejle Hospital August 16, 2017
NCT01673607 Recruiting Poitiers University Hospital August 28, 2012
NCT02574663 Active, not recruiting TG Therapeutics, Inc. October 14, 2015
NCT01792934 Recruiting VU University Medical Center February 15, 2013
NCT02758951 Recruiting Catharina Ziekenhuis Eindhoven May 3, 2016
NCT01803282 Active, not recruiting Gilead Sciences March 4, 2013
NCT02015923 Recruiting Hospital Universitari de Bellvitge December 19, 2013
NCT01650428 Active, not recruiting University College, London July 26, 2012
NCT03245203 Not yet recruiting Chinese PLA General Hospital August 10, 2017
NCT01923987 Recruiting Korea Cancer Center Hospital August 16, 2013

According to statistics, a total of 70 Bevacizumab projects targeting colorectal cancer VEGF are currently in clinical stage, of which 30 are recruiting and 40 are not recruiting.

Table 2 Clinical trials of VEGF mAB Ramucirumab

Nct id Status Lead sponsor Study first posted
NCT03520946 Not yet recruiting IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest May 10, 2018
NCT01079780 Active, not recruiting Pam Cogliano March 3, 2010
NCT03251612 Recruiting Vejle Hospital August 16, 2017
NCT03271255 Not yet recruiting Shenzhen People's Hospital September 5, 2017

Table 3 Clinical trials of VEGF mAB Aflibercept

Nct id Status Lead sponsor Study first posted
NCT02970916 Active, not recruiting Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) November 22, 2016
NCT03530267 Not yet recruiting IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest May 21, 2018
NCT02624726 Recruiting Hellenic Oncology Research Group December 8, 2015
NCT02331927 Recruiting University of Ulm January 6, 2015
NCT01652196 Active, not recruiting John Hays July 27, 2012
NCT03251612 Recruiting Vejle Hospital August 16, 2017
NCT03271255 Not yet recruiting Shenzhen People's Hospital September 5, 2017
NCT02340949 Active, not recruiting Grupo Espanol Multidisciplinario del Cancer Digestivo January 19, 2015
NCT03043729 Recruiting AIO-Studien-gGmbH February 6, 2017

Table 4 Clinical trials of EGFR mAB Cetuximab

Nct id Status Lead sponsor Study first posted
NCT01251536 Active, not recruiting Universitaire Ziekenhuizen Leuven December 2, 2010
NCT03391934 Recruiting Cinnagen January 5, 2018
NCT02117466 Recruiting VU University Medical Center April 21, 2014
NCT01719380 Active, not recruiting Array BioPharma November 1, 2012
NCT02826837 Not yet recruiting Taiwan Leader Biotech Corp. July 11, 2016
NCT02063529 Recruiting Sun Yat-sen University February 14, 2014
NCT02164916 Active, not recruiting Southwest Oncology Group June 17, 2014
NCT02953782 Recruiting Forty Seven, Inc. November 3, 2016
NCT02717923 Recruiting Huazhong University of Science and Technology March 24, 2016
NCT02934529 Recruiting Ludwig-Maximilians - University of Munich October 17, 2016
NCT03356158 Recruiting Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd. November 29, 2017
NCT01079780 Active, not recruiting Pam Cogliano March 3, 2010
NCT01801904 Active, not recruiting National Cancer Institute, Naples March 1, 2013
NCT01832467 Active, not recruiting Chinese University of Hong Kong April 16, 2013
NCT02978313 Not yet recruiting Ruijin Hospital November 30, 2016
NCT03405272 Not yet recruiting Sinocelltech Ltd. January 23, 2018
NCT01878422 Active, not recruiting Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori June 17, 2013
NCT03491709 Not yet recruiting Dragonboat Biopharmaceutical Company Limited April 9, 2018
NCT03174405 Recruiting AIO-Studien-gGmbH June 2, 2017
NCT03286738 Recruiting Joong Bae Ahn September 18, 2017
NCT01776307 Active, not recruiting Boston Biomedical, Inc January 28, 2013
NCT03446157 Recruiting UNC Lineberger Comprehensive Cancer Center February 26, 2018
NCT03524820 Recruiting Hadassah Medical Organization May 15, 2018
NCT02948985 Not yet recruiting Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine October 31, 2016
NCT02515734 Not yet recruiting Japan Clinical Cancer Research Organization August 5, 2015
NCT03401957 Recruiting National Health Research Institutes, Taiwan January 17, 2018
NCT02484833 Recruiting Carlo Barone June 30, 2015
NCT02292758 Active, not recruiting Academic and Community Cancer Research United November 17, 2014
NCT01703390 Recruiting Arbeitsgemeinschaft medikamentoese Tumortherapie October 10, 2012
NCT01871311 Recruiting Georgetown University June 6, 2013
NCT01741038 Not yet recruiting Immunovative Therapies, Ltd. December 4, 2012
NCT03031444 Recruiting Beijing Cancer Hospital January 25, 2017
NCT03017807 Recruiting Sichuan Kelun Pharmaceutical Research Institute Co., Ltd. January 11, 2017
NCT03485638 Recruiting Yonsei University April 2, 2018
NCT01675999 Recruiting Assistance Publique - Hôpitaux de Paris August 30, 2012
NCT01874860 Recruiting University of Louisville June 11, 2013
NCT03135652 Recruiting Wuhan Union Hospital, China May 1, 2017
NCT03428958 Not yet recruiting NuCana plc February 12, 2018
NCT01726309 Recruiting Cancer Trials Ireland November 14, 2012
NCT03169777 Not yet recruiting NantKwest, Inc. May 30, 2017
NCT03146338 Recruiting Weprom May 9, 2017
NCT03567629 Active, not recruiting Peking University June 25, 2018
NCT03470350 Not yet recruiting The Netherlands Cancer Institute March 19, 2018
NCT01895257 Recruiting Universiteit Antwerpen July 10, 2013
NCT02391727 Recruiting Synermore Biologics Co., Ltd. March 18, 2015
NCT03251612 Recruiting Vejle Hospital August 16, 2017
NCT02318901 Active, not recruiting Western Regional Medical Center December 17, 2014
NCT00647530 Active, not recruiting University of Birmingham March 31, 2008
NCT03259009 Not yet recruiting Association des Gastroentérologues Oncologues August 23, 2017
NCT03311750 Recruiting Hellenic Cooperative Oncology Group October 17, 2017
NCT03319459 Recruiting Fate Therapeutics October 24, 2017
NCT03206151 Recruiting Taizhou Mabtech Pharmaceutical Co.,Ltd July 2, 2017
NCT03323424 Not yet recruiting Institut de Cancérologie de la Loire October 27, 2017
NCT01420874 Active, not recruiting Barbara Ann Karmanos Cancer Institute August 22, 2011
NCT03391843 Active, not recruiting RenJi Hospital January 5, 2018
NCT01621217 Active, not recruiting Lund University Hospital June 18, 2012
NCT00316888 Active, not recruiting ECOG-ACRIN Cancer Research Group April 21, 2006
NCT01923987 Recruiting Korea Cancer Center Hospital August 16, 2013
NCT03381352 Recruiting Chinese Academy of Medical Sciences December 22, 2017

According to statistics, a total of 59 Cetuximab projects targeting colorectal cancer EGFR are currently in clinical stage, of which 31 are recruiting and 28 are not recruiting.

Table 5 Clinical trials of EGFR mAB Panitumumab

Nct id Status Lead sponsor Study first posted
NCT02008383 Recruiting John Strickler, M.D. December 11, 2013
NCT03087071 Recruiting M.D. Anderson Cancer Center March 22, 2017
NCT02476045 Recruiting Fondazione IRCCS Istituto Nazionale dei Tumori, Milano June 19, 2015
NCT03311750 Recruiting Hellenic Cooperative Oncology Group October 17, 2017
NCT01991873 Recruiting AIO-Studien-gGmbH November 25, 2013
NCT01591421 Active, not recruiting Canadian Cancer Trials Group May 4, 2012
NCT01801904 Active, not recruiting National Cancer Institute, Naples March 1, 2013
NCT00940316 Active, not recruiting Northwestern University July 16, 2009
NCT02904031 Recruiting Gruppo Oncologico del Nord-Ovest September 16, 2016
NCT03263429 Recruiting Vanderbilt-Ingram Cancer Center August 28, 2017
NCT02980510 Recruiting UNICANCER December 2, 2016
NCT00647530 Active, not recruiting University of Birmingham March 31, 2008
NCT01776307 Active, not recruiting Boston Biomedical, Inc January 28, 2013
NCT03227926 Recruiting Fondazione del Piemonte per l'Oncologia July 24, 2017
NCT02301962 Recruiting GlaxoSmithKline November 26, 2014
NCT01814501 Recruiting John Hays March 20, 2013
NCT03043950 Recruiting iOMEDICO AG February 6, 2017
NCT03584711 Recruiting Federation Francophone de Cancerologie Digestive July 12, 2018
NCT03300609 Recruiting University of Southern California October 3, 2017
NCT03167268 Recruiting Ospedale San Carlo Borromeo May 25, 2017
NCT02162563 Recruiting Dutch Colorectal Cancer Group June 12, 2014
NCT01750918 Active, not recruiting Novartis Pharmaceuticals December 17, 2012
NCT03442569 Recruiting UNC Lineberger Comprehensive Cancer Center February 22, 2018
NCT01416688 Active, not recruiting Southwest Oncology Group August 15, 2011
NCT03428958 Not yet recruiting NuCana plc February 12, 2018
NCT01726309 Recruiting Cancer Trials Ireland November 14, 2012
NCT03470350 Not yet recruiting The Netherlands Cancer Institute March 19, 2018
NCT01895257 Recruiting Universiteit Antwerpen July 10, 2013
NCT03146338 Recruiting Weprom May 9, 2017
NCT02934529 Recruiting Ludwig-Maximilians - University of Munich October 17, 2016
NCT02015923 Recruiting Hospital Universitari de Bellvitge December 19, 2013

According to statistics, a total of 31 Panitumumab projects targeting colorectal cancer EGFR are currently in clinical stage, of which 22 are recruiting and 9 are not recruiting.

Table 6 Clinical trials of PI3K inhibitor Buparlisib

Nct id Status Lead sponsor Study first posted
NCT02008383 Recruiting John Strickler, M.D. December 11, 2013
NCT03087071 Recruiting M.D. Anderson Cancer Center March 22, 2017
NCT02476045 Recruiting Fondazione IRCCS Istituto Nazionale dei Tumori, Milano June 19, 2015
NCT03311750 Recruiting Hellenic Cooperative Oncology Group October 17, 2017
NCT01991873 Recruiting AIO-Studien-gGmbH November 25, 2013
NCT01591421 Active, not recruiting Canadian Cancer Trials Group May 4, 2012
NCT01801904 Active, not recruiting National Cancer Institute, Naples March 1, 2013
NCT00940316 Active, not recruiting Northwestern University July 16, 2009
NCT02904031 Recruiting Gruppo Oncologico del Nord-Ovest September 16, 2016
NCT03263429 Recruiting Vanderbilt-Ingram Cancer Center August 28, 2017
NCT02980510 Recruiting UNICANCER December 2, 2016
NCT00647530 Active, not recruiting University of Birmingham March 31, 2008
NCT01776307 Active, not recruiting Boston Biomedical, Inc January 28, 2013
NCT03227926 Recruiting Fondazione del Piemonte per l'Oncologia July 24, 2017
NCT02301962 Recruiting GlaxoSmithKline November 26, 2014
NCT01814501 Recruiting John Hays March 20, 2013
NCT03043950 Recruiting iOMEDICO AG February 6, 2017
NCT03584711 Recruiting Federation Francophone de Cancerologie Digestive July 12, 2018
NCT03300609 Recruiting University of Southern California October 3, 2017
NCT03167268 Recruiting Ospedale San Carlo Borromeo May 25, 2017
NCT02162563 Recruiting Dutch Colorectal Cancer Group June 12, 2014
NCT01750918 Active, not recruiting Novartis Pharmaceuticals December 17, 2012
NCT03442569 Recruiting UNC Lineberger Comprehensive Cancer Center February 22, 2018
NCT01416688 Active, not recruiting Southwest Oncology Group August 15, 2011
NCT03428958 Not yet recruiting NuCana plc February 12, 2018
NCT01726309 Recruiting Cancer Trials Ireland November 14, 2012
NCT03470350 Not yet recruiting The Netherlands Cancer Institute March 19, 2018
NCT01895257 Recruiting Universiteit Antwerpen July 10, 2013
NCT03146338 Recruiting Weprom May 9, 2017
NCT02934529 Recruiting Ludwig-Maximilians - University of Munich October 17, 2016
NCT02015923 Recruiting Hospital Universitari de Bellvitge December 19, 2013

According to statistics, a total of 31 Buparlisib projects targeting colorectal cancer PI3K are currently in clinical stage, of which 22 are recruiting and 9 are not recruiting.

Table 7 Clinical trials of PI3K inhibitor BYL719

Nct id Status Lead sponsor Study first posted
NCT01719380 Active, not recruiting Array BioPharma November 1, 2012

Table 8 Clinical trials of AKT inhibitor MK-2206

Nct id Status Lead sponsor Study first posted
NCT01802320 Active, not recruiting National Cancer Institute (NCI) March 1, 2013

Table 9 Clinical trials of mTOR inhibitor Temsirolimus, Everolimus, Sirolimus

Nct id Status Lead sponsor Study first posted
NCT03439462 Recruiting Aadi, LLC February 20, 2018
NCT00409994 Active, not recruiting Maastricht Radiation Oncology December 12, 2006
NCT03095703 Recruiting Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) March 30, 2017
NCT00600496 Active, not recruiting AstraZeneca January 25, 2008

Table 10 Clinical trials of MEK1/2 inhibitor Trametinib

Nct id Status Lead sponsor Study first posted
NCT03087071 Recruiting M.D. Anderson Cancer Center March 22, 2017
NCT02230553 Recruiting The Netherlands Cancer Institute September 3, 2014
NCT03377361 Recruiting Bristol-Myers Squibb December 19, 2017
NCT02399943 Recruiting University Health Network, Toronto March 26, 2015
NCT01750918 Active, not recruiting Novartis Pharmaceuticals December 17, 2012
NCT03317119 Recruiting City of Hope Medical Center October 23, 2017
NCT02079740 Recruiting National Cancer Institute (NCI) March 6, 2014
NCT01740648 Active, not recruiting Terence Williams December 4, 2012

3.3 Colorectal cancer therapy for TGF-β pathway

Inactivation of TGF-β signaling in CRC also contributes to carcinogenesis. The genes encoding the downstream proteins of TGF-β signaling are also affected in CRC, such as the loss of the genes SMAD2 and SMAD4 caused by the deletion of chromosome 18q. More clinical trials regarding this topic are needed.

3.3 Colorectal cancer therapy for TNF-α pathway

TNF-α stimulates the acute phase response, mediates the inflammatory response, activates other cytokines, and increases vascular permeability. The compound Lenalidomide has been used in clinical trials for the treatment of patients with CRC. This drug inhibits TNF-a production, stimulates T cells, reduces the serum levels of VEGF and basic fibroblast growth factor, and inhibits angiogenesis. Dulanermin binds to and activates TRAIL receptors 1 and 2, which might activate caspases and induce p53-independent apoptosis in TRAIL receptor 1/2-expressing tumor cells.

Table 11 Clinical trials of TNF-α inhibitor Lenalidomide

Nct id Status Lead sponsor Study first posted
NCT01254617 Active, not recruiting National Cancer Institute (NCI) December 6, 2010

References:

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  2. Moriarity A, O'Sullivan J.; et al. Current targeted therapies in the treatment of advanced colorectal cancer: a review[J]. Therapeutic Advances in Medical Oncology, 2016, 8(4):276.
  3. Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway[J]. Oncogene, 2006, 25(57):7531.
  4. Yoshihito O, Naoki F.; et al. Role of targeted therapy in metastatic colorectal cancer:[J]. World Journal of Gastrointestinal Oncology, 2016, 8(9):642.
  5. Barzi A, Lenz A M.; et al. Molecular Pathways: Estrogen Pathway in Colorectal Cancer[J]. Clinical Cancer Research, 2013, 19(21):5842-5848.
For research use only. Not intended for any clinical use.