Malignant Pleural Mesothelioma: from the laboratory bench to the bedside
Introduction
Malignant pleural mesothelioma (MPM) is a rare tumor with an incidence in growth, characterized by a high aggressiveness that often leads to a poor prognosis. Currently has not yet been clearly defined the perfect therapeutic management of this disease, since there is still no effective treatment unquestioned. However, there are practical guidelines that have been proposed by several scientific societies and that are applied in the common clinical practice. These guidelines have emphasized the difficulty diagnosing MPM and showed the poor results of current treatments, thus emphasizing the need for innovative therapies and techniques for monitoring of patients suffering from this disease.Although the prognosis of MPM is often fatal and prospects prove pessimistic, recent studies on the pathogenesis and biology of this disease have highlighted some interesting discoveries, which encourage a promising future progress, significant for the treatment of these patients. The translational research regarding this disease is progressing very different and oncogenic molecular pathways related to the growth and progression of MPM were characterized and better defined, leading to interesting developments pharmaceuticals. However, further studies are needed most in-depth, to define in more detail the processes ranging from early increase in proliferation of mesothelial until progression in mesoteliloma invasive. All this information will contribute to the definition of an effective therapy and more personalized for patients suffering from this cancer.The objective of this literature review of the scientific literature, therefore, is to provide an overview on recent advances in understanding the biology of MPM and their potential diagnostic and therapeutic applications.
You will have preferred a little language-specific text to make this easy dissemination and accessible to a diverse audience. Therefore, stakeholders and experts refer to the section on references, which can be useful for all readers who want to explore in more detail the studies analyzed in this review.
New therapeutic approaches
The role of surgery and radiotherapy in the treatment of MPM remains controversial, and further studies will be necessary to make any further information in this regard.
Medical therapy, however, is considered the standard of care of the common clinical practice and, in particular, the combination chemotherapy based on platinum compounds in association with certain antimetabolites (pemetrexed / raltitrexed) was considered the optimal therapy for the first-line patients with MPM (1.2). However, the results obtained are limited particularly in terms of survival.
The main objective is to increase knowledge about the pathogenesis of MPM, to define and improve therapies and target new therapeutic agents, which are currently under study. This review of the literature aims to show the main therapeutic approaches currently tested in preclinical and clinical studies.
The epidermal growth factor receptor
The receptor of the epithelial growth factor receptor (EGFR) plays a role in proliferation, differentiation, migration, in 'adhesion and cell survival (3) and is sovraerespresso in more than 50% of patients with MPM (4). The expression of this receptor at the level of mesothelioma cells has led to the hypothesis of a therapy against the target EGRF to try to inhibit it and prevent its activity uncontrolled and often deleterious. For this reason, several studies have evaluated the efficacy of drugs such as EGFR inhibitors gefitimib or erlotinib in patients who had never been treated with chemotherapy. These investigations have shown that these drugs, administered in monotherapy and therefore not associated with any standard chemotherapy, are not very effective as first line treatment in MPM (5, 6, 7). However, although there is an important expression of the EGF receptor in mesothelioma, the explanation for the lack of efficacy of EGFR inhibitors may be linked to the rarity of mutations in this same receptor (8).
There are conflicting studies regarding the correlation between the overexpression of EGFR in the mesothelial cells and the response to treatment with inhibitors of this receptor. Some research groups have shown that there is no relationship between the overexpression of EGFR and the clinical outcome ("outcome") of the patients with MPM (9,10), while others, demonstrate that patients with an increased expression of receptor may have a better outcome (11-14). The discrepancy of the results confirms the need for further research to better define these results. In any case, it has been shown that overexpression of EGFR in the MPM is more common in epithelial histological subtype, which is associated with a better survival of the patient, but is not an independent prognostic marker (13,14).
Recent results have indicated the presence of an important network of communication between the way of the EGFR and other cellular signaling pathways. For example, some proteins such as PI3K and AKT that play a role in the signaling pathway of EGFR, also act in other pathways of cell growth and interact with other factors such as c-Met and IGF-1 (15,17). It 'been documented histologically overexpression of c-MET protein in MPM and also in some samples of normal pleura.According to this rationale, were tested inhibitors of c-MET in mesothelioma cell lines, the first results showed dose-dependent inhibition of tumor growth (18).
Dose-dependent inhibition of this type has also been noted in cell lines of MPM subjected to IGF-receptor inhibitors (19). In addition, it was also shown an increase of the cytotoxic effects of cisplatin when administered in combination with these inhibitors (20). An important biological communication is also present between EGFR cyclooxygenase-2 (COX-2) (21).
The COX2 is overexpressed in many solid tumors and, for this reason, is considered as a potential therapeutic target (22-24). In MPM, Research immunohistochemistry of this protein has demonstrated its overexpression in a 59-100% of the tumor samples analyzed (25-27).Furthermore, it was demonstrated that treatment of mesothelioma cell lines with inhibitors of COX2 involve a cytotoxicity than an enhancement of the effect of pemetrexed (28-29).
K-ras, and BRAF mutations PI3KCA
In the search for therapeutic targets, the researchers analyzed the possible presence of genetic mutations associated with cancer pathogenesis. For this reason, it has been sought gene mutations in the K-ras, and BRAF PI3KA.
Unfortunately, the early studies did not reveal the presence of genetic alterations in charge of K-ras (30-32) and thus have reduced their expectations regarding a possible target therapy against this protein.
They were also analyzing mutations in the BRAF gene and research have shown that these changes are absent in different tissues and tumor cell lines (33) O ther authors (34) have studied different cell lines of MPM to also analyze the gene PI3ka, but no mutation has not been documented.
PTEN
PTEN is a protein that was analyzed in the MPM to evaluate a possible treatment time interaction with this pathway pathogenesis. Recent studies have shown that in different samples of mesothelioma exists a loss of expression of the protein and that the alteration of this protein expression can be considered a negative prognostic value. In fact, patients who had a decreased or absent expression of PTEN were characterized by a worse prognosis, but those who did not have this genetic alteration had a longer survival (35).
E 'was also noticed that the loss of PTEN expression would involve a subsequent increased AKT, another important factor related to the pathogenesis of cancer (36, 34). In particular, the loss of PTEN expression, resulting in a constitutive activation of AKT, can induce resistance to various biological processes such as the inhibitors of EGFR or anti-EGFR monoclonal antibodies. These changes have, therefore, impact on other pathogenetic pathways and this demonstrates the complexity of the pathogenesis and intersected network that exists between these biological factors.
VEGF / VEGF Receptors
Mesothelial cells were also searches the VEGF receptors and preclinical studies have demonstrated their expression in patients with MPM, both at the level of tumor tissue, both in the peripheral blood (37).The rational use of drugs that inhibit this biological pathway arises from the fact that the levels of expression of these factors are greater in patients with MPM, than that in healthy subjects.Furthermore, the increased levels of VEGF was correlated with the increase in microvascular density and seems associated with a poor prognosis (38) over which the probability of disease progression (39-41).
Were tested anti-VEGF risultatano active in inhibiting this factor. Furthermore, there are studies that analyze the effectiveness of the combined treatment between VEGF inhibitors and inhibitors of EGF. According to these studies, the combination of these treatments would result in a stable disease in 50% of patients, progression-free survival of 2.2 months and a median survival of 5.8 months (42, 43).
Among the drugs currently under study include the vatalanib and cediranib that are inhibitors of VEGF receptor and have anti-tumor activity in various solid tumors (44-47). Semaxanib is another inhibitor of VEGF receptor-1, but also acts on the PDGF receptor (PDGFR) and c-kit (48). Another drug is thalidomide that has been tested in patients with MPM and led to the following results: no complete or partial response, 27.5% of patients were progression-free at 6 months, and median overall survival 7 6 months (49).
In patients with unresectable MPM, was used sorafenib has been shown that limited activity (50).However, this drug was also tested in combination with doxorubicin and studies have confirmed good tolerance of this association pharmacology, justifying further clinical investigation (51).
Sunitinib has been tested in MPM, in a clinical phase II, as a second-line treatment after chemotherapy with platinum and antimetabolites, making the following findings: partial response in 12% of cases, stable disease in 65% of cases, median time to progression of 3.5 months and overall survival of 7 months (Nowak et al. IMIG 2011 unpubl. data).
Several phase II studies have been conducted to determine enforceability of imatinib mesylate in MPM refractory to chemotherapy or in patients who had never received chemotherapy (52-54).Currently studies are underway between the pharmacology of combination imatinib, cisplatin and pemetrexed (55). New searches are verifying the utility of these drugs which would appear to be active in MPM due to their ability to induce apoptosis of tumor cells and by inhibition of different metabolic pathways such as for example that of AKT/PI3K; moreover, has been demonstrated 'effectiveness of these compounds as they are able to increase the sensitivity of the tumor to chemotherapy with gemcitabine or pemetrexed (56).
PDGF / PDGFR
The discovery of high expression of the PDGF receptor in the cells of mesothelioma has better defined the rational treatment target against this molecule (57). The increased secretion of PDGF appears to be related to a condition of thrombocythemia, which in turn is considered to be a prognostic factor of adverse events and that occurs in many patients with MPM (58-59). In fact, high levels of PDGF in the serum of patients with MPM seem ssere a predictor of poor prognosis.
In the cells of MPM has also been demonstrated that the expression of c-kit in 26% of cases and this has suggested several clinical trials aimed at testing the imatinib in this disease (60).
The inhibition of PDGFR by the administration of imatinib and paclitaxel has been shown to reduce the pressure of the interstitial fluid with a resulting improvement in the administration of drugs and the increase of 'effectiveness in vitro (61). In a phase I study of imatinib in combination with gemcitabine has been documented partial response to this treatment (62). In preclinical studies, dasatinib had cytotoxic effects and led to a decrease in migration and invasion of mesothelioma cell lines (63-64).
PI3K/AKT/mTOR Pathway
The biological pathway of PI3K/AKT/mTOR is often aberrant in MPM, and several in vitro studies have demonstrated that inhibition of this intracellular pathway can induce apoptosis in cell lines MPM (36, 65].
Sirolimus is a drug that has been approved as an immunosuppressant, which is currently used mainly in the kidney transplant and has an antiproliferative effect on the course PI3K/AKT/mTOR.
Temsirolimus, a derivative of rapamycin, was evaluated in a phase I study, but have not been documented some interesting answers (66). I'm going to study even the associations of the combination of cisplatin and sirolimus, which demonstrated synergistic anti-tumor effects in MPM cell lines (67).
Mesothelin
Mesothelin is highly expressed in several types of cancer, including cancer of the ovary, the pancreatic, some squamous cell carcinomas and the subtype of epithelioid MPM (68, 69). The high membrane expression of mesothelin in the MPM and its contemporary limited distribution at the level of normal tissue has raised an interest questq protein, considering it a potential anticancer target (70).Preliminary studies have not yet shown great results (71), however, we are testing different pharmacological agents that have activity against the target mesothelin (72). Have been documented from the synergistic effects of the combination of these new agents with chemotherapy (73), offering promising results.
Ribonuclease
The ribonuclease are proteins that act at the level of cellular RNA and protein ranpirnasi belongs to this group and was tested for its possible ability to induce apoptosis of cancer cells and to inhibit the growth and cell proliferation.However, there were several documented adverse events associated with this treatment such as kidney failure, allergic reactions, arthralgia and 'peripheral edema (73).
Asparagine-Glycine-Arginine-human
TNF has known anti-tumor activity that is carried out by activating the apoptosis of cancer cells.This could push the systemic treatment using this drug, however, there are studies that show a high toxicity of this drug and, therefore, not to create debilitating side effects should be administered at a dose so low as to be ineffective (75 - 76).
Some researchers have analyzed this molecule and have defined a drug compound by TNF in association with a peptide (tumor-homing peptide asparagine-glycine-arginine (NGR)) that is able to bind selectively to the mesothelial cells, demonstrating a good tolerance of the drug plus some promising responses (77).
HDACi
It has been shown that inhibitors of histone deacetylases (HDACi) alter the growth of several types of cancer cells. These molecules, many of which have been isolated from natural sources, have shown the ability to inhibit proliferation, induce differentiation, and cause apoptosis of cancer cells.Preliminary data of a phase I study suggested that vorinostat may exert clinically significant activity in patients with mesothelioma (78).
However, there are conflicting studies with the first results that do not demonstrate an increase in survival due to the use of this drug (79).
This therapy has also been studied in combination with carboplatin and paclitaxel (80) and have been documented stabilizations of disease.
Another drug in this category is the belinostat but did not improve much the results obtained with other treatments (81). In any case, there are in vitro studies that indicate an increase in the effectiveness of these inhibitors when administered in combination with other agents (82, 83).
CBP501 EIMC-A12
Cells undergo the process of continuous monitoring to ensure they are free of alterations and can progress in their cell cycle and proliferation, or whether they have the faults for which it is necessary for their life cycle stops and ports apoptosis and their destruction, to avoid more extensive damage. There are, therefore, real checkpoints that cells must overcome in order to get the "without prejudice" and proceed in their cell cycle. Cancer cells have the ability to overcome these controls, although they are characterized by abnormal cell, and therefore unable to escape their destruction.
Were then defined of drugs that act on these cenkpoint with the aim of blocking the cell cycle of tumor cells that otherwise would continue in their proliferation and multiplication (84). There are also research has documented partial responses to treatment with these drugs in combination with cisplatin (20), due to the enhancement of chemotherapy induced by these drugs.
Immunotherapy and Gene Therapy
Immunotherapy is an alternative therapy that has contributed to significant progress and is still under study. An example of this treatment has been the systemic administration of IL-2, which has made, however, only limited efficacy, and some side effects (85-86). E ', however, was also evaluated intrapleural administration of IL-2, which was rather well tolerated and has contributed to objective responses, although in need of further studies to assess the additional benefits that it could bring compared with conventional treatment (87).
However, it shall also studies of systemic therapy Conil-2, as well as artificial regulation, by gene transfer of IL-2 endogenous (88).
Rapamycin is a macrolide natural that has been approved as an immunosuppressant and sembrebbe exert antiproliferative effects by inhibiting certain kinases, such as mTOR. There are also synthetic derivatives of rapamycin defined 'rapalogs', that have been developed to improve the pharmacological properties of this macrolide; are some example everolimus, temsirolimus and the deforolimus.
Bortezomib is a potent inhibitor of the proteasome and showed some interesting cytotoxic effects in vitro and in vivo (89-90). Based on promising preclinical data, some studies with this drug are of the currently ongoing (91).
There are also studies that evaluated the combination of interferon and different patterns of standard chemotherapy who have made varying rates of response to treatment (92-95).
were also evaluated therapeutic approaches using vaccines with the aim of stimulating 'immune activity against cancer cells in patients with MPM.
Definitely very interesting are the studies that aim to activation of the immune capacity of dendritic cells to these agents and also the results are definitely promising. These studies led to the variable results, but definitely promising (97-99).
Intrapleural therapy
The pleural space provides easy access for therapeutic molecules and certainly the intrapleural administration of active drugs in this disease could be definitely an excellent therapeutic perspective (100).
Several studies have evaluated the administration of intracavitary chemotherapy even after surgical resection of the tumor, with the iobiettivo to improve local control of the disease (101-103). These findings have led to a recurrence rate of the disease by 50% after surgical treatment associated with intrapleural chemotherapy administration, but further studies are needed to confirm these findings that could probably make even better answers.
There are also studies that evaluate the intrapleural instillation of recombinant viruses to try to make cancer cells sensitive to drug therapies administered later (104-106).
Were injected into the cavity pelurica also agents that had as target mesothelin (107-112), with the aim to induce an immune response that may also be active against tumor cells (113).
Conclusion
It is obvious that continued collaboration between clinicians, pathologists (114) and basic researchers is crucial to improve the treatment of rare diseases, but very aggressive and often characterized by a poor prognosis as the MPM.
In recent years there have been numerous studies aimed at the targeted treatment against molecules and biological pathways involved in the pathogenesis of this disease.
It 's definitely need to better understand the mechanisms underlying the development of this tumor to have an adequate knowledge of the molecular pathways that play a role in carcinogenesis and in this way to be able to inhibit them more effectively. All of these new studies, including those currently under way have contributed to new discoveries in progress or at least encouraging. However, further studies and more detailed analyzes and carefully conducted and controlled, could confirm the results achieved so far as well as bringing new information with the aim of achieving an effective therapy.
Therefore, as noted by all the experts of MPM, it is essential that all patients with MPM may have the opportunity to enter clinical trials in progress, not simply to contribute to translational research, but above all to have the opportunity to access treatments that, although being defined and the study may contribute to treatment lines is not defined (115).
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