FDA approvals for antiangiogenic drugs.
\r\n\t
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53483",title:"Anti-VEGF Therapy in Cancer: A Double-Edged Sword",doi:"10.5772/66763",slug:"anti-vegf-therapy-in-cancer-a-double-edged-sword",body:'\nOxygen and nutrients are critical to the functioning and survival of cells in the body. This need is met through the creation of an extensive vascular system, which is maintained through the process of angiogenesis, and the creation of blood vessels from the existing vasculature [1]. In the angiogenesis process, endothelial cells initially respond to changes in the local environment and migrate toward the growing tumor. The endothelial cells then migrate together forming tubular structures that are ultimately encapsulated by recruiting periendothelial support cells to establish a vascular network that facilitates tumor growth and metastasis. Angiogenesis is subject to a complex regulatory system of both pro- and antiangiogenic factors after a tissue is fashioned [1–3] and deregulating angiogenesis–a classic trademark of cancer–leads to an aberrant microenvironment and promotion of tumor progression. Angiogenesis is initiated by the binding actions of vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGF1/2) [4].
\nVEGF is an essential proangiogenic factor whose production is itself extensively regulated by a plethora of growth factors, cytokines, and other extracellular molecules produced in response to the various metabolic and mechanical conditions present in the cell’s environment [2–6]. VEGF plays a pivotal role in tumor angiogenesis. The overexpression of VEGF is one of the central factors that leads to the onset and progression of cancer. In order to sustain their growth beyond any current size, tumors require an increased supply of blood, and this is achieved through the expression and secretion of VEGF, which stimulates the induction of new blood vessels around the tumor. Furthermore, the cancer cells, through the action of this subfamily of growth factors, invade other organs and areas of the body (metastasis) [4]. Consequently, VEGF and the resulting tumor angiogenesis present an attractive therapeutic target in the treatment of cancer. Inhibitors of VEGF/angiogenesis have been garnering interest and studied for their therapeutic application in most solid tumors [7, 8]. Moreover, a series of preclinical studies have revealed that anti-VEGF compounds increase the efficacy of ensuing antitumor treatment, although the mechanism of this effect is unclear [9].
VEGF is a dimeric glycoprotein secreted by cells that is able to induce permeability of blood vessels and promotes angiogenesis. The VEGF family contains seven members, all part of the platelet-derived growth factor (PDGF) supergene family: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PlGF [10, 11]. All members contain a core region comprised of eight cysteine residues forming a cysteine knot motif. These residues are involved in both inter- and intramolecular disulfide bonds at one end of a central four-stranded β-sheet within each monomer, which dimerizes in antiparallel fashion [11]. VEGFs A–D and PlGF are all produced in humans, whereas VEGF-E is produced in the Orf virus, has a 25% amino acid homology to mammalian VEGF, and lacks a heparin-binding domain [12]. VEGF-F is produced in snake venom and varies its structure and function by species, helping to produce a variety of venom [13].
\nThe VEGF-A gene contains eight different exons that create six different isoforms through alternative splicing. These isoforms have lengths (in amino acids) of 121, 145, 165, 183, 189, and 206 that are produced by the alternate splicing of a single gene containing eight exons, and they all contain exons 1–5 and 8. All forms of VEGF-A except for VEGF-A121 can bind to heparin [11]. VEGF165 is the one most commonly secreted by tumor cells and acts most strongly on endothelial cells to lead them to form new capillaries. VEGF-B exists as two isoforms of lengths 167 and 186 amino acids and has been shown to act as a cell survival factor while exhibiting little proangiogenic effect [14]. VEGF-C and VEGF-D are resealed proteolytically from their respective precursor proteins and play important roles in regulating lymphangiogenesis [10, 11]. PlGF upregulates angiogenesis through binding to VEGFR-1 (thereby freeing VEGF-A to bind to VEGFR-2) and exists in four isoforms of amino acid lengths 131, 152, 203, and 224 [15]. It has also been shown to induce a specific phosphorylation and activation of c-Jun N-terminal kinase (JNK) and p38 [16].
\nVEGF signaling pathway plays a major role in angiogenesis. VEGF receptors (VEGFRs) are type V receptor tyrosine kinases (RTKs) activated upon ligand-mediated dimerization [17]. Two high-affinity VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), have been identified in endothelial cells. Flk-1 (R2) has been shown to play a major role in tumor angiogenesis. In all, there are three types of receptors, with VEGFR-3 only binding to VEGFs –C and –D. Each of the three types of receptor (VEGFR-1, -2, and -3) is composed of seven immunoglobulin-like domains in the extracellular region, a transmembrane region, and a tyrosine kinase sequence with a kinase insert domain [11].
\nSignaling of VEGF is initiated via binding to its receptors, which are tyrosine kinases that are able to transphosphorylate tyrosine residues of SH2 domain-containing signaling molecules, thus activating kinase-dependent transcription factors known as STAT proteins, to modulate cell responses induced by VEGF. VEGFR-1 and -2 are both involved in endothelial cell function and angiogenesis [18], while VEGFR-3, to which only VEGFs –C and –D can bind, plays a critical role in lymphangiogenesis and primarily involved in normal embryonic development [11]. VEGF-1 has also been shown to be required in inducing the migration of monocytes and macrophages [19]. Neuropilins-1 and -2 are important coreceptors for VEGF signaling and increase the affinity of VEGF-A165 for its receptors [5]. Refer to Figure 1 for a summary of how each VEGF pairs with each VEGF receptor.
A summary of the functions of each form of VEGF and PlGF and each VEGF receptor. VEGFR-1 regulates cell migration and gene expression in monocytes and macrophages; VEGFR-2 regulates vascular endothelial functions; and VEGFR-3 regulates lymphatic endothelial functions. VEGF-A is a proangiogenic factor; VEGF-B is a prosurvival factor; VEGF-C and –D regulate lymphangiogenesis; VEGF-E is found in the Orf virus; and PlGF encourages VEGF-A to bind to VEGFR-2, thereby stimulating angiogenesis, and encourages the transcription of JNK and p38.
VEGF is heavily involved in promoting angiogenesis and research suggests that it also plays a role in regulating intussusceptive angiogenesis as well. In sprouting angiogenesis, hypoxia induces parenchymal cells to release VEGF-A into the extracellular matrix (ECM). VEGF-A then causes tip cells to produce the Delta-like-4 (Dll4) ligand, which is a membrane-bound ligand that serves to activate the Notch receptor, a highly conserved transmembrane receptor that regulates cell proliferation, cell fate, and cell death in metazoans on neighboring cells through cell to cell contact [20]. Dll4 then inhibits migratory behavior through activating the Notch receptor on neighboring stalk cells. Tip cell filopodia, actin-rich protrusions on the cell membrane that serve as a mechanism for a cell to explore its environment, sense a gradient in VEGF-A and align their sprouting to this gradient. The tip cell then anchors itself onto the substratum while actin microfilaments in the filopodia contract, pulling the tip cell toward the VEGF-A source while stalk cells proliferate. When the tip cells from different sprouts meet, they fuse to become a functional capillary through which blood can flow [1]. The function of VEGF in sprouting angiogenesis is less well understood, although it is suspected that VEGF cooperating with angiopoietin-1 (Ang-1) plays a role in stimulating the process [21, 22].
Tumors need oxygen to survive. At first, they are able to obtain enough oxygen by coopting the surrounding vasculature, altering its morphology, physiology, and response to therapy in the process. However, when a tumor becomes too large to be sufficiently supplied by existing vasculature, an “angiogenic switch” is turned on, and the tumor begins the process of tumor angiogenesis, thereby creating its own vasculature for an oxygen supply [23–26].
\nThe angiogenic switch is triggered by hypoxia occurring when the tumor becomes too large for oxygen to diffuse from existing vasculature to tumor cells [27]. Hypoxia induces the production of VEGF in tumor cells through hypoxia-inducible factor-1α (HIF-1α) [25, 27], a master transcriptional factor that regulates a group of downstream genes including VEGF that promote angiogenesis and metastasis, while inhibitors of angiogenesis such as angiostatin and interferon are downregulated [23]. A suite of other proangiogenic genes (such as Ang-1 and -2) and regulatory mechanisms (such as micro-RNAs) are also regulated by the hypoxia-induced HIF pathway [25]. Tumor cells then release VEGF into the surrounding extracellular space, which binds to VEGF R of surrounding or nearby endothelial cells, promoting local angiogenesis and forming tumor-associated microvessels in order to delivering oxygen-carrying blood to the tumor.
\nCompared with normal vasculature, tumor vessels are highly irregular and inefficient at delivering nutrients. They branch irregularly, follow a tortuous path, are far larger than their normal counterparts, are unusually permeable to large molecules, have a high interstitial pressure, and are inefficient at carrying blood [26, 28]; these abnormalities of the tumor vasculature result in poor delivery of nutrients, causing certain areas of the tumor to be chronically hypoxic, stabilizing the HIF/VEGF signaling pathway described above and therefore resulting in even more tumor vasculature [25]. The overproduction of VEGF-A results in an abundance of tip cells from the Dll4 signaling pathway, which in part causes the malformed vasculature associated with tumors through excessive branching of these tip cells [25, 29].
\nTumor blood vessel can be divided into six general classes: (1) mother vessels, which are enlarged, tortuous, thin-walled, lacking in pericytes, and highly permeable; (2) capillaries, which are similar to normal capillaries; (3) glomeruloid microvascular proliferations, which are tangles of vessels situated within a mixture of disordered pericytes; (4) vascular malformations, which are large vessels with an irregular coat of smooth muscle cells; (5) feeder arteries; and (6) draining vessels, which are enlarged, serpentine smooth muscle cell-coated vessels that supply and drain the blood vessels within the tumor [30]. The irregular pericyte and smooth muscle cell formations on these vessels, which in normal vasculature serve to enhance tight junctions and decrease leakiness, serve to decrease vessel efficacy in tumor angiogenesis [31].
\nOncogenes play a prominent role in triggering the angiogenic switch. Expression of the H-Ras oncogene in the immortalized rat intestinal epithelial cell line IEC-18 led to the upregulation of VEGF and a significant increase of in vivo vascularization [32]. Ras signaling also results in the stabilization of the resulting mRNAs and possible enhancement of their transcription [33]. The p53 suppressor gene normally serves to downregulate VEGF while upregulating thrombospondin-1, an antiangiogenic factor; mutations in these genes serve to increase the activity of VEGF [34, 35]. p53 acts as a foil to C-Myc, a gene that triggers the expression of VEGF while downregulating thrombospondin-1. In tumors, mutations in p53 serve to increase the activity of c-Myc, thereby increasing the activity of VEGF [34].
\nCompared to VEGF-A, VEGF-B plays an insignificant role in angiogenesis. Rather, it acts as a potent survival factor, inhibiting the production of several proapoptotic factors such as BH-3-related proteins. The prosurvival effects of VEGF-B are mediated by both VEGFR-1 and the coreceptor NP-1 [36, 37]. More recent research suggests that VEGF-B may trigger tumor angiogenesis through a VEGF-A-independent pathway and that it may even be a prognostic marker for cancer metastasis [38].
\nVEGF-C and VEGF-D are both heavily involved in lymphangiogenesis. In tumors, these two forms of VEGF are overexpressed and activate VEGFR-3 by means of a paracrine signaling loop, thereby encouraging lymphatic growth within the tumor [39, 40]. Lymphatic vessels created through tumor angiogenesis tend to be larger than normal, enhancing the delivery of tumor cells to the lymph nodes, from which metastasis can occur (while VEGFR-3 activation causes lymphatic vessels to sprout, it should be noted that VEGFR-2 causes the vessels to become dilated) [41]. For example, metastasis of breast cancer occurs primarily through the lymphatic system, and VEGF-C has been shown to enhance tumor metastasis in this disease [42]. Because both lymphatic vessels and blood vessels provide nutrients and a metastatic pathway for a tumor, vascular density (lymphatic vessels density or blood vessel density) within the tumor may be a prognostic factor of metastatic potential [41, 43].
Because of tumor dependence on VEGF for growth and survival, much work has been put into developing VEGF inhibitors for use in the clinic. Most of these inhibitors fall under two broad categories that differ in structure and mechanism of action: small-molecule inhibitors (SMIs) and monoclonal antibodies (mAbs). Table 1 contains a list of the anti-VEGF medications mentioned in this chapter, their types, FDA approval dates, the forms of cancer they are approved to treat, and some common side effects associated with their use.
Medicine | Type of medication | FDA approval date | Types of cancers approved for to date | Common Grade 3-4 side effects |
---|---|---|---|---|
Apatinib [114] | SMI | N/A | N/A | N/A |
Bevacizumab [125] | mAb | 26-Feb-04 | Metastatic colorectal cancer, nonsmall cell lung cancer, glioblastoma, metastatic renal cell carcinoma, cervical cancer (in combination with chemotherapy), platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with chemotherapyFDA approval for the use of bevacizumab in metastatic HER2-negative breast cancer was revoked on 18 Nov. 2011 on account of potentially life-threatening side effects and the few benefits associated with its use | Sensory neuropathy, hypertension, fatigue, neutropenia, vomiting, diarrhea |
Cabozantinib [116] | SMI | 25-Apr-16 | Renal cell carcinoma in patients who have received prior antiangiogenic therapy | Abdominal pain, pleural effusion, diarrhea, and nausea |
Pazopanib [126] | SMI | Oct-09 | Advanced renal cell carcinoma, advanced soft tissue sarcoma | Diarrhea, hypertension, and proteinuria |
Ramucirumab [96] | mAb | 21-Apr-14 | Gastric/gastroesophageal junction adenocarcinoma (with and without paclitaxel), with docetaxel for platinum-resistant metastatic nonsmall cell lung cancer, with FOLFIRI for metastatic colorectal cancer | Hypertension, hyponatremia, neutropenia, pneumonia |
Sorafenib [50] | SMI | 20-Dec-05 | Advanced renal cell carcinoma, unresectable hepatocellular carcinoma, progressive differentiated thyroid carcinoma | Diarrhea, hand-foot syndrome |
Sunitinib [46] | SMI | 26-Jan-06 | Gastrointestinal stromal tumor, advanced kidney cancer, pancreatic neuroendocrine tumors | Hypertension, diarrhea, nausea, vomiting |
Vandetanib [52] | SMI | 6-Apr-11 | Medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease | Diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash |
Zif-Aflibercept [127] | VEGF-Trap (hybrid of VEGFR-1 binding domain and VEGFR-2 domain 3) | 3-Aug-12 | Metastatic colorectal cancer that is resistant to an oxaliplatin-containing regimen | Neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia |
33C3 [57] | mAb | N/A | N/A | N/A |
FDA approvals for antiangiogenic drugs.
Some SMIs targeting VEGF signaling pathway are able to pass through the cellular membrane and interact with the cytoplasmic domain of receptor tyrosine kinases (RTKs) [44, 45]. Most act as competitive inhibitors with ATP. As the ATP binding site is common to all RTKs, specificity in the SMI is created by engineering the part of the molecule not similar to ATP [44]. Small molecule tyrosine kinase inhibitors (SMTKIs) can be divided into three broad categories: those that hydrogen bond with the ATP binding site of the enzyme’s active conformation (type I), those that hydrogen bond with the hydrophobic pocket directly next to the ATP binding site in the enzyme’s inactive conformation (type II), and those that bond covalently and irreversibly with specific cysteine residues on the kinase (type III) [44].
\nSunitinib is a type I SMTKI [44] that is able to inhibit RTKs containing a split-kinase domain, such as VEGFRs -1, -2, and -3; PDGFRs –A and –B; cKIT; FLT3; CSF-1R; and RET [46]. The inhibition of the RTKs blocks signal transduction, thereby preventing tumor growth and angiogenesis among other processes. Sunitinib is administered orally in a recommended dose of 50 mg once daily for 4 weeks followed by a 2-week rest [47]. The medicine is currently FDA approved for use in progressive well-differentiated pancreatic neuroendocrine tumors in patients with unresectable, locally advanced, or metastatic disease; metastatic renal cell carcinoma; and gastrointestinal stromal tumors after intolerance to imatinib mesylate [46].
\nSorafenib is a type II SMTKI [45]. Sorafenib inhibits VEGFR-2, VEGFR-3, PDGFR-β, and Kit; therefore, it operates through a dual mechanism of action, inhibiting both tumor growth and angiogenesis [48]. Sorafenib is administered in a recommended dose of 400 mg twice daily around mealtimes [47]. The medicine is FDA approved for use in recurrent or metastatic progressive differentiated thyroid carcinoma, advanced renal cell carcinoma, and unresectable hepatocellular carcinoma [49].
\nVandetanib is a type III SMTKI [44]. It inhibits VEGFR-2, EGFR, and RET, blocking several signal transduction pathways that control tumor growth and angiogenesis [50]. Vandetanib was approved in 2011 for use against unresectable, locally advanced, or metastatic medullary thyroid cancer. The recommended daily dose of the medicine is 300 mg per day, administered orally [51].
\nIn contrast to small molecule inhibitors, monoclonal antibodies (mAbs) cannot translocate through the plasma membrane to interact with the cytoplasmic domains of RTKs; they are, however, more specific in action than SMIs [45]. mAbs used in antiangiogenic therapies can be divided into two broad categories: those that bind to VEGF and inhibit VEGF’s ability to bind with its receptors, and those that bind to VEGFRs and inhibit ligand-receptor interaction and activate immune responses.
\nPerhaps the most well-known mAb targeting VEGF is bevacizumab, first approved in the EU in January 2005 [52]. The medicine targets all forms of VEGF-A, thereby inhibiting its ability to activate angiogenesis [53]. 2C3 is another mAb that binds to VEGF, preventing it from interacting with VEGFR-2, but not VEGFR-1; it blocks the growth of blood vessels in tumors and inhibits increases in vascular permeability [54]. IMC1121B (ramucirumab) binds to the ligand binding site of VEGFR-2 [55]. 33C3 is an antibody that binds to Ig domains 4-7 of VEGFR-2 and therefore, on account of binding to VEGFR-2 as opposed to a VEGF molecule, has the potential to act independently of VEGF concentration [56].
\nA type of VEGF inhibitor that defies simple classification into one of these two categories was developed recently as VGEF-trap, otherwise known as aflibercept. Aflibercept is a fusion protein consisting of the VEGFR-1 and VEGFR-2 binding domains and the Fc region of the IgG1 antibody [57, 58]. The protein binds to VEGF-A, VEGF-B, and PlGF, inhibiting activation of VEGFR-1 and VEGFR-2 and thereby inhibiting angiogenesis [57, 58]. Aflibercept was approved as Zaltrap on 3 August 2012 for use in combination with a FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy regimen in adults with colorectal cancer [59], and has been shown to provide significant benefits in OS and PFS [60].
No metabolically active tissue in the human body is more than a few hundred micrometers away from a capillary vesicle. The extensive nature of the vascular system in humans is produced and maintained through angiogenesis; changes in metabolic activity lead to changes in demand for oxygen which in turn regulate angiogenesis [1]. Therefore, angiogenesis inhibitors are bound to have adverse side effects. These side effects are generally less severe than those encountered from chemotherapy, although they can still be life-threatening [61]. Common side effects include hypertension, arterial thromboembolic events (ATEs), cardiotoxicity, and problems with bleeding, gastrointestinal perforation, and wound healing. See Table 2 for a description of grades of adverse events.
Grade | Description | Example with gastric fistula |
---|---|---|
I | Mild with few or no symptoms; no interventions required | Asymptomatic; clinical or diagnostic observations only; intervention not indicated |
II | Moderate, with minimal intervention needed; some limitation of activities | Symptomatic; altered GI function |
III | Severe but not life threatening; hospitalization required; limitation of patient\'s ability to care for him or herself | Severely altered GI function; bowel rest tube feeding; TPN or hospitalization indicated |
IV | Life threatening; urgent intervention required | Life-threatening consequences; urgent operative intervention indicated |
V | Death related to adverse event | death |
Explanation of grades of adverse events [76].
Perhaps the most well documented side effect of angiogenesis inhibitors is hypertension. VEGF has been shown to decrease blood pressure; for example, in a phase I clinical trial (the VIVA trial, a double-blind placebo-controlled study), recombinant VEGF was shown to decrease systolic blood pressure by as much as 22% [62]. This decrease in blood pressure is caused by the generation of blood capillaries, which increases the total cross-sectional surface area available for blood to flow and thereby reduces blood pressure, and VEGF-induced vasodilation, which occurs when VEGF induces the production of nitric oxide and PGI2 as part of its signal transduction pathway [63]. VEGF inhibitors therefore cause hypertension by inhibiting the production of nitric oxide and PGI2, leading to vasoconstriction and an increase in blood pressure [64, 65]. Hypertension caused from VEGF inhibition can be managed using standard therapies, such as angiotensin-converting enzyme inhibitors, beta blockers, calcium channel blockers, diuretics, and angiotensin II receptor blockers [66].
\nVEGF-dependent interactions between the glomeruli and endothelial cells are also inhibited through anti-VEGF therapies (such as bevacizumab, sunitinib, and sorafenib [67]), leading to proteinuria, a common side effect in anti-VEGF treatment [65, 68]. Inhibition of the VEGF signaling pathway leads to the suppression of nephrin, which in turn leads to a decrease in maintenance of the glomerular slit diaphragm [68]. Luckily, most instances of proteinuria are mild, presenting as only grades I and II, although more severe proteinuria has been reported in a share of cases [67, 68].
\nTreatment with VGEF inhibitors is also associated with an increased risk of arterial thromboembolic events (ATEs) [65, 69, 70]. This increased risk is caused by a reduction in the regenerative capacity of endothelial cells and can diminish antiapoptotic factors while encouraging procoagulant changes in the blood vessels [70]. The rate of venous thromboembolic events does not seem to be affected by VEGF inhibition, at least when comparing bevacizumab with chemotherapy and chemotherapy alone [69]. It is recommended that patients on anti-VEGF therapy who develop an ATE be taken off the therapy immediately [65]. The use of aspirin during therapy has been shown to increase the likelihood of grade 3 and 4 bleeding events, although no significant difference has been found between aspirin users in control and bevacizumab-treated groups [69]. Patients with a history of ATEs and older patients are at greater risk in developing a thromboembolic event when using VEGF inhibitors such as bevacizumab [69].
\nCardiotoxicity is also a common side effect of VEGF inhibition, and has been observed in patients on bevacizumab, sunitinib, and sorafenib. The exact mechanisms of this toxicity are often unclear, and they may either have to do with inhibition of VEGF, inhibition of other signaling pathways concomitantly with VEGF, or both. Cardiomyopathy has been observed in sunitinib monotherapy in a phase I/II trial in which 11% of all participants (8/75) had a cardiovascular event [71]. Another study found evidence that sunitinib induces cardiotoxocity through the inhibition of the AMPK signal transduction pathway [72]. Moreover, bevacizumab given after acute myelogenous leukemia chemotherapy resulted in an increase in cardiovascular toxicity, although the mechanisms for this toxicity remain unknown [73]. Sorafenib has also been demonstrated to cause cardiotoxicity in mice due to myocyte necrosis [74].
\nSome side effects are caused by the fact that VEGF impairment impairs wound healing on account of its antiangiogenic properties [65]. Gastrointestinal perforation has been known to occur in patients on anti-VEGF therapy. In the AVOREN trial, three patients receiving bevacizumab in combination with IFN-α experienced grade 4 gastrointestinal perforations, while one patient experienced grade 3 gastrointestinal perorations [66]. Sorafenib and sunitinib have also been shown to cause gastrointestinal perforations [65]. These perforations are caused by tumors, often metastatic, and the healing of these perforations is impaired because angiogenesis is itself prevented. Moreover, a significantly increased risk of hemorrhagic events of all grades is observed in patients on sorafenib, sunitinib, pazopanib, bevacizumab, and aflibercept [65, 75].
Although much progress has been made in angiogenesis inhibition therapy, research in the field is still ongoing. The following section reviews (i) how does tumor resistance against anti-VEGF mediation grow? (ii) what are the challenges in assessing biomarkers for the efficacy of antiangiogenic therapies in specific cases? and (iii) how can treatment methodologies and new treatments improve overall survival (OS)?
\nTumor resistance to antiangiogenic therapies can be classified into two broad categories: intrinsic and acquired [65, 77]. Acquired antiangiogenic resistance, in contrast to normal methods of acquired drug resistance in which mutational alteration of the drug target prevent the drug from working, consists of tumors initiating alternative methods to cope with hypoxia [77]. There are at least four distinct mechanisms through which this acquired resistance operates: (1) through the activation and upregulation of alternative proangiogenic pathways; (2) through the recruitment of bone marrow-derived proangiogenic cells including increased pericyte coverage of tumor vasculature; (3) through increased tumor aggressiveness resulting in metastasis to provide vasculature through widespread vessel cooption as opposed to tumor angiogenesis; and (4) through the adoption of alternative angiogenic mechanisms [77].
\nSeveral proangiogenic molecular pathways are upregulated when the VEGF/VEGFR pathway is inhibited. This often results in a return of tumor vascularization after a period of refractoriness [65, 78]. Some examples of alternative proangiogenic pathways include fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs), tumor necrosis factor-α (TNF-α), placenta growth factor (PlGF), angiogenin, stromal-derived factor 1α (SDF-1α), and interleukins-1α and -1β (IL-1α, IL-1β) [79–81]. Several of these molecules are regulated through HIF-1 expression, which in turn is controlled by hypoxia [79]. Therefore, through inducing the regression of tumor vasculature, anti-VEGF therapies can induce the expression of other proangiogenic pathways that reduce their own efficacy.
\nSeveral therapies are being developed that target both VEGF and alternative angiogenic pathways at the same time. For example, blockage of both VEGF and bFGF with brivanib resulted in prolonged tumor stasis following previous angiogenic inhibition in mouse neuroendocrine tumors [82]. Another study reported that inhibiting SDF-1α after irradiating mice with implanted human U251 GBM tumors prevented the revascularization of irradiated tumors more effectively than inhibiting VEGF, thereby suggesting that SDF-1α may be involved in acquired resistance to anti-VEGF therapies as well [81]. It has also been suggested that synergism between FGF-2 and PDGF-bb could induce angiogenesis, even if they are only present at low concentrations within the cytoplasm [79]. Taken together, these results suggest that inhibition of alternative angiogenic pathways in addition to inhibiting VEGF could increase the efficacy of antiangiogenic therapy.
Bone marrow–derived cells (BMDCs) such as pericytes and macrophages play important roles in both normal and pathological angiogenesis [1, 83, 84]. Tumor-associated macrophages (TAMs) are attracted to hypoxic regions of tumors through the upregulation of chemoattractants caused by hypoxia. Following extravasation into the tumor region, monocytes migrate into hypoxic areas of the tumor, following a chemoattractant gradient [85]. Monocyte chemoattractant protein-1 (MCP-1) has been shown to be an important chemoattractant in this process [86]. Once in the hypoxic region of the tumor, macrophages will promote tumor progression and metastasis through their trophic role (breaking down the ECM and encouraging tumor cell motility) and through excreting compound such as mutagenic oxygen, nitrogen radicals, and several proangiogenic factors such as VEGF and angiopoietin-2 [83, 87].
\nThe process through which pericytes contribute to cancer progression and metastasis is poorly understood. Normally, pericytes are associated with newly formed blood vessels, creating a single, often discontinuous, layer around the endothelial cell tube that serves to support a mature vessel. However, in tumor angiogenesis, pericyte coverage can be greater than, or less than normal tissue vasculature depending on the tumor type; for example, glioblastoma exhibits lower than normal pericytes coverage, while islet carcinomas exhibit higher than normal coverage. This aberrant pericyte coverage can result in tumor growth and metastasis [88]. Current pericytes-targeted cancer therapies aim to reach a balance between pro-and antiangiogenic factors, encouraging vascular normalization [89].
In most cancers, the appearance of a proinvasive phenotype following antiangiogenic therapy is in question; however, in glioblastoma it is relatively undisputed [78], and there is evidence suggesting its occurrence in pancreatic cancer [90]. The proinvasive phenotype allows tumors from these cancers to circumvent the need for a blood supply, obviating the necessity of tumor angiogenesis. The mechanisms underlying this increased tumor aggressiveness are not fully known. HIFs have been widely accepted as playing a role in increased tumor aggressiveness and metastasis [90]. Moreover, increased collagen signaling in the presence of VEGF inhibition, including activation of discoidin domain receptor 1, protein tyrosine kinase 2, and pseudopodium-enriched atypical kinase 1, has been shown to increase tumor progression and aggressiveness in murine models of pancreatic ductal adenocarcinoma [91]. In glioblastoma, VEGF inhibition creates hypoxic conditions in the tumor, which in turn causes increased expression of c-Met, an HGF receptor tyrosine kinase, through HIF-1α; this increase in c-Met expression correlates with increased invasion and poorer survival [80]. When both VEGF and c-Met are blocked, the increased tumor invasiveness and aggressiveness associated with anti-VEGF medications is suppressed in murine GBM and PNET, suggesting new routes for research in antiangiogenic therapies [80, 92].
Another method through which tumors can circumvent angiogenic inhibition is though alternative angiogenic mechanisms such as intussusceptive angiogenesis, glomeruloid angiogenesis, vasculogenic mimicry, looping angiogenesis, and vessel cooption [78, 83]. These forms of angiogenesis occur through other signaling pathways that do not involve VEGF, and are upregulated when VEGF signaling is inhibited. One such alternative angiogenic pathway is vasculogenic mimicry (VM), which may be encouraged when anti-VEGF medications provide selective pressure for stem-like cancer cells that participate in the process. This phenomenon highlights the need for novel therapeutic methods that target the signaling pathways that control VM in addition to VEGF [93]. Similar combination therapies could be used to increase the efficacy of antiangiogenic medication in general by restricting the tumor’s ability to acquire resistance to antiangiogenic therapies.
Unfortunately, no validated biomarkers are currently available for determining which patients will respond best to antiangiogenic therapy [93, 94]. An array of biomarkers has been studied in hope to find effective biomarkers, including systemic measurements, gene analysis, circulating biomarkers, tissue markers, and imaging parameters [95]. Various challenges stand in the way of establishing effective biomarkers, such as the inability to perform repeated biopsies (inhibiting researchers’ ability to assess dynamic biomarkers), the unpredictability of response and toxicity, the expensive and complex nature of human trials, the unpredictability of toxicity and response to therapies, and the specificity of each biomarker to disease [95].
\nThe degree of hypertension experienced by a patient has been proposed as a potential systemic biomarker of tumor response, although more research is needed to establish the validity of this measurement [95, 96, 97]. Because hypertension is dependent on the VEGF-signaling pathway, it is possible that patients who do not develop hypertension are not responding to VEGF treatment at the current dose. In fact, the degree of hypertension correlates with survival, with patients who develop more severe hypertension experiencing better cancer remission than patients who develop no hypertension [97]. Interestingly, VEGF polymorphisms may play a role in determining the degree of hypertension, of anti-VEGF medications, which certain polymorphisms being more susceptible to inhibition than others. For example, VEGF-634 SNP (single nucleotide polymorphism) G/G is correlated with higher hypertension in suninitib-treated patients with mRCC than either VEGF-634 C/G or VEGF-634 C/C [98].
\nSeveral circulating biomarkers have been proposed that circulate in the bloodstream of patients. For example, high levels of soluble VEGF-R1 (sVEGFR1) correlate with decreased efficacy of bevacizumab in GBM, rectal carcinoma, breast cancer, hepatocellular carcinoma, and metastatic colorectal carcinoma. This correlation is probably caused by sVEGFR1 acting as an endogenous VEGF-trap, so adding a VEGF-specific monoclonal antibody does little to further inhibit VEGF signaling pathways [94]. Another potential circulating biomarker is SDF1α, as levels of this chemokine correlate with evasion of anti-VEGF therapies, although further study is needed to assess this potential biomarker [94]. Pretreatment levels of circulating VEGF-A has been shown to be prognostic in metastatic colorectal, lung, and renal cell cancers, but it is not predictive for bevacizumab treatment [99]. Moreover, a phase II study presented evidence that plasma concentrations of VEGF-A and IL-8 are prognostic for OS in MRCC, with high levels being unfavorable, while low plasma levels or sVEGFR-3 are may be predictive for a positive outcome in patients with mRCC receiving sunitinib [100]. Another phase II trial found that serum levels of Ang-2 and MMP-2, along with tumor levels of HIF-1α, are potential baseline efficacy biomarkers for sunitinib in advanced RCC [101]. Finally, low circulating endothelial cell levels (<65 CEC/4 mL blood) have been found to correlate with longer median PFS and OS in patients with colorectal cancer receiving bevacizumab [102].
\nImaging techniques provide potential of imaging parameters as biomarkers as well. For example, MRI- and CT-based tissue vascular measured such as blood flow, blood volume, and permeability have been shown to occur after bevacizumab administration, although more research is needed to assess the efficacy of these measures as biomarkers [95]. Moreover, pretreatment ADC histogram analysis has been shown to be a possible predictive biomarker for bevacizumab treatment in recurrent glioblastoma [103]. Imaging studies can also be used to augment other biomarker studies, and can be used in cooperation with systems pharmacology to create multilevel computational models that predict the efficacy of treatment in patients, as well as suggesting dosing schedules that could be more efficacious than current practices [104]. Another potential biomarker could be patient genotype. As discussed above, some VEGF SNPs may be more receptive to treatment than others. However, some genes show little or no correlation with the efficacy of antiangiogenic therapies. For example, the mutation status of KRAS, a common oncogene, does not correlate with VEGF therapy efficacy [105]. More research must be done to establish which genes can and cannot be considered biomarkers.
According to the normalization hypothesis, during the course of antiangiogenic therapy, there is a dose-dependent window of time during which aberrant tumor vasculature is normalized. In this state, it is easier to deliver cytotoxic drugs from conventional chemotherapy to the tumor in a treatment schedule that takes advantage of the window presented by antiangiogenic agents given in low doses [106]. However, there are two important considerations to take into account when scheduling chemotherapy with antiangiogenic agents: first, the dose of antiangiogenic agents affects the normalization window during which chemotherapy can be delivered effectively. Second, the size of the chemotherapeutic agents matters, as vascular normalization causes the pores in aberrant tumor vessels to shrink, limiting the ability of large molecules to pass through to the tumor [94]. Vascular normalization has also been shown to improve the outcome of immunotherapy, making delivery of immune cells to the tumor easier, and can even decrease the intravasation of cancer cells, limiting the possibility of metastasis [94].
\nMost of the time, resistance to chemotherapy occurs through heritable changes in the tumor genotype. However, because resistance to VEGF inhibitors does not occur through natural selection, as discussed above, it is possible that rechallenging after disease progression following an intervening interval of time during which VEGF therapy is suspended may allow for a return of efficacy in antiangiogenic VEGF inhibitors. For example, patients with metastatic renal cell carcinoma (mRCC) who experience disease progression after initial response to sunitinib can eventually respond to the drug upon rechallenge after an intervening period on alternative therapies, such as sorafenib (patients with more than 6 months off sunitinib experienced greater PFS than patients with less than 6 months off sunitinib, although in each case the second PFS was shorter than the original) [99]. Moreover, in a randomized phase III trial, patients with unresectable metastatic colorectal cancer progressing up to 3 months after discontinuing bevacizumab plus chemotherapy experienced moderate survival benefits when bevacizumab plus chemotherapy was given as a second line treatment as compared to chemotherapy alone [107].
\nMore research must be done to assess the efficacy of antiangiogenic agents in the adjuvant and neoadjuvant settings. In the neoadjuvant setting, VEGF inhibition may cause tumor regression, converting an unresectable tumor to a resectable one [82], with 12 of 30 patients in one single-arm phase II study who received oxaliplatin plus bevacizumab having initial nonsynchronous unresectable CLM become resectable [108]. However, antiangiogenic neoadjuvant treatment in mouse models of metastatic disease has been shown not to correlate with postsurgical survival [109]. In the adjuvant setting, it is possible that antiangiogenic therapies may prevent relapse by preventing the reestablishment of tumor vasculature. However, bevacizumab has delivered poor results in OS when used in combination with chemotherapy for adjuvant colorectal cancer, although PFS is improved [78].
\nSome work is also being put into developing novel VEGF and VEGFR inhibitors. For example, ramucirumab, a monoclonal antibody that inhibits VEGFR-2, was given FDA approval in 2014 for use as a single agent in the treatment of patients with gastroesophageal carcinoma; it has since been given approval for use in combination with paclitaxel, docetaxel, and FOLFIRI [110]. Ramucirumab is the first biological treatment to show moderate survival benefits as a single agent after gatroesophageal adenocarcinoma progression following first-line chemotherapy in a phase 3 trial (ramucirumab vs. placebo, OS = 5.2 months vs. 3.8 months, respectively) [111]. The drug has also shown moderate OS benefits when used in combination with docetaxel for second-line treatment of stage IV NNSCLS compared with docetaxel alone after progression on platinum-based chemotherapy (10.5 months vs. 9.1 months, ramucirumab plus docetaxel vs. docetaxel alone, respectively) [112]. Apatinib is another novel VEGFR-2 inhibitor, a small molecule not yet given FDA approval (although it is approved for use in China in treating metastatic gastric or gastroesophageal adenocarcinoma after second-line chemotherapy) [113]. The drug thus far has shown only moderate survival benefits of 1.8 months, and several trials are ongoing to assess its efficacy in different settings [114].
\nYet another new small molecule VEGF inhibitor, cabozantinib (Cabometyx, Exelixis, Inc.) was given FDA approval on 25 April, 2016, for the treatment of renal cell carcinoma in patients who have received prior antiangiogenic therapy. Approval was given based on improved progression-free survival (7.4 months vs. 3.8 months in the cabozantinib and everolimus arms, respectively), improved overall survival (21.4 months vs. 16.5 months) and improved confirmed response rate (17 vs. 3%). The drug exhibits the standard side effects associated with VEGF inhibition; 40% of patients who received cabozantinib experienced a serious adverse event such as abdominal pain, pleural effusion, diarrhea, and nausea [115].
\nAnother potential target for anticancer therapy has also been found in lymphangiogenesis. Several studies are examining the potential of inhibiting the VEGFR-3/VEGF-C/VEGF-D signaling axis in preventing lymph-node-mediated metastasis and disease progression. Inhibition of VEGF-C/-D with soluble VEGFR-3 has been shown to reduce tumor metastasis in mouse models, as has blocking VEGF-C/-D proteolysis or blocking VEGF-C from binding with the Nrp-2 receptor [116]. Moreover, foretinib, a multiple kinase inhibitor currently undergoing clinical trials, has shown promise in inhibiting the activity of VEGFR-3 and lymphangiogenesis and could potentially be used to inhibit lymph-node-mediated metastasis [117]. Corosolic acid has also been shown to induce apoptosis in CT-26 colon carcinoma in a mouse model, in addition to inhibiting lymphangiogenesis, but more study is needed before this substance becomes useable as a cancer therapy [118].
\nPlGF inhibition is another potential novel therapeutic approach in the fight against cancer, and preclinical studies have shown that inhibiting PlGF using genetic inhibition or anti-PlGF antibodies slows tumor growth and metastasis, and can even induce tumor regression in preexisting medulloblastoma [119]. However, the efficacy of inhibiting PlGF in tumors has come under question, with some preclinical studies showing that inhibiting PlGF does not significantly inhibit tumor grows [120, 121]. More research is needed to assess whether PlGF inhibition could be an efficacious cancer therapy.
Ever since its discovery, VEGF has been at the center of attention in new and developing cancer therapies. Since its early successes, however, antiangiogenic therapy has often presented only modest improvements in overall survival and progression-free survival [122]. Researchers have not given up hope that this therapeutic technique contains promise in the arsenal against cancer. Therefore, much recent research has been done in pushing the frontier of antiangiogenic therapies, trying to improve patient outcome.
\nBecause the biology of VEGF and its receptors is well understood, current research focuses on why some tumors become resistant to antiangiogenic therapies and others are intrinsically resistant, how to circumvent this intrinsic or acquired resistance, and how to best utilize these expensive therapies by developing predictive biomarkers for treatment outcome. More research is also being done to develop novel VEGF inhibition techniques, and in characterizing the rare yet serious toxicities associated with these drugs.
\nAs they stand now, antiangiogenic therapies face a set of limitations that severally impacts their efficacy. Tumors can acquire resistance to the drugs (if they do not already have intrinsic resistance) and demonstrate an increase in aggressiveness. Moreover, antiangiogenic therapies may cause a decrease in chemotherapy perfusion, lowering the efficacy of chemotherapies given in combination with antiangiogenic medicine [123]. These difficulties suggest that, at least when given alone, antiangiogenic therapies may face severe limitations in survival benefits. Therefore, future research should focus on more than simply inhibiting VEGF on a continuous schedule. Rather, it should focus on increasing the efficacy of chemotherapy through utilizing antiangiogenic therapy to induce vascular normalization, allowing for more efficient delivery of chemotherapeutic agents [123, 124]. Moreover, research should also find ways to decrease resistance to these therapies through inhibiting proangiogenic factors that are upregulated in response to the inhibition of VEGF and through developing predictive biomarkers for the efficacy of these expensive treatments [123, 124].
The Ministry of Education and Culture through the Directorate General of Secondary Education and the Directorate General of Higher Education have implemented entrepreneurship education as a study are to examine of fostering a creative, innovative, competitive spirit as well as entrepreneurial spirit in edges as an elaboration of the development of the Creative Economy (Presidential Decree No. 6 of 2009). In particular, the aim of providing this content, among others, is to provide skills in the form of basic skills related to the freedom of graduates to be able to work independently. It is suggested that students will be able to apply entrepreneurship theory to work experience in this learning process. Besides, the expected education imposes further emphasis on the mastery of certain fields of work which are essentially carried out in academic units. Its essence, entrepreneurship education in its vocational schools has been carried out by “development units” in various fields of study/expertise programs. Even so, the viability of real entrepreneurship research in vocational schools also varies greatly in terms of success. The number of entrepreneurs in a country could be seen as a reflection about whether or not a country is developing, since by getting more entrepreneurs in that country entirely, there would be many independent businesses in the form of large corporate entities and small and medium-sized businesses. This would have an impact on the increase and wide opening of the number of jobs, which in turn raises the level of the country’s economy. It has not happened in our beloved country of Indonesia. Indonesia’s mental entrepreneurship is still weak. That is demonstrated by a limited number of entrepreneurs with independent companies. There are still a lot of people who are still uncertain about getting a job every year. Government Regulation No 29 of 1990, Article 3(2), in the context of the vocational schools’ goals, must therefore include:
Join the job market and be able to cultivate a professional mindset within the framework of company and management skills.
Able to include career, be able to compete, and be able to establish within the scope of business and management.
Become a middle-level workforce to meet the present and future needs of the corporate sector and industry in terms of market share and management.
Be active, resilient, and innovative people.
As a result, vocational school graduates are actively trained to reach the field of employment either by career ladders to become middle-level employees or to become single, self-employed, or entrepreneurial. First, this paper will outline the goals and growth of Indonesia’s Vocational High School, relevant government policies. Secondly, the implementation of entrepreneurship education through apprenticeship programs, the implementation of apprenticeship programs, and assessment.
\nThe level of education is the stage of education defined based on the level of student progress, the goals to be accomplished and the skills to be developed. Formal education in Indonesia covers primary education, secondary and higher education. Each level has a specific age range and period of education. Indonesia has completed 12 years of compulsory education. Twenty years of compulsory education must, therefore, be the standard of primary education consisting of 6 years of primary school or equivalent and 3 years of junior high school or equivalent. For now, though, the upper secondary school is taken up to 3 years and is generally conducted up to 4 years for higher education (S1) (Figure 1).
\nFormal education level in Indonesia (source: [4]).
Primary education is the basic curriculum to be pursued during the first nine years of school and consists of a six-year primary school education system and a three-year junior secondary school educational program. Primary education takes the form of elementary school (SD) and junior high school (SMP). Primary education is the beginning of children’s education, as it teaches children to read properly, develop their math and reasoning skills. Primary literacy aims to lay the foundations for intelligence, knowledge, maturity, good character, and capacity to live independently and pursue further education. To attempt to achieve primary education goals, a teacher’s position to the learning process is required to ensure that students have consistency between cognitive, emotional, and psychomotor skills.
\nSecondary education is an extension of primary education. This form of secondary education is a secondary school (SMA), madrasah aliyah (MA), vocational school (SMK), and vocational madrasah aliyah (MAK) or other similar types. The general aim of secondary education is to improve comprehension, knowledge, personality, moral strength, and the ability to live independently and engage in further education. While the general aim of vocational secondary education is to improve intellect, knowledge, personality, moral strength, and ability to live independently and pursue further education in compliance with their vocational training.
\nHigher education is an extension of secondary school education. Higher education is no longer carried in schools but universities. Including a variety of diplomas, bachelor, master, doctoral and specialized programs organized by universities. Higher education institutions are required to provide education, research, and community services. At this level, students are required to be more active in practicing/directly involved in each learning activity, because the ultimate goal of this level of education is that students are expected to be human beings who are useful to others. Higher education institutions may organize academic, vocational programs.
\nEntrepreneurship is ultimately a creative and imaginative way of thinking that is used as a framework, tools, and driving force, goals and strategies, and tips to deal with the challenges of life. According to Agus Wibowo’s statement, entrepreneurship is the ability to merge existing expertise, innovation, and opportunities. Entrepreneurs are people who know how to take risks, are imaginative, inventive, never give up, and are willing to cope with opportunities properly [1]. Entrepreneurship is a mindset, a spirit, and a capacity to build something new that is very important and useful, both for oneself and for others [1, 2]. Entrepreneurship is a mental attitude and a soul that is often active or productive, motivated, innovative, creative, humble, and seeks to increase income for its company. While entrepreneurs are people who are willing to take advantage of opportunities to grow their businesses, intending to improve their lives.
\nEntrepreneurship is a creative and imaginative ability that is used as a framework, tips, and tools to find growth opportunities [3]. Creative and creative processes typically begin with the creation of ideas and concepts to create something new and special. Creativity is the ability to develop new ideas and ways of solving problems and finding opportunities (thinking new things). Innovation is the desire to apply ingenuity to solve problems and discover ways (to do new things). Emigawaty added that the cycle of entrepreneurship is beginning with challenges [3]. Ideas, motivation, and ability to take the initiative, which is nothing but fresh thinking and constructive action, should arise from the challenges.
\nVocational education is education that incorporates, matches, and teaches people to have working habits to be able to join and expand the world of work (industry) so that they can be used to better their lives. National Education System Law (UUSPN) No. 20 of 2003 Article 15 states that vocational education is secondary education which prepares students, in particular, to work in certain fields [4]. Vocational education is associated with grooming an individual for employment and enhancing the development of a future workforce. This involves different forms of schooling, training, or further development to prepare someone to join or continue working in a legal role. Vocational education is certainly part of the national education program, which intends to train workers who have skills and expertise following the requirements of job requirements and who are able to strengthen their capacity by embracing and adapting to technological developments.
\nVocational education is part of the national education program, structured as a continuation of the Junior Secondary School and Madrasah Tsanawiyah:
In line with the skills, interests, and abilities to meet the needs/job opportunities that are and will be created in the community.
Vocational school graduates are trained, educated, and trained workers.
Able to engage in further education and/or respond to technological changes.
Impact as a promoter of (small or large) industrial development.
Significant decrease in unemployment and crime rates.
Economic growth and national income by income tax and value-added.
UUSPN No. 20 of 2003 Article 15 states that vocational education aims, in particular, to prepare students to work in plenty of other fields. This goal can be further transferred as follows by [4] into general objectives and precise objectives:
\nGeneral Aims
\nAs part of the vocational education system, the goals of Vocational Schools are:
Preparing students to succeed in a decent life.
Improve the students’ faith and modesty;
Preparing students to become independent and accountable individuals;
Prepare students to appreciate and acknowledge the rich cultural heritage of the people of Indonesia, and
Prepare students for a healthy lifestyle, environmental insight, knowledge, and art.
Specific Aims
\nVocational schools are especially purposeful:
Prepare students to be able to work independently or to fill established positions in the business community and industry as middle-level employees, in keeping with the fields and knowledge system of their preference;
Equip students to be able to choose professions, to be versatile and to remain competitive and to be able to construct professional attitudes in areas of expertise or interest, and
Equip students with science and technology to be able to enhance themselves through higher education.
In contrast, according to the Directorate of Secondary and Vocational Education (Dikmenjur) in 2006, the SMK learning system adheres to the concept of full learning (Mastery Learning) in addition to being able to master behaviors, information, and skills to be able to function following their career. As required by competence. In addition to being able to research extensively, it is necessary to develop the overall evaluation principles:
Learning by doing (learning by actual activities or activities that provide meaningful learning experiences) is transformed into production-based learning.
Objectives of Vocational Education and Entrepreneurship Education Implications Government Regulation No 19 of 2005 on National Education Standards (SNP) Section 25 paragraph 4 implicitly notes that graduates (SMKs) are required to meet graduate-level competency requirements representing the ability of graduates to act, know-how and skills. Therefore, the learning process in educational units is carried out in an active, interactive, creative, challenging, fun, and independent manner according to self-potential, physical development, talents, and interests, as well as students’ psychology. Individualized learning (learning with emphasis on the uniqueness of each individual) with a modular program. Empirical statistics show that most vocational school graduates are not yet following customer expectations or requirements of stakeholders.
Graduates tend to be “job hunters” and not many are able to work “independently” to incorporate and improve their skills (survival skills). On the other hand, the work ethic of vocational school graduates is still weak in terms of entrepreneurial thought. In accordance with Law No. 20 of 2003 on the National Education System, secondary education consists of general secondary education and vocational secondary education (Article 18, paragraph 2). Senior High School is a general education unit, while Specialized School is a specialized secondary education unit. The objective of the introduction of high school is to provide academic competence for students to pursue their higher education, while at the same time, vocational schools emphasize more on preparing students to be ready to work under certain fields. The introduction of the SMK also offers incentives for students who have the qualifications and skills to pursue professional, professional, and academic education (dual purpose).
\nThe terms of vocational education and technology are currently being established, there are a stigma and a tendency to define vocational education and technology as an institution that seeks to prepare the workforce in accordance with the interests of students. However, there are quite many limitations related to vocational education and technology in its advancement, namely, among other things, the differing viewpoints of professionals, such as the following.
\nIn the 1920s, Barlow [5] stated that vocational education was a means for someone to prepare and prepare for the services we need. These restrictions are very specific since the word “services” has very different definitions. Struck [5] provides another perspective on vocational education and technology, which leads to the provision of experience to students to be able to carry out work in the field. It seems that this restriction is still very common, as it does not specifically reflect the form and quality of education, both within and outside the classroom.
\nOne form of technical and technological education, namely vocational high school technology. The educational goal is to produce students who comply with the intermediate level work requirements as interpreters or technicians in compliance with other forms of vocational training. Therefore, the management of the learning cycle is more oriented towards the incorporation of vocational skills theory and practice, which refers to the intermediate level of work requirements required by the industrial environment. The presence of an imbalance between what is created by educational institutions and the needs of the labor market is a serious concern of the Directorate for Vocational High School Growth. This seriousness is expressed in the 100-day flagship program of the “Indonesia Bersatu” Cabinet Volume II. Processes, strategies, and action plans should be developed to resolve this mismatch in the 100-day program, in particular the education program.
\nIn order to improve the quality of vocational school graduates, the Ministry of Education and Culture will increase industrial simulations for each vocational school. The purpose of the industrial simulation is to provide vocational students with knowledge of the working culture, the real conditions in the industry, and the mastery of technology. The creation of a cooperation model will also be carried out as a policy action plan. The relationship will be formed between vocational school, vocational higher education, and skills training with the industrial environment, including the creative sector.
\nThis is achieved in order to improve the prospects for intermediation and apprenticeship as well as the suitability of education or training for the world of work [5]. On the other hand, the competitiveness of education can be accomplished through the growth of entrepreneurship, including technology entrepreneurs (IT entrepreneurs) through collaboration between educational institutions and the business world. By the numerous measures outlined above, it is hoped that the connection between education and jobs required by the labor market can be developed and that the unemployment rate will be reduced to the lowest level.
\nThe idea of connection and match has essentially been implemented since the 1994s, when five PSG model schools (Jakarta, Karawang, Semarang, Surabaya, and Medan) were set up, supported by the German Technical Zuzamenarbeit (GTZ). Nevertheless, in its growth, ups and downs are induced, among other things, by the lack of a consistent partnership pattern that can lead to mutually beneficial relationships (mutual benefits). The concept of establishing a mutually beneficial relationship was initially designed to provide tax relief for manufacturing communities that have collaborated intensively with vocational schools and can report on the outcomes. It takes time and a clear political will from the Government in the process of understanding the notion. In addition to applying the principle of linkage and equivalence (link and match), the structuring of study programs or skill programs (re-engineering) is an evolution of existing fields and skill programs in all vocational schools (public and private) to meet the geographic capacity and the requirements of the job market.
\nThe outcomes of the re-engineering structuring would benefit: (1) vocational school, because the field of expertise program designed is in line with the needs of the future of employment; (2) prospective students and parents, so they can select a field of expertise program that facilitates integration in the future of employment; (3) business and industry, as it makes it easier to find employees who suit them. The structuring of the vocational education framework approach would eventually lead to the introduction of a CBT (Curriculum Based Training) that complies with the concepts of a competency-oriented curriculum that is now being developed into a unit level curriculum (KTSP). Competence-based education and training offer, ultimately, individual learning programs.
\nThe introduction of vocational schools will, therefore, be successful and productive where: (1) provision of appropriate teaching materials/modules in terms of number, form, and quality; (2) provision of sufficient learning time in accordance with each student’s learning pace and ability; (3) provision of learning facilities that allow classical learning in schools and industrial practices outside of school.
\nThere are educational courses in entrepreneurship in technical schools that students will take. Entrepreneurship training courses are conducted in Class X to Class XII. The competencies offered are different for each class. Class X competencies include: (1) recognizing entrepreneurial attitudes and behaviors; (2) adopting attitudes and job habits (always trying to move forward); (3) formulating problem solutions; (4) cultivating entrepreneurial spirit; (5) creating loyalty to oneself and others; (6) taking business risks; (7) making decisions. Whereas in the same semester the competencies given include: (1) displaying an unyielding and resilient attitude; (2) handling conflicts; (3) developing a business vision and task.
\nFor reality, entrepreneurship training courses are structured into adaptive training courses. Adaptive education and subject training is a training and subject training community that acts to educate students as individuals so that they have a broad and strong knowledge base to adopt or adapt to changes in the social climate, the economic environment and to be able to learn based on the advancement of science, technology, and art. Adaptive programs provide training courses that emphasize majorly on offering opportunities for students to learn and master the fundamental concepts and principles of science and technology that can be applied to daily life or underpin work skills. Adaptive approaches ensure that students not only understand and learn “what” and “how” a job is done, but also provide comprehension and mastery of “why” a job needs to be done.
\nVocational School is one of the national education systems which strives to equip students with skills or expertise through the Dual System Education (PSG) program or whatever is often referred to as an internship. Vocational schools are introducing Technical and Vocational Education Training (TVET) in Indonesia. According to Putu Sudira [6], TVET also brings schools closer to the business environment and the industrial sector. PSG aims to sync the business community and the field of education. Vocational school in legislation No. 20 of 2003 on the National Education Framework Article 18, paragraphs 2 and 3. Vocational in secondary school is organizes vocational education that gives legitimacy to student preparation to join the workforce and establishes professional attitudes (Article 1 paragraph 2 of the Decree of the Minister of Education and Culture of the Republic of Indonesia No 323/U/1997 on the introduction of the Dual System of Education at vocational school.
\nVocational schools seek to develop students’ knowledge and skills in such a way that they are ready and willing to work based on their expertise in their respective fields following graduation from secondary education. The competence of vocational school graduates will be expressed in the form of achievement as real or unidentified activities, including (a) both a strong character and a weak character. (b) The development of knowledge mastery, which is characterized by a process of knowledge that is capable of processing information (a process of understanding, know-how, and know-how). (c) Professional development (tool capacity development) characterized by adherence to protocols, punctuality, resistance to fatigue, precision, and thoroughness. (d) The creation of critical thought process skills is characterized by developing new concepts, looking at problems in new ways, and preparing for strategic problem-solving. Based on the outline of the vocational school teaching program (1993: 11A), priority is given to the adoption of the vocational school curriculum: (a) Prepare students to enter the workforce and build professional attitudes. (b) Preparing students to be able to have a career, succeed, and grow to a better standard of living. (c) Preparing a middle-level workforce to meet the present and future needs of the corporate sector and industry. (d) Prepare for graduation so that they are active people who are ready to create, adapt, and be innovative.
\nThe internship is an absolute prerequisite for the introduction of technical education. This is the primary reason for the introduction of internships in most technical education institutions. Training may also provide tangible benefits for vocational education and training programs, such as meeting the criteria of accreditation and attempts to develop the credibility of a school. Recognition of the need to expose students to the world of industry is the biggest motivation for vocational education institutions to coordinate internship programs [8, 9]. In the meantime, for industry, there are many explanations for promoting collaboration through apprenticeship programs, including (a) Public care (b) 2.2. The interpersonal connection between industry and vocational education institutions, for example, business players, is alumni of the school concerned. (c) And get a workforce that suits your needs. According to the rules, the minimum length of the internship is three months, but in certain places, the optimal maturity is six months to one year. In summary, the apprenticeship program will be carried out in the following stages (Figure 2).
\nInternship adoption batch (source: [7]:p. 17).
The prerequisites for the completion of the internship [7] include: (a) the department at school must be in keeping with the area of jobs in industrial apprenticeship location. (b) Schools must ensure that the definition of internships to be introduced complies with Regulation. (c) Schools must set industry standards for the location of apprenticeships. Evaluation practices must be seen as part of the growth of all businesses, schools, and students. In particular, internships are also supposed to be a feedback platform. Therefore, evaluations should be carried out regularly, not only at the end of the industrial working cycle, but even once a month, for example. Bon and Eschborn [7] listed a variety of items that were evaluated, including the achievement of the internship participants is consistent with the objectives set for the internship. (a) Creation of technical competence. (b) Creation of non-technical competencies (soft skills and attitudes) focused, in particular, on the goals of competence. (c) Quality according to job requirements and client commitment. (d) Another capacity of the participants. According to Duc in Billet [10], “The contribution of the student is linked to the various ways in which internship guidance can be given or not depending on the context in which they are trained.” In our study of vocational education in the Swiss VET dual program, observations find workplaces where spontaneous types of instruction are much more common than others, or where vocational trainers respond easily and enthusiastically to assist requests. Conversely, we often identified firms where contested modes of instruction were the prevailing pattern of interaction and staff fought for knowledge and became a valid teacher. In particular, the requirements given to students can differ from one background to another [11]. This degree of high contextual variability is an essential challenge for practice-based learning models, as it greatly undermines overall performance. The introduction of the PSG is carried out in phases at SMK, to ensure the quality and efficacy of coaching, as well as allow the process of improving the PSG to take place. In other words, the adoption of this initial stage is a trial that is often accompanied by constant evaluation and review, and, in effect, it is expected that the principle and application of the PSG, which is legitimately solid and in line with the school, will be formulated. The distribution of the adoption of the PSG in schools will be decided by the readiness of the vocational school concerned, in particular, the readiness to develop cooperative ties with industry or companies to become partner institutions.
\nThe internship is part of a vocational curriculum that aims to prepare students’ skills or abilities in a specific field in order to be able to work. Through the apprenticeship training course, students are prepared to face the true world of life, both through the mindset, the job is done, and the actual working environment. It is expected that the graduates of this apprenticeship program will be better qualified mentally and in their abilities to succeed in the real work environment.
\nVia internships, students are required (1) to experience the working climate in the world of work directly, (2) to acquire work experience, including expertise, skills, work attitudes and character-based values that emerge from industrial culture, (3) to know the real working environment in the world of work, (4) to know the working processes of the business (products, labor, discipline, values of work), (5) contrasting the knowledge and skills acquired at school with the knowledge and skills acquired during the internship in industry, (6) acquiring the most recent knowledge from the internship, (7) applying the principles of attitudes and character, knowledge and skills acquired at the internship, and (8) getting stronger soft skills in terms of motivation, communication, freedom.
\nThe introduction of the internship has similar features to the apprenticeship program as provided for in Regulation No 36 of 2016 of the Minister of Labor of the Republic of Indonesia on the implementation of the Domestic Apprenticeship, which states that the apprenticeship is stipulated as part of the vocational training system that is carried out in an integrated manner between the training. Directly under the direction and supervision of teachers or staff who are more knowledgeable in the manufacturing process of products and/or services within the business, intending to acquire those skills or expertise.
\nAs an Open Access publisher, IntechOpen is dedicated to maintaining the highest ethical standards and principles in publishing. In addition, IntechOpen promotes the highest standards of integrity and ethical behavior in scientific research and peer-review. To maintain these principles IntechOpen has developed basic guidelines to facilitate the avoidance of Conflicts of Interest.
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\\n\\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
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\\n\\nEXAMPLES OF CONFLICTS OF INTEREST:
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\\n\\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\\n\\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
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\\n\\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\\n\\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\\n\\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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