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

Fig.1 Melanoma 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 melanoma.

An Introduction to Melanoma

Melanoma is the most serious type of skin cancer developing in the skin, eye, inner ear, and leptomeninges. Main signs and symptoms of melanomas include a change of an existing mole, a new pigmented or unusual-looking growth on the skin, such as an increase in size, irregular edges, change of mole color, itchiness, or skin breakdown. The main cause of most of the cancer cases is the exposure to ultraviolet (UV) radiation from the sun and from tanning lamps and beds. Other melanoma cases occur in the body that don't receive exposure to UV light mainly attribute to some risk factors including fair skin, a history of sunburn, excessive ultraviolet (UV) light exposure, living closer to the equator or at a higher elevation, having many moles or unusual moles, a family history of melanoma and weakened immune system. Currently, the treatment options for the melanoma include surgery to remove affected lymph nodes, chemotherapy, radiation therapy, biological therapy and targeted therapy.

1 Main Signaling Pathways in Melanoma Therapy

1.1 RAS-RAF-MEK-ERK signaling cascade

The breakthrough discovery of B-Raf mutation in most melanoma in 2002 has triggered numerous new studies focusing on mitogen-activated protein kinase (MAPK) signaling in melanoma. These studies revealed that constitutive activation of the extracellular signal-regulated protein kinase (Ras-Raf-MEK-ERK) signaling cascade is a hallmark of cutaneous malignant melanoma. In this pathway, Ras is mutated in approximately 15-20% of human melanomas. The Ras proteins plays a critical role in regulating cell proliferation, survival and differentiation by activating a variety of effector proteins, including the Ral guanine nucleotide dissociation stimulator (GDS) exchange factors, the phosphatidylinositol-3 kinase (PI3Ks), and the three Raf protein kinases (A-Raf, B-Raf and C-Raf). Constitutive activation of the signaling cascade has been shown to contribute to melanoma tumorigenesis by increasing cell proliferation, tumor invasion and metastasis, and by inhibiting apoptosis. The importance of constitutive activation of this pathway for the maintenance of melanoma phenotypes has been confirmed by specific targeting of the BRaf and MEK pathways using kinase inhibitors in in vitro and xenotransplantation models.

1.2 PI3K/AKT signaling cascade

The PI3K/Akt pathway has been found to be activated in various cancers including melanoma, mostly due to mutations in the tumor suppressor gene PTEN. The PTEN gene encodes a phosphatase that functions to degrade the products of PI3K by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate at the 3 position. Once PTEN loses function in tumor cells, which can result in the accumulation of these critical second messenger lipids. This process then increases Akt phosphorylation and activity, leading to decreased apoptosis and/or increased mitogenic signaling. A PTEN mutation was found in 30-50% melanoma cell lines, and 57-70% showed homozygous deletion of the PTEN gene. Importantly, PTEN protein levels were found to be altered in metastatic melanoma in the absence of genetic alterations. In addition to PTEN mutation, other mechanisms, such as epigenetic silencing, altered subcellular localization or ubiquitination also can cause the PTEN inactivation. Ectopic expression of PTEN was demonstrated to suppress melanoma cell growth and melanoma tumorigenicity and metastasis. All study results revealed that PTEN and PI3K play an important role in melanoma tumorigenesis.

1.3 WNT signaling cascade

Wnts are secreted glycoproteins acting as ligands to stimulate receptor-mediated signal transduction pathways involved in cell proliferation, survival, behavior and fate. Wnt proteins activate at least three different intracellular signaling pathways including the Wnt/β-catenin, the Wnt/ Ca2+ and the Wnt/planar polarity pathways. The first pathway involves in stabilization of β-catenin. The other two involve activation of protein kinase C (PKC) and cJun N-terminal kinases (JNKs), respectively. In the canonical Wnt pathway, in the absence of a Wnt signal, cytoplasmic β-catenin is phosphorylated through the action of casein kinase Iα and GSK3β and degraded in a complex that also includes adenomas polyposis coli (APC) and axin. Upon Wnt binds to its receptor Frizzled and to a low-density lipoprotein receptor-related protein-5 or -6 (LRP5 or 6) coreceptors, the pathway can be activated. Subsequently, this ternary complex causes activation of the cytoplasmic phosphoprotein Dishevelled, which inhibits the degradation of β-catenin. Finally, β-catenin interacts with specific transcription factors T cell factor/lymphoid-enhancing factor (TCF/LEF) by the nuclear translocation to regulate target genes. Mutations of genes especially CTNNB1 and APC encoding members of the Wnt-signaling cascade are frequent in various types of human cancer such as colorectal carcinoma, hepatocellular carcinoma, hepatoblastoma and melanoma.

1.4 JNK/c-JUN signaling cascade

JNKs kinases have been studied for their importance in the regulation of mammalian physiology, including cell proliferation, cell survival, cell death, DNA repair and metabolism. JNK can be activated by a large number of extracellular stimuli, growth factors, cytokines, tumor promoters, UV radiation and hormones, which is activated by sequential protein phosphorylation through a MAP kinase module (MAP3KMAP2K-MAPK). Two MAP2Ks (JNKK1/MKK4/SEK1 and JNKK2/MKK7) have been demonstrated for JNK. Phosphorylation of JNK by these dual-specificity protein kinases is essential for its activation. Some MAP3Ks, including members of the map-erk kinase kinase (MEKK) family, activator of S-phase kinase 1 (ASK1), mixed lineage kinase (MLK), TGF-beta-activated kinase 1 (TAK1) and Tumor progression loci-2 (TPL 2), have been found to serve as MAP3Ks for JNK. JNK can elicit both positive and negative effects on tumor development based on the cellular and genetic context. JNK activation is required for Ras-mediated transformation to regulate proliferation and tumor growth.

1.5 NF-κB signaling cascade

The mammalian NF-κB family contains five members, i.e. p105/p50 (NF-κB1), p100/p52 (NF-κB2), RelA (p65), RelB and cRel. NF-κB1 and NF-κB2 are synthesized as the inactive cytosolic precursors p105 and p100, respectively. The canonical activation of NF-κB pathway relates to TNF-α stimuli to cause the activation of TNFR and association of TRAF2/MAP3K module with subsequent phosphorylation/activation of IKK. In turn, IKK-mediated phosphorylation of IκB can result in IκB ubiquitination and proteasomal degradation, releasing an active NF-κB complex. The composition of activated NF-κB complexes will determine the type of genes that will be trans-activated. Numerous mechanisms were proposed to contribute to the elevated level of NF-κB activity in malignant melanoma. For example, sustained NF-κB activation leads to induction of chemokines CXCL1 and CXCL8. CXCL1, in turn can activate IKK and NF-κB demonstrating the presence of a feed-forward mechanism that could contribute to the constitutive activation of NF-κB in melanoma cells. The CXC chemokine MGSA/GROα is constitutively expressed in melanoma that can induce NF-κB (RelA) activation in a manner dependent on Ras-MEKK1-MEK3/6-p38 pathway. By contrast, UV-induced activation of ASK1-p38 disrupts IκBα phosphorylation and decreases transcriptional activity of NF-κB, suggesting that multiple factors are cooperating, in concert, in the activation of NF-κB in melanoma.

1.6 JAK/STAT signaling cascade

STAT proteins consist of a family of transcription factors involved in the activation of target genes in response to cytokines and growth factors. Tyrosine-phosphorylated STATs undergo homodimerization or heterodimerization, followed by translocation to the nucleus for gene transcription. Four mammalian JAKs and seven STAT members render distinct patterns of gene transcription upon specific stimulation. Various mechanisms regulating the level and duration of STAT activation contributes to the complexity of the pathway, including dephosphorylation of the receptor complex or nuclear STAT dimers by PTPases, interaction of activated STATs with inhibitory molecules from the protein inhibitor of activated STAT family, and feedback inhibition of the pathway by suppressor of cytokine signaling (SOCS) proteins through inhibition and/or degradation of JAKs. In addition, different kinases can mediate STAT activity. There are two mechanisms to regulate STAT’s effect on carcinogenesis such as melanoma, i.e. immune surveillance and control of growth factor signaling, apoptosis and angiogenesis. Among the different STATs, STAT3 play a vital role in melanoma development. For example, expression of a STAT3 dominant-negative variant, STAT3β can induce cell death in B16 melanoma cells and cause inhibition of tumor growth and tumor regression by increased apoptosis. STAT3 can control IL-6-induced growth inhibition of normal melanocytes and early-stage melanoma cells, and facilitate growth of advanced melanomas.

1.7 TGF-β signaling cascade

The TGF-β family consists of multiple factors possessing dual tumor suppressor and oncogenic ability. TGF-β binding to membrane receptors can cause the assembly of a receptor complex where phosphorylates proteins of the SMAD family bind to DNA and regulate transcription of several genes to induce diverse effects. The overexpression of TGF-β1 in human melanoma cells can stimulate the neighboring stroma cells through increased production and deposition of extracellular matrix proteins. The activation of stroma causes a tumor cell survival advantage and increased metastasis.

1.8 Notch signaling cascade

Notch is an evolutionarily conserved signaling mechanism involved in many cellular processes including cell differentiation, proliferation, apoptosis, adhesion, EMT, migration and angiogenesis. Notch and its ligands Delta and Jagged, are transmembrane proteins expressed on an adjacent cell and can activate Notch signaling through a direct cell-cell interaction. Upon ligand binding, Notch intracellular domain is cleaved and translocated to the nucleus leading to the activation of target gene transcription. Notch signaling functions in several cancers including the melanoma. Expression of Notch-1/2 and Notch ligands are upregulated in “dysplastic nevi” and melanomas compared with common melanocytic nevi. Notch signaling is essential for melanoma survival.

Testis Cancer Diagnosis

2.1 Molecular Markers for Melanoma

For melanoma, detecting molecular markers or genetic alterations has emerged as an innovative form of testing that guides therapeutic decisions and aids the diagnosis of histologically challenging cases. Analysis methods including comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and quantitative gene expression profiling contribute to the detection of genetic mutations and determination of expression levels. A large number of prognostic or diagnostic markers have been found and detected in melanoma. GNAQ and GNA11 mutations result in overamplification of signaling through the MAPK and PI3K pathways via inhibiting GTPase activity. With GNAQ and GNA11 mutations, GTP is persistently bound to the G protein and leads to constitutive downstream signaling. These mutations can be detected in most of uveal melanoma. CDKN2A gene mutation is the most common alteration in hereditary melanoma, which can result in hyperphosphorylation of retinoblastoma protein (RB1), releasing the E2F1 transcription factor to promote cell cycle progression from G1 to S, loss of p14ARF function to promote the ubiquitination of p53, and reducing cell cycle arrest and apoptosis. BAP1 is a tumor suppressor gene and its mutations are associated with melanoma development. SF3B1 encodes a subunit of splicing factor 3b, and its mutations are a marker of good prognosis for uveal melanoma. EIF1AX is a gene involved in regulating protein translation. EIF1AX mutations are found in uveal melanoma to be used as diagnosis marker. Other molecular markers include vitamin D receptor (VDR), melanocortin 1 receptor (MC1R), Microphthalmia transcription factor (MITF) and hyaluronan and proteoglycan link protein 1 (HAPLN1).

2.2 Protein Markers for Melanoma

Melanin is produced in melanocytes through a series of enzymatic reactions resulting in production of variety of intermediates of melanogenesis. Tyrosinase (TYR) and tyrosinase-related proteins 1 and 2 (TRP1, TRP2) participate in the melanin synthesis. TYR has been used in the diagnosis of melanoma for its high sensitivity and specificity. B-raf is one of the signaling kinases in the MAPK pathway, and its mutations are the most common genetic alteration in cutaneous melanoma. The N-ras GTPase is essential in the transduction of extracellular growth signals. When the oncogene is mutated, GTPase activity is reduced, leading to a constitutively active GTP-bound G protein to propagate downstream signals. In contrast to BRAF mutations, NRAS-mutant melanomas are associated with the nodular subtype and found in umulative solar damage (CSD) skin. The contrast between this observation and the association of NRAS mutation with skin with CSD indicates that detecting the UV signature mutations can help diagnose melanoma. C-KIT is a receptor tyrosine kinase (RTK) involved in binding to growth factors as the first signal down the MAPK and PI3K pathways. The majority of c-KIT mutations are identified in mucosal and acral melanomas, and these mutations relate to worse survival as compared with wild-type melanomas. Immune checkpoint proteins cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) have been used as targets in the targeted melanoma therapy.

3 Targeted Therapy for Melanoma

Numerous molecular mechanisms involved in the pathogenesis of melanoma render effective ways for targeted therapy. Major components of cell signaling pathways, such as the RAS-RAF-MEK-ERK, PI3K/AKT, WNT, JNK/c-JUN, NF-κB, JAK/STAT, TGF-β and Notch signaling pathways, are altered in melanoma cells by oncogenes through overexpression or mutation, leading to dysregulated cell signaling and cell proliferation. Here, we summarize the potential targets and new drugs developed that have been used in recent, ongoing and future clinical trials to try to improve the clinical outcomes of this disease (Table1-12).

3.1 Melanoma therapy for RAS-RAF-MEK-ERK pathway

Inhibitors targeting BRAF have now been developed and are highly clinically effective. Several selective BRAF inhibitors have been tested in phase III studies against chemotherapy (DTIC), and showing an improvement in overall survival (OS). Vemurafenib (PLX4032) is an oral, highly selective and competitive inhibitor of mutant BRAF, which is investigated in melanoma (BRIM-3) phase III study as first-line treatment in patients with BRAF V600E-mutant metastatic melanoma. Dabrafenib (GSK2118436) is a reversible selective inhibitor against mutant BRAF. Phase III study (BREAK-3) results in unresectable stage III or IV BRAF V600E-mutated melanoma showed that Dabrafenib has a significant improvement in progression free survival (PFS) and response rate (RR) over DTIC with an acceptable safety Profile. MEK162 is the first inhibitor targeting NRAS-mutant and demonstrate clinical activity in patients with melanoma. Sorafenib (BAY43-9006) is a potent multi-kinase inhibitor that targets also the receptor tyrosine kinase-associated angiogenesis (VEGFR-2, VEGFR-3, PDGF-β) and tumor progression, which is effective in the treatment of a small percentage of melanomas. MEK1/2 inhibitors include Trametinib (GSK1120212) and Selumetinib (AZD6244).

Table 1 Clinical trials of BRAF inhibitor Vemurafenib

Nct id Status Lead sponsor Study first posted
NCT02036086 Active, not recruiting Sunnybrook Health Sciences Centre 14-Jan-14
NCT02818023 Active, not recruiting Yana Najjar 29-Jun-16
NCT01657591 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 6-Aug-12
NCT01909453 Active, not recruiting Array BioPharma 26-Jul-13
NCT02303951 Recruiting University Hospital Tuebingen 1-Dec-14
NCT03224208 Recruiting Fondazione Melanoma Onlus 21-Jul-17
NCT03625141 Recruiting Hoffmann-La Roche 10-Aug-18
NCT02908672 Active, not recruiting Hoffmann-La Roche 21-Sep-16
NCT02902029 Active, not recruiting University Hospital, Essen 15-Sep-16
NCT03101254 Active, not recruiting Dana-Farber Cancer Institute 5-Apr-17
NCT02721459 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 29-Mar-16
NCT01659151 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 7-Aug-12
NCT03514901 Recruiting Intergruppo Melanoma Italiano 3-May-18
NCT02968303 Recruiting Radboud University 18-Nov-16
NCT03430947 Recruiting Technische Universitt Dresden 13-Feb-18
NCT03543969 Recruiting H. Lee Moffitt Cancer Center and Research Institute 1-Jun-18
NCT03554083 Recruiting Mayo Clinic 12-Jun-18
NCT04158544 Recruiting University of Regensburg 8-Nov-19
NCT01973322 Recruiting Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori 31-Oct-13
NCT02279004 Recruiting Dana-Farber Cancer Institute 30-Oct-14

According to statistics, a total of 20 Vemurafenib projects targeting melanoma BRAF are currently in clinical stage, of which 11 are recruiting and 9 are not recruiting.

Table 2 Clinical trials of BRAF inhibitor Dabrafenib

Nct id Status Lead sponsor Study first posted
NCT03272464 Recruiting Massachusetts General Hospital 5-Sep-17
NCT01972347 Active, not recruiting Melanoma Institute Australia 30-Oct-13
NCT03944356 Recruiting EuMelaReg gGmbH 9-May-19
NCT01682083 Active, not recruiting Novartis Pharmaceuticals 10-Sep-12
NCT03754179 Recruiting Universitair Ziekenhuis Brussel 27-Nov-18
NCT02967692 Active, not recruiting Novartis Pharmaceuticals 18-Nov-16
NCT02872259 Active, not recruiting Haukeland University Hospital 19-Aug-16
NCT03026517 Recruiting Memorial Sloan Kettering Cancer Center 20-Jan-17
NCT03551626 Active, not recruiting Novartis Pharmaceuticals 11-Jun-18
NCT02083354 Active, not recruiting Novartis Pharmaceuticals 11-Mar-14
NCT02392871 Recruiting Melanoma and Skin Cancer Trials Limited 19-Mar-15
NCT04059224 Recruiting Universitair Ziekenhuis Brussel 16-Aug-19
NCT02858921 Recruiting Melanoma Institute Australia 8-Aug-16
NCT03455764 Recruiting Dana-Farber Cancer Institute 7-Mar-18
NCT03352947 Recruiting Cambridge University Hospitals NHS Foundation Trust 24-Nov-17
NCT02974803 Active, not recruiting Canadian Cancer Trials Group 28-Nov-16
NCT03332589 Recruiting Spirita Oncology, LLC 6-Nov-17
NCT02382549 Recruiting Craig L Slingluff, Jr 6-Mar-15
NCT02130466 Active, not recruiting Merck Sharp & Dohme Corp. 5-May-14
NCT02257424 Active, not recruiting Abramson Cancer Center of the University of Pennsylvania 6-Oct-14
NCT03088176 Recruiting West Cancer Center 23-Mar-17
NCT02231775 Recruiting M.D. Anderson Cancer Center 4-Sep-14
NCT04310397 Recruiting M.D. Anderson Cancer Center 17-Mar-20
NCT03149029 Recruiting Massachusetts General Hospital 11-May-17
NCT02196181 Active, not recruiting National Cancer Institute (NCI) 21-Jul-14
NCT01989585 Recruiting National Cancer Institute (NCI) 21-Nov-13
NCT02910700 Recruiting M.D. Anderson Cancer Center 22-Sep-16
NCT02097225 Active, not recruiting National Cancer Institute (NCI) 27-Mar-14
NCT01940809 Active, not recruiting National Cancer Institute (NCI) 12-Sep-13
NCT02224781 Recruiting National Cancer Institute (NCI) 25-Aug-14
NCT03340506 Recruiting Novartis Pharmaceuticals 13-Nov-17
NCT04439292 Active, not recruiting National Cancer Institute (NCI) 19-Jun-20
NCT03563729 Recruiting Inge Marie Svane 20-Jun-18
NCT03808441 Recruiting The Christie NHS Foundation Trust 17-Jan-19
NCT03416933 Recruiting Institut de Cancrologie de Lorraine 31-Jan-18
NCT04158544 Recruiting University of Regensburg 8-Nov-19
NCT03979651 Recruiting Hospices Civils de Lyon 7-Jun-19
NCT03949153 Recruiting University Hospital, Strasbourg, France 14-May-19
NCT02968303 Recruiting Radboud University 18-Nov-16
NCT02645149 Not yet recruiting Melanoma Institute Australia 1-Jan-16
NCT02465060 Recruiting National Cancer Institute (NCI) 8-Jun-15
NCT02977052 Recruiting The Netherlands Cancer Institute 30-Nov-16
NCT04154163 Recruiting University of Dundee 6-Nov-19

According to statistics, a total of 43 Dabrafenib projects targeting melanoma BRAF are currently in clinical stage, of which 29 are recruiting and 14 are not recruiting.

Table 3 Clinical trials of NRAS inhibitor MEK162

Nct id Status Lead sponsor Study first posted
NCT01909453 Active, not recruiting Array BioPharma 26-Jul-13
NCT02159066 Active, not recruiting Pfizer 9-Jun-14
NCT01320085 Active, not recruiting Pfizer 22-Mar-11
NCT04074096 Not yet recruiting UNICANCER 29-Aug-19
NCT04045691 Recruiting Pierre Fabre Pharma GmbH 5-Aug-19
NCT03878719 Recruiting Pfizer 18-Mar-19
NCT02631447 Active, not recruiting Fondazione Melanoma Onlus 16-Dec-15
NCT02902042 Recruiting Prof. Dr. med. Dirk Schadendorf 15-Sep-16
NCT03898908 Recruiting Grupo Espaol Multidisciplinar de Melanoma 2-Apr-19
NCT03235245 Recruiting European Organisation for Research and Treatment of Cancer - EORTC 1-Aug-17
NCT03864042 Recruiting Pfizer 6-Mar-19
NCT04375527 Not yet recruiting Jonsson Comprehensive Cancer Center 5-May-20
NCT04221438 Not yet recruiting ECOG-ACRIN Cancer Research Group 9-Jan-20
NCT03911869 Recruiting Pfizer 11-Apr-19
NCT04439344 Active, not recruiting National Cancer Institute (NCI) 19-Jun-20
NCT03979651 Recruiting Hospices Civils de Lyon 7-Jun-19
NCT04158544 Recruiting University of Regensburg 8-Nov-19
NCT03563729 Recruiting Inge Marie Svane 20-Jun-18
NCT02465060 Recruiting National Cancer Institute (NCI) 8-Jun-15

According to statistics, a total of 19 MEK162 projects targeting melanoma NRAS are currently in clinical stage, of which 11 are recruiting and 8 are not recruiting.

Table 4 Clinical trials of BRAF inhibitor Sorafenib

Nct id Status Lead sponsor Study first posted
NCT01303341 Active, not recruiting National Cancer Institute (NCI) 24-Feb-11

According to statistics, a total of 1 Sorafenib project targeting melanoma BRAF is currently in clinical stage and is not recruiting.

Table 5 Clinical trials of MEK1/2 inhibitor Trametinib

Nct id Status Lead sponsor Study first posted
NCT03272464 Recruiting Massachusetts General Hospital 5-Sep-17
NCT01972347 Active, not recruiting Melanoma Institute Australia 30-Oct-13
NCT04059224 Recruiting Universitair Ziekenhuis Brussel 16-Aug-19
NCT03944356 Recruiting EuMelaReg gGmbH 9-May-19
NCT01682083 Active, not recruiting Novartis Pharmaceuticals 10-Sep-12
NCT03754179 Recruiting Universitair Ziekenhuis Brussel 27-Nov-18
NCT02967692 Active, not recruiting Novartis Pharmaceuticals 18-Nov-16
NCT02872259 Active, not recruiting Haukeland University Hospital 19-Aug-16
NCT03026517 Recruiting Memorial Sloan Kettering Cancer Center 20-Jan-17
NCT03551626 Active, not recruiting Novartis Pharmaceuticals 11-Jun-18
NCT02083354 Active, not recruiting Novartis Pharmaceuticals 11-Mar-14
NCT02392871 Recruiting Melanoma and Skin Cancer Trials Limited 19-Mar-15
NCT02858921 Recruiting Melanoma Institute Australia 8-Aug-16
NCT03455764 Recruiting Dana-Farber Cancer Institute 7-Mar-18
NCT03352947 Recruiting Cambridge University Hospitals NHS Foundation Trust 24-Nov-17
NCT02296112 Active, not recruiting Vanderbilt-Ingram Cancer Center 20-Nov-14
NCT02974803 Active, not recruiting Canadian Cancer Trials Group 28-Nov-16
NCT02382549 Recruiting Craig L Slingluff, Jr 6-Mar-15
NCT02130466 Active, not recruiting Merck Sharp & Dohme Corp. 5-May-14
NCT02257424 Active, not recruiting Abramson Cancer Center of the University of Pennsylvania 6-Oct-14
NCT03979651 Recruiting Hospices Civils de Lyon 7-Jun-19
NCT03088176 Recruiting West Cancer Center 23-Mar-17
NCT02231775 Recruiting M.D. Anderson Cancer Center 4-Sep-14
NCT03149029 Recruiting Massachusetts General Hospital 11-May-17
NCT04310397 Recruiting M.D. Anderson Cancer Center 17-Mar-20
NCT01989585 Recruiting National Cancer Institute (NCI) 21-Nov-13
NCT02196181 Active, not recruiting National Cancer Institute (NCI) 21-Jul-14
NCT02910700 Recruiting M.D. Anderson Cancer Center 22-Sep-16
NCT02097225 Active, not recruiting National Cancer Institute (NCI) 27-Mar-14
NCT02974725 Recruiting Novartis Pharmaceuticals 28-Nov-16
NCT01940809 Active, not recruiting National Cancer Institute (NCI) 12-Sep-13
NCT02645149 Not yet recruiting Melanoma Institute Australia 1-Jan-16
NCT02224781 Recruiting National Cancer Institute (NCI) 25-Aug-14
NCT04417621 Not yet recruiting Novartis Pharmaceuticals 4-Jun-20
NCT03340506 Recruiting Novartis Pharmaceuticals 13-Nov-17
NCT04439292 Active, not recruiting National Cancer Institute (NCI) 19-Jun-20
NCT03563729 Recruiting Inge Marie Svane 20-Jun-18
NCT03808441 Recruiting The Christie NHS Foundation Trust 17-Jan-19
NCT03416933 Recruiting Institut de Cancrologie de Lorraine 31-Jan-18
NCT03932253 Recruiting Shanghai Fosun Pharmaceutical Development Co, Ltd. 30-Apr-19
NCT04158544 Recruiting University of Regensburg 8-Nov-19
NCT03949153 Recruiting University Hospital, Strasbourg, France 14-May-19
NCT02968303 Recruiting Radboud University 18-Nov-16
NCT02465060 Recruiting National Cancer Institute (NCI) 8-Jun-15
NCT02977052 Recruiting The Netherlands Cancer Institute 30-Nov-16
NCT04154163 Recruiting University of Dundee 6-Nov-19

According to statistics, a total of 46 Trametinib projects targeting melanoma MEK1/2 are currently in clinical stage, of which 30 are recruiting and 16 are not recruiting.

Table 6 Clinical trials of MEK1/2 inhibitor Selumetinib

Nct id Status Lead sponsor Study first posted
NCT02768766 Recruiting Richard D. Carvajal 11-May-16
NCT01364051 Active, not recruiting National Cancer Institute (NCI) 2-Jun-11
NCT00600496 Active, not recruiting AstraZeneca 25-Jan-08

According to statistics, a total of 3 Selumetinib projects targeting melanoma MEK1/2 are currently in clinical stage, of which 1 is recruiting and 2 are not recruiting.

3.2 Melanoma therapy for PI3K/AKT pathway

A variety of oral tyrosine kinase inhibitors (TKIs) are currently under evaluation in advanced melanoma, such as imatinib, dasatinib, nilotinib and sunitinib. Imatinib has beeen evaluated in three phase II trials in patients with c-KIT-mutated metastatic melanoma. A phase II study has been evaluated the predictive role of KIT activation for response to treatment with sunitinib. A phase II study of dasatinib in a molecularly unselected population of patients with advanced melanoma demonstrated two partial responses lasting 24 weeks or most of patients evaluable for response. Nilotinib is a second-generation TKI with a similar potency as imatinib against c-KIT. It is currently being evaluated in multiple phase II studies. Other PI3K-mTOR inhibitors include BEZ235, GSK2126458, BYL719, CCI-779 (Temsirolimus) and RAD001 (Everolimus), etc.

Table 7 Clinical trials of tyrosine kinase inhibitor imatinib

Nct id Status Lead sponsor Study first posted
NCT01738139 Recruiting M.D. Anderson Cancer Center 30-Nov-12

According to statistics, a total of 1 imatinib project targeting melanoma tyrosine kinase is currently in clinical stage and is recruiting.

Table 8 Clinical trials of tyrosine kinase inhibitor dasatinib

Nct id Status Lead sponsor Study first posted
NCT00700882 Active, not recruiting Eastern Cooperative Oncology Group 19-Jun-08
NCT02465060 Recruiting National Cancer Institute (NCI) 8-Jun-15

According to statistics, a total of 2 dasatinib projects targeting melanoma tyrosine kinase are currently in clinical stage, of which 1 is recruiting and 1 is not recruiting.

Table 9 Clinical trials of tyrosine kinase inhibitor sunitinib

Nct id Status Lead sponsor Study first posted
NCT02068586 Recruiting Sidney Kimmel Cancer Center at Thomas Jefferson University 21-Feb-14
NCT02465060 Recruiting National Cancer Institute (NCI) 8-Jun-15

According to statistics, a total of 2 sunitinib projects targeting melanoma tyrosine kinase are currently in clinical stage, and not recruiting.

Table 10 Clinical trials of PI3K-mTOR inhibitor CCI-779

Nct id Status Lead sponsor Study first posted
NCT03190174 Recruiting Sarcoma Oncology Research Center, LLC 16-Jun-17
NCT00600496 Active, not recruiting AstraZeneca 25-Jan-08
NCT03767660 Recruiting Peking Union Medical College Hospital 6-Dec-18
NCT01625351 Active, not recruiting St. Jude Children's Research Hospital 21-Jun-12

According to statistics, a total of 4 CCI-779 projects targeting melanoma PI3K-mTOR are currently in clinical stage, of which 2 is recruiting and 2 are not recruiting.

3.3 Immunotherapy for melanoma

CTLA4 is a member of the CD28:B7 immunoglobulin superfamily. It is normally expressed at low levels on the surface of effector and regulatory T cells. T cells autoregulate their activation through expression of CTLA4, which functions as a negative costimulatory molecule for the T cell. Two anti-CTLA4 antibodies ipilimumab and tremelimumab have been tested in phase III clinical trials. Ipilimumab is a fully human immunoglobulin G1 monoclonal antibody that targets CTLA4 and thereby leads to T-cell hyper responsiveness with disinhibition of antitumour immunity. Ipilimumab was the first drug in the management of metastatic melanoma to demonstrate a survival benefit. Tremelimumab is a fully human IgG2 monoclonal antibody that also targets CTLA4. The half-life of tremelimumab is longer than ipilimumab, so its dosing schedule is less frequent. It is assessed in phase II study for the melanoma treatment.

Table 11 Clinical trials of CTLA4 inhibitor Ipilimumab

Nct id Status Lead sponsor Study first posted
NCT04091750 Recruiting Georgetown University 17-Sep-19
NCT02403778 Active, not recruiting University of Colorado, Denver 31-Mar-15
NCT03929029 Not yet recruiting Dana-Farber Cancer Institute 26-Apr-19
NCT03313323 Recruiting VU University Medical Center 18-Oct-17
NCT03445533 Active, not recruiting Idera Pharmaceuticals, Inc. 26-Feb-18
NCT02626962 Active, not recruiting Grupo Espaol Multidisciplinar de Melanoma 10-Dec-15
NCT01740297 Active, not recruiting Amgen 4-Dec-12
NCT02068196 Active, not recruiting Oslo University Hospital 21-Feb-14
NCT01827111 Active, not recruiting M.D. Anderson Cancer Center 9-Apr-13
NCT00790010 Active, not recruiting Dana-Farber Cancer Institute 13-Nov-08
NCT03528408 Recruiting Suthee Rapisuwon 17-May-18
NCT04382664 Recruiting Ultimovacs ASA 11-May-20
NCT02970981 Active, not recruiting NYU Langone Health 22-Nov-16
NCT02978443 Active, not recruiting Georgetown University 1-Dec-16
NCT04464759 Not yet recruiting Ravi Amaravadi, MD 9-Jul-20
NCT02320058 Active, not recruiting Bristol-Myers Squibb 19-Dec-14
NCT03241186 Recruiting Robert R. McWilliams, MD 7-Aug-17
NCT02275416 Active, not recruiting Ultimovacs ASA 27-Oct-14
NCT03999749 Recruiting NYU Langone Health 27-Jun-19
NCT02523313 Active, not recruiting Prof. Dr. med. Dirk Schadendorf 14-Aug-15
NCT03068455 Active, not recruiting Bristol-Myers Squibb 1-Mar-17
NCT04250246 Not yet recruiting Italian Network for Tumor Biotherapy Foundation 31-Jan-20
NCT01927419 Active, not recruiting Bristol-Myers Squibb 22-Aug-13
NCT02599402 Active, not recruiting Bristol-Myers Squibb 6-Nov-15
NCT02913417 Recruiting David Minor, MD 23-Sep-16
NCT02032810 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 10-Jan-14
NCT03978611 Recruiting Bristol-Myers Squibb 7-Jun-19
NCT04495010 Not yet recruiting Bristol-Myers Squibb 31-Jul-20
NCT01676649 Active, not recruiting Jewish General Hospital 31-Aug-12
NCT02659540 Active, not recruiting Ludwig Institute for Cancer Research 20-Jan-16
NCT01701674 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 5-Oct-12
NCT02278887 Recruiting The Netherlands Cancer Institute 30-Oct-14
NCT04133948 Recruiting The Netherlands Cancer Institute 21-Oct-19
NCT01844505 Active, not recruiting Bristol-Myers Squibb 1-May-13
NCT02717364 Recruiting Bristol-Myers Squibb 23-Mar-16
NCT02388906 Active, not recruiting Bristol-Myers Squibb 17-Mar-15
NCT01585194 Active, not recruiting M.D. Anderson Cancer Center 25-Apr-12
NCT03225365 Not yet recruiting Hospices Civils de Lyon 21-Jul-17
NCT03958383 Recruiting University of Wisconsin, Madison 22-May-19
NCT04196452 Active, not recruiting Bristol-Myers Squibb 12-Dec-19
NCT02990611 Recruiting Bristol-Myers Squibb 13-Dec-16
NCT02498756 Not yet recruiting The First People's Hospital of Changzhou 15-Jul-15
NCT02857569 Recruiting Gustave Roussy, Cancer Campus, Grand Paris 5-Aug-16
NCT02743819 Recruiting University of Chicago 19-Apr-16
NCT03903640 Recruiting Washington University School of Medicine 4-Apr-19
NCT02714218 Active, not recruiting Bristol-Myers Squibb 21-Mar-16
NCT03235245 Recruiting European Organisation for Research and Treatment of Cancer - EORTC 1-Aug-17
NCT03597282 Active, not recruiting BioNTech SE 24-Jul-18
NCT03724968 Active, not recruiting Elizabeth Davis 30-Oct-18
NCT01950390 Active, not recruiting National Cancer Institute (NCI) 25-Sep-13
NCT01176474 Active, not recruiting H. Lee Moffitt Cancer Center and Research Institute 6-Aug-10
NCT02097732 Active, not recruiting University of Michigan Rogel Cancer Center 27-Mar-14
NCT04495257 Not yet recruiting Yale University 31-Jul-20
NCT02107755 Active, not recruiting Ohio State University Comprehensive Cancer Center 8-Apr-14
NCT03949153 Recruiting University Hospital, Strasbourg, France 14-May-19
NCT02553642 Active, not recruiting Memorial Sloan Kettering Cancer Center 17-Sep-15
NCT04463368 Not yet recruiting Sahlgrenska University Hospital, Sweden 9-Jul-20
NCT03769155 Recruiting Emory University 7-Dec-18
NCT02374242 Active, not recruiting Melanoma Institute Australia 27-Feb-15
NCT03340129 Recruiting Melanoma Institute Australia 13-Nov-17
NCT03873818 Active, not recruiting M.D. Anderson Cancer Center 13-Mar-19
NCT03161756 Recruiting Melanoma and Skin Cancer Trials Limited 22-May-17
NCT03293784 Recruiting Institut Claudius Regaud 26-Sep-17
NCT02089685 Active, not recruiting Merck Sharp & Dohme Corp. 18-Mar-14
NCT03711188 Recruiting Immodulon Therapeutics Ltd 18-Oct-18
NCT03728465 Recruiting University Hospital Tuebingen 2-Nov-18
NCT02854488 Recruiting Bristol-Myers Squibb 3-Aug-16
NCT03033576 Active, not recruiting National Cancer Institute (NCI) 27-Jan-17
NCT03122522 Recruiting Memorial Sloan Kettering Cancer Center 20-Apr-17
NCT01708941 Active, not recruiting National Cancer Institute (NCI) 17-Oct-12
NCT03719131 Recruiting Emory University 25-Oct-18
NCT04283890 Recruiting Leiden University Medical Center 25-Feb-20
NCT01134614 Active, not recruiting National Cancer Institute (NCI) 2-Jun-10
NCT02631447 Active, not recruiting Fondazione Melanoma Onlus 16-Dec-15
NCT03068624 Active, not recruiting M.D. Anderson Cancer Center 3-Mar-17
NCT01274338 Active, not recruiting National Cancer Institute (NCI) 11-Jan-11
NCT02968303 Recruiting Radboud University 18-Nov-16
NCT02506153 Active, not recruiting National Cancer Institute (NCI) 23-Jul-15
NCT02977052 Recruiting The Netherlands Cancer Institute 30-Nov-16
NCT03646617 Recruiting Abramson Cancer Center of the University of Pennsylvania 24-Aug-18
NCT03450876 Recruiting Bristol-Myers Squibb 1-Mar-18
NCT02027935 Active, not recruiting M.D. Anderson Cancer Center 6-Jan-14
NCT04013854 Active, not recruiting Abramson Cancer Center of the University of Pennsylvania 10-Jul-19
NCT02054520 Active, not recruiting NewLink Genetics Corporation 4-Feb-14
NCT02656706 Recruiting Maria Constantinou 15-Jan-16
NCT02668770 Active, not recruiting M.D. Anderson Cancer Center 29-Jan-16
NCT03070392 Active, not recruiting Immunocore Ltd 3-Mar-17
NCT03922880 Active, not recruiting Memorial Sloan Kettering Cancer Center 22-Apr-19
NCT03732560 Active, not recruiting Bristol-Myers Squibb 6-Nov-18
NCT03425461 Active, not recruiting University of Utah 7-Feb-18
NCT04074967 Recruiting Jason J. Luke, MD 30-Aug-19
NCT03526185 Recruiting Yale University 16-May-18
NCT04223648 Not yet recruiting Yale University 10-Jan-20
NCT01940809 Active, not recruiting National Cancer Institute (NCI) 12-Sep-13
NCT04021420 Not yet recruiting Assistance Publique - Hpitaux de Paris 16-Jul-19
NCT03396952 Recruiting University of California, San Francisco 11-Jan-18
NCT01511913 Active, not recruiting Bristol-Myers Squibb 19-Jan-12
NCT03354962 Active, not recruiting Institut Claudius Regaud 28-Nov-17
NCT03563729 Recruiting Inge Marie Svane 20-Jun-18
NCT02224781 Recruiting National Cancer Institute (NCI) 25-Aug-14
NCT03472586 Recruiting Sidney Kimmel Cancer Center at Thomas Jefferson University 21-Mar-18
NCT03850691 Recruiting Masonic Cancer Center, University of Minnesota 22-Feb-19
NCT04305145 Not yet recruiting Massachusetts General Hospital 12-Mar-20
NCT02519322 Recruiting M.D. Anderson Cancer Center 10-Aug-15
NCT04462406 Not yet recruiting ECOG-ACRIN Cancer Research Group 8-Jul-20
NCT03348891 Recruiting Institut Claudius Regaud 21-Nov-17
NCT02700971 Recruiting AHS Cancer Control Alberta 7-Mar-16
NCT02658890 Recruiting Bristol-Myers Squibb 20-Jan-16
NCT04060407 Not yet recruiting OncoImmune, Inc. 19-Aug-19
NCT01738139 Recruiting M.D. Anderson Cancer Center 30-Nov-12
NCT03538314 Recruiting Ultimovacs ASA 29-May-18
NCT02304458 Active, not recruiting National Cancer Institute (NCI) 2-Dec-14
NCT03627026 Recruiting Institut Claudius Regaud 13-Aug-18
NCT03816332 Recruiting National Cancer Institute (NCI) 25-Jan-19
NCT04158544 Recruiting University of Regensburg 8-Nov-19
NCT02983045 Active, not recruiting Nektar Therapeutics 6-Dec-16
NCT01973322 Recruiting Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori 31-Oct-13
NCT02938728 Not yet recruiting Assistance Publique - Hpitaux de Paris 19-Oct-16
NCT04169867 Recruiting Ardigen 20-Nov-19
NCT04136470 Recruiting Ardigen 23-Oct-19
NCT04093323 Not yet recruiting Roswell Park Cancer Institute 18-Sep-19
NCT03618641 Recruiting Diwakar Davar 7-Aug-18
NCT03171064 Recruiting University Hospital Heidelberg 31-May-17
NCT04401995 Not yet recruiting Diwakar Davar 26-May-20
NCT02475213 Active, not recruiting MacroGenics 18-Jun-15
NCT04107168 Recruiting CCTU- Cancer Theme 27-Sep-19
NCT03693014 Recruiting Memorial Sloan Kettering Cancer Center 2-Oct-18
NCT03808441 Recruiting The Christie NHS Foundation Trust 17-Jan-19
NCT03755739 Recruiting Second Affiliated Hospital of Guangzhou Medical University 28-Nov-18
NCT03872947 Recruiting Toray Industries, Inc 13-Mar-19
NCT04434560 Not yet recruiting Sarah Sammons, MD 17-Jun-20
NCT02780089 Active, not recruiting Bristol-Myers Squibb 23-May-16
NCT03347123 Active, not recruiting Incyte Corporation 20-Nov-17
NCT04157985 Recruiting Antoinette J Wozniak 8-Nov-19
NCT03126110 Active, not recruiting Incyte Biosciences International Srl 24-Apr-17
NCT02922764 Recruiting Rgenix, Inc. 4-Oct-16
NCT04146064 Recruiting University Health Network, Toronto 31-Oct-19

According to statistics, a total of 137 Ipilimumab projects targeting melanoma CTLA4 are currently in clinical stage, of which 10 are recruiting and 7 are not recruiting.

Table 12 Clinical trials of CTLA4 inhibitor tremelimumab

Nct id Status Lead sponsor Study first posted
NCT02141542 Active, not recruiting F. Stephen Hodi, MD 19-May-14
NCT04223648 Not yet recruiting Yale University 10-Jan-20
NCT02535078 Recruiting Immunocore Ltd 28-Aug-15
NCT02639026 Active, not recruiting Abramson Cancer Center of the University of Pennsylvania 24-Dec-15
NCT00378482 Active, not recruiting AstraZeneca 20-Sep-06
NCT02643303 Recruiting Ludwig Institute for Cancer Research 31-Dec-15
NCT04107168 Recruiting CCTU- Cancer Theme 27-Sep-19
NCT03693612 Recruiting GlaxoSmithKline 3-Oct-18

According to statistics, a total of 8 tremelimumab projects targeting melanoma CTLA4 are currently in clinical stage, of which 4 are recruiting and 4 are not recruiting.

References

  1. Lopez-Bergami, P.; et al. Understanding signaling cascades in melanoma. Photochemistry and photobiology. 2008, 84(2): 289-306.
  2. Yang, K.; et al. Current Molecular Markers of Melanoma and Treatment Targets. International Journal of Molecular Sciences. 2020, 21(10): 3535.
  3. Rother, J.; Jones, D. Molecular markers of tumor progression in melanoma. Current genomics. 2009, 10(4): 231-239.
  4. Russo, A.; et al. Emerging targeted therapies for melanoma treatment. International journal of oncology. 2014, 45(2): 516-524.
  5. Khattak, M.; et al. Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Therapeutic advances in medical oncology. 2013, 5(2): 105-118.
  6. Davies, M. A.; Gershenwald, J. E. Targeted therapy for melanoma: a primer. Surgical Oncology Clinics. 2011, 20(1): 165-180.
  7. Czarnecka, A. M.; et al. Targeted therapy in melanoma and mechanisms of resistance. International Journal of Molecular Sciences. 2020, 21(13): 4576.