Maligní mezoteliom: vybrané studie o možnostech léčby

Advances in the management of peritoneal mesothelioma

Recently, studies investigating agents targeting S1P signaling have been tested in various settings[Source]. Among these, FTY720 has shown some promise; FTY720 (Fingolimod; trade name Gilenya, Novartis) is a FDA-approved drug for treating relapsing forms of multiple sclerosis[Source]. It has been shown FTY720 acts as a pro-drug which is mainly phosphorylated in vivo by SphK2[Source, Source, Source]. The phospho-FTY720 mimics S1P action by binding to S1PR1 which is then internalized and degraded[Source, Source]. S1PR1 signaling, itself, is important for lymphocyte egress from thymus and secondary lymphoid organs to the periphery[Source, Source]. The down-regulation of S1PR1, therefore, through the known action of FTY720, is considered as immunomodulatory by inducing lymphopenia without generalized immunosuppression[Source, Source]. In addition to the immunosuppressant property, several reports about FTY720 as an anti-cancer drug in various malignancies have rapidly accumulated[Source, Source]. We recently reported, in a murine colitis-associated colon cancer model, the administration of FTY720 dramatically reduced tumor size, multiplicity, and tumor load via the reduction of SphK1 and S1PR1 expression[Source, Source]. Others have gone onto also characterize FTY720 as a SphK1 inhibitor in multiple cancer cell lines[Source, Source, Source]. In hematopoietic malignancies or lung cancer, FTY720 acts as an activator of tumor suppressor protein phosphatase 2A (PP2A) and shows promising preclinical activity[Source, Source, Source, Source]. In hepatocellular carcinoma, FTY720 was found to decrease recurrence after liver transplantation via down-regulation of S1PR1[Source]. FTY720 was additionally suggested in combinational therapy with sunitinib for breast cancer, with milatuzumab for lymphoma, and radiotherapy for prostate cancer[Source, Source, Source]. Taken together, targeting S1P signaling by FTY720 might be a potential strategy for pharmoco-therapeutics for peritoneal mesothelioma.

Malignant Pleural Mesothelioma

The combination of pemetrexed and platin-based chemotherapy has become the preferred treatment; however, other combinations have also shown activity.

Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

In this review, we have described the reported activity of a series of new agents, together with several well-known cytotoxic drugs; currently most of them are under in vitro investigation in hMPM combined with the standard ‘old’ drugs. Parallely, an interesting fall-out on clinical studies using the early novel compounds, together with some synergistic combination emerging from preclinical studies, is already detectable.

CD30 is a potential therapeutic target in malignant mesothelioma

There have been sporadic reports of CD30 expression in non-lymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody-drug conjugate directed against CD30 antigen, in lymphoid malignancies, we undertook a study to examine the incidence of CD30 in mesothelioma and to investigate the ability to target CD30 antigen in mesothelioma. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. Our studies validate the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicate that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment.

Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma

Temsirolimus, a kinase inhibitor used to treat advanced renal cell carcinoma (RCC), may offer a promising new way to treat malignant pleural mesothelioma.

Temsirolimus appeared to work against the mesothelioma cells in two different ways. By blocking the action of a gene pathway called mammalian target of rapamycin (mTOR), which is highly expressed in some mesothelioma lines, temsirolimus makes it harder for cancer cells to grow and divide. At the same time, the drug also acts on two other compounds – vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) – to prevent the formation of blood vessels (angiogenesis) needed to feed a growing tumor.

Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy

The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.

Placebo Controlled Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma (COMMAND)

Defactinib could play the role of a successful maintenance treatment following standard chemotherapy treatment with pemetrexed and cisplatin.

Defactinib disrupts communication between cells to prevent mesothelioma cells from migrating and forming new tumors.

Defactinib is a focal adhesion kinase (FAK) signaling pathway inhibitor.

A study presented in The Journal of Cell Biology showed a reduction in metastasis in breast cancer patients when FAK was removed. The hope is for it to be just as successful in reducing metastasis of mesothelioma cells:

• New Mesothelioma Drug Offers Hope for Longer Life
• New Clinical Trial Tests Drug to Control Mesothelioma Cancer Stem Cells

A trial of ganetespib with pemetrexed and cisplatin for pleural mesothelioma (MESO 2)

Meso2, a study funded by Synta Pharmaceuticals, aims to test the effectiveness of a drug called ganetespib in preventing mesothelioma tumours.

Ganetespib inhibits the action of a protein in cells called heat shock protein 90 (HSP90) — which is required for the stabilization and proper functioning of many proteins required for tumour growth.

Laboratory tests show ganetespib is extremely active in mesothelioma — and combined with chemotherapy, this treatment could shrink cancers down and improve symptoms for patients:

• http://www.sciencedaily.com/releases/2013/09/130923092748.htm

Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy

Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.

Dampening the immune system improves response to mesothelioma treatment

But now, researchers from the National Cancer Institute in the US have combined an immunotoxin called SS1P with two other drugs – pentostatin and cyclophosphamide – that suppress the body’s natural defences and reduce the number of antibodies targeting the therapy.

Dr Raffit Hassan and colleagues treated 10 patients with late-stage disease and the combined treatment successfully reduced the number of antibody-generating immune cells in the patient’s blood and increased the amount of SS1P available to target the tumour cells.

Tumours in three of the patients shrank, including two patients who had originally failed to respond to anti-cancer drugs.

These patients showed a substantial improvement following SS1P treatment, according to the study published in Science Translational Medicine.

A molecular targeting against nuclear factor-κB, as a chemotherapeutic approach for human malignant mesothelioma.

NF-κB inhibitor IMD-0354 reduced cyclin D3 in both epithelial tissue type NCI-H28 and sarcomatoid tissue type NCI-H2052. In a sphere formation assay, IMD-0354 effectively decreased the number and diameter of MSTO-211H spheres. Preincubation of MSTO-211H cells with IMD-0354 delayed tumor formation in transplanted immunodeficient mice. Furthermore, administration of IMD-0354 markedly rescued the survival rate of mice that received intrathoracic injections of MSTO-211H cells.

Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy

The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.

Researchers Learn How Selenite Combats Mesothelioma

Selenite triggered cell death (apoptosis) in 15% of sarcomatoid cells, compared to just 8% of epithelioid mesothelioma cells. Total cell death after 24 hours of treatment was about 25% in the epithelioid cells and 30% in the sarcomatoid cells. The researchers discovered that the treatment activated different signaling processes in sarcamatoid and epithelioid cells, particularly in Bcl—a family of proteins that either promote or inhibit cell death. Sarcomatoid cells produced excess amounts of a protein in this family called Bax, which promotes cell death. This may be why sarcomatoid cells are more sensitive to the effects of selenite.

Amino acid blocker could help treat mesothelioma

Sixty eight patients took part in the trial and results so far have shown that treatment with the arginine-lowering drug significantly slowed down disease progression amongst 44 patients receiving the drug and best supportive care, extending progression-free survival by almost six weeks, compared with the 24 patients receiving best supportive care alone.

Our research found that putting the tumours on an arginine starvation diet was an effective way of weakening the cancer, which in turn prolonged progression-free survival amongst patients. Our latest research suggests that combining arginine starvation drugs with standard chemotherapy could show an even stronger effect in combating mesothelioma. With the positive signal coming from the current trial, we are eager to launch a new combination trial in early 2014.

Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels.

Zoledronic acid (ZOL)-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels.
These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

Synergistic effect of combined treatment with gamma-tocotrienol and statin on human malignant mesothelioma cells

The present study is the first to demonstrate the synergetic effect of statins (atorvastatin and simvastatin) and gamma-tocotrienol (γ-T3) on human malignant mesothelioma (MM). Statin + γ-T3 combinations induced greater cell growth inhibition more than each single treatment via inhibition of mevalonate pathway, a well-known target of both γ-T3 and statins. γ-T3 was necessary for endoplasmic reticulum stress markers CHOP and GRP78, whereas an intrinsic apoptotic marker, caspase 3 activation was induced only in the presence of statins. Overall, the combination of γ-T3 and statins could be useful for MM therapy and functions in a complementary style.

Vaccination with epigenetically treated mesothelioma cells induces immunisation and blocks tumour growth

Our data demonstrate that epigenetic drugs, such as SAHA/Vorinostat, can stimulate tumour immunogenicity and improve the recognition of aggressive MM cells by the immune system in vivo.

Malignant Pleural Mesothelioma

The advantage of the dual PI3K/mTOR-inhibitor NVP-BEZ235 compared to conventional mTOR-inhibiting agents is the inhibition of PI3K as well as mTOR and hence various effectors of the signaling pathway, which may result in superior efficacy as well as improved drug compatibility. In the present study this inhibitor will be tested in a mouse model.

Sialic acid-binding lectin (leczyme) induces apoptosis to malignant mesothelioma and exerts synergistic antitumor effects with TRAIL

Sialic acid-binding lectin (SBL) induced tumor-selective cytotoxicity that was attributed to induction of apoptosis. Combinatorial treatment of SBL and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) showed synergistic apoptosis-inducing effect.

These results suggested that SBL could be a promising candidate for the therapeutics for malignant mesothelioma. Furthermore, the combinatorial treatment of SBL and TRAIL could be an effective regimen against malignant mesothelioma.

Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention

Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 x 10(-5) M; p < or = 0.05) and it elicited remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM. Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10(-6) M-10(-2) M), indometacin (10(-6) M-10(-2) M) and the COX-2 inhibitor NS-398 (10(-6) M-10(-4) M).

Celecoxib, in a dose- and time-dependent manner, induced MM cell apoptosis, which involved decreased Akt phosphorylation, loss of Bcl-2 and Survivin protein expression and caspase-3 activation. Furthermore, vascular endothelial growth factor (VEGF), an MM autocrine growth factor and Akt inducer, rescued celecoxib-induced apoptosis and Akt dephosphorylation. When the VEGF receptor (KDR/Flk-1) inhibitor, SU-1498, was used in combination with celecoxib, IC50 of celecoxib in vitro was reduced up to 65%. These data demonstrate that celecoxib may have antitumor properties in MM and provide a rationale for the therapeutic use of celecoxib in combination with a selective VEGF inhibitor.

COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function

We found that large numbers of infiltrating Myeloid-derived suppressor cells (MDSC) co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. The function of MDSC was impaired as was noticed by reduced levels of ROS and NO and reversal of T cell tolerance; resulting in refinement of immunotherapy.

We conclude that celecoxib is a powerful tool to improve dendritic cell-based immunotherapy and is associated with a reduction in the numbers and suppressive function of MDSC. These data suggest that immunotherapy approaches benefit from simultaneously blocking cyclooxygenase-2 activity.

Cisplatin and irinotecan (CPT-11) for peritoneal mesothelioma

The overall response rate was 24%, but 76% of patients improved on treatment. The combination of cisplatin and Irinotecan (CPT-11) is well tolerated and has clinical benefits in patients with peritoneal mesothelioma.

Raltitrexed in mesothelioma

A Phase III randomized study demonstrated that the combination of raltitrexed and cisplatin improves overall survival in malignant pleural mesothelioma (MPM) and is superior compared with cisplatin alone, without harmful effect on health-related quality of life. Moreover, the cost-effectiveness analysis found raltitrexed plus cisplatin to be cost effective compared with cisplatin and compared with active supportive care.

Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509

Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib.

A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine

It is almost 10 years since the Ad-p53 was approved in China as the first gene medicine worldwide for head and neck cancer, and the E1B-55 kD-defective Ad has 7-year clinical experiences in major Chinese hospitals.
Gene therapy currently remains an experimental approach for mesothelioma treatments, but the preceding clinical trials provided many points to be considered for the future application of gene therapy.

All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice

Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

Phase I Trial of Cisplatin, Pemetrexed, and Imatinib Mesylate in Chemonaive Patients With Unresectable Malignant Pleural Mesothelioma

The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted.

A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

The drug paclitaxel may be useful in the treatment of cisplatin-resistant cancer; the mechanism for this activity is unknown.

Ranpirnase as a potential antitumor ribonuclease treatment for mesothelioma and other malignancies

Most clinical studies have been conducted in patients with malignant mesothelioma, and a confirmatory Phase IIIb trial is currently underway for the treatment of this disease. Owing to its selective destruction of malignant cells and favorable toxicology profile, ranpirnase is a promising antitumor agent with ideal attributes that are generally lacking in conventional cytotoxic drugs.

Ranpirnase Interferes with NF-κB Pathway and MMP9 Activity, Inhibiting Malignant Mesothelioma Cell Invasiveness and Xenograft Growth

The results demonstrate that the combination of ranpirnase and doxorubicin is a safe and feasible treatment in unresectable MM and showed a significant impact on the survival of pretreated patients compared to doxorubicin alone. Although it is known that ranpirnase is a RNAse that suppresses protein synthesis, its precise antitumor mechanisms in MM remain elusive:

• Reck M, Krzakowski M, Jassem J, et al. Randomized, multicenter phase III study of ranpirnase plus doxorubicin (DOX) versus DOX in patients with unresectable malignant mesothelioma (MM) [abstract]. J Clin Oncol. 2009;27:15s.
• Ranpirnase and its potential for the treatment of unresectable malignant mesothelioma

Malignant pleural mesothelioma: current and future perspectives

More specifically, up-regulation of epidermal growth factor receptor (EGFR) is an important part of MPM development, thus, EGFR-tyrosine kinase inhibitors (TKIs) such as ZD1839 (gefitinib) and OSI-774 (erlotinib) might represent novel therapeutic options. In vitro studies have shown that gefitinib inhibited MPM cell growth and survival preventing EGF-dependent activation of ERK1/2 pathway by blocking EGFR-TK phosphorylation and stabilizing inactive EGFR dimers:

• Receptor tyrosine kinase inhibitors and cytotoxic drugs affect pleural mesothelioma cell proliferation: insight into EGFR and ERK1/2 as antitumor targets
• Inhibition of proliferation, migration, and matrix metalloprotease production in malignant mesothelioma cells by tyrosine kinase inhibitors

Vascular endothelial growth factor (VEGF) signaling also plays a very important role in MPM. Several angiogenesis inhibitors have been used in clinical trials such as bevacizumab (Avastin; Genentech, South San Francisco, CA), a recombinant humanized monoclonal antibody, or other antiangiogenic agents SU5416, vatalanib, thalidomide and sorafenib which have shown modest activity as single-agent treatments:

• Systemic treatments for mesothelioma: standard and novel. Curr Treat Options

Recently, Nascreen et al. in their review included receptor EphA2 as a novel potential molecular target in MPM:

• Advances in malignant pleural mesothelioma therapy: targeting EphA2 a novel approach

Other inhibitors include histone deacetylase (HDAC) inhibitor which plays a role in cellular differentiation and malignant transformation of MPM. HDAC has shown a partial response in a phase I trial:

• Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid

Met signaling pathway is also a very promising target of MPM for patients expressing both Met and HGF, as selective small molecular inhibitors of c-Met kinase were shown to be effective in vitro and in vivo experiments:

• Inhibition of the met receptor in mesothelioma

Another promising drug is ranpirnase, a ribonuclease (RNase) isolated from early embryos of the Northern Leopard Frog, which proved to have disease-modifying activity against malignant mesothelioma:

• Ranpirnase Interferes with NF-κB Pathway and MMP9 Activity, Inhibiting Malignant Mesothelioma Cell Invasiveness and Xenograft Growth
• Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma

A potent antitumor agent is vandetanib which markedly enhanced pemetrexed and carboplatin activity against established MPM cell lines:

• Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin

In addition, a phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha (NGR-hTNF), a selective vascular targeting agent, in previously treated patients with MPM found modest results warranting additional evaluation:

• Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma

Modest results were shown in a phase II trial for BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects, as second line therapy in MPM after first line pemetrexed/platinum chemotherapy:

• A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma
• Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation

According to reports extracellular signal-regulated kinase 5 ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma:

• Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas

Another study combined negative ERCC1 and class III β-tubulin immunostaining to be associated with significantly prolonged PFS and OS in MPM patients receiving cisplatin–vinorelbine therapy:

• A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma

In a prospective phase II study of cisplatin and bortezomib a protease inhibitor, as first line treatment of MPM was investigated. The researchers reported validation of progression free survival rate at 18 weeks (PFSR-18) as primary end-point which was confirmed as a strong predictor of survival:

• Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials

Other researchers evaluated a new combined therapy consisting of ascorbate/epigallocatechin-3-gallate/gemcitabine mixture (called AND, for Active Nutrients/Drug). The authors concluded that this combination was synergistic in vitro on MPM cells, and blocked in vivo tumor progression and metastasization in REN-based xenografts:

• Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma

Systemic Treatment of Malignant Pleural Mesothelioma

To date, the combination of cisplatin and pemetrexed is the only evidence-based systemic treatment that leads to clinically significant survival improvement and amelioration of quality of life for MPM patients. Results of ongoing trials investigating bevacizumab and cisplatin plus pemetrexed are eagerly awaited.

Gemcitabine has been combined with cisplatin, carboplatin and oxaliplatin, with a RR ranging from 12 to 40%, median TTP of 6–7 months and median OS of 13–15 months:

• Kalmadi SR, Rankin C, Kraut MJ et al. Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: a Phase II study of the Southwest Oncology Group (SWOG 9810). Lung Cancer60(2),259–263 (2008).
• Favaretto AG, Aversa SM, Paccagnella A et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric Phase II study. Cancer97(11),2791–2797 (2003).
• Schutte W, Blankenburg T, Lauerwald K et al. A multicenter Phase II study of gemcitabine and oxaliplatin for malignant pleural mesothelioma. Clin. Lung Cancer4(5),294–297 (2003).

A synergistic antitumor effect of sirolimus and cisplatin has been shown in MPM cell lines:

• artman ML, Esposito JM, Yeap BY, Sugarbaker DJ. Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma. J. Thorac. Cardiovasc. Surg.139(5),1233–1240 (2010).

Everolimus, an oral mTOR inhibitor, is currently being evaluated in a Phase II study planned to enroll 55 patients with the primary end point being to determine the 4-month PFS:

• Everolimus in Treating Patients With Pleural Malignant Mesothelioma That Cannot Be Removed By Surgery

In a Phase I study testing the oral inhibitor of PI3K and mTOR, GDC-0980, antitumor activity was demonstrated in three patients with MPM:

• Wagner AJ, Bendell JC, Dolly S et al. A first-in-human Phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors. J. Clin. Oncol.29(Suppl.), Abstract 3020 (2011).

NGR–hTNF consists of human TNF-α coupled to the tumor-homing peptide NGR that binds a particular form of CD13, a receptor selectively expressed by tumour blood vessels:

• NGR015: Study in Second Line for Patient With Advanced Malignant Pleural Mesothelioma Pretreated With Pemetrexed
• NGR019: Phase II Study of NGR–hTNF Versus Placebo as Maintenance Treatment in Patients With Advanced Malignant Pleural Mesothelioma

Most cancer cells are dependent on the G2 checkpoint to survive, and this has led to the development of the G2 checkpoint inhibitor CBP501. In a Phase I study in combination with cisplatin, of the three patients with MPM included, one had a PR lasting 9.7 months and two had stable disease, lasting 11 and 3 months, respectively:

• Shapiro GI, Tibes R, Gordon MS et al. Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors. Clin. Cancer Res.17(10),3431–3442 (2011)
• Study of CBP501 + Pemetrexed + Cisplatin in Patients With Solid Tumors (Phase I) and Patients With Malignant Pleural Mesothelioma (Phase II)

Immunotherapy – One of the most intriguing targets for systemic treatment of MPM is mesothelin, a tumor differentiation antigen overexpressed by most epithelioid mesothelioma but not in normal cells:

• Comprehensive review of the potential role of mesothelin as a target for mesothelioma therapy. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. J. Cancer44(1),46–53 (2008).

Three mesothelin-targeted agents are currently in different stages of clinical development: SS1P, a recombinant immunotoxin; MORAb 009, a chimeric antimesothelin monoclonal antibody; and CRS-207, a live attenuated Listeria monocytogenes vector encoding human mesothelin:

• Hassan R, Schweizer C, Lu KF et al. Inhibition of mesothelin–CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: implications for cancer therapy. Lung Cancer68(3),455–459 (2010).

Some hints of activity for these agents have been shown in Phase I studies. Preclinical models suggested a synergism with systemic chemotherapy and trials of combined therapy are underway:

• Hassan R, Broaddus VC, Wilson S, Liewehr DJ, Zhang J. Anti-mesothelin immunotoxin SS1P in combination with gemcitabine results in increased activity against mesothelin-expressing tumor xenografts. Clin. Cancer Res.13(23),7166–7171 (2007).

A seven-year disease-free survivor of malignant pleural mesothelioma treated with hyperthermia and chemotherapy: a case report

This report describes a rare case of a long-term survivor with MPM. Our patient has been disease-free for more than seven years without any complications. The combination of hyperthermia and chemotherapy may be a novel and safe therapeutic option for MPM and can be considered in cases ineligible for radical treatment.

Our patient refused any invasive therapies including surgery and radiotherapy, and was therefore treated with hyperthermia and systemic chemotherapy with agents such as cisplatin and irinotecan. He underwent three hyperthermia sessions and a single course of chemotherapy without any severe complications.

Hyperthermia was performed using a radiofrequency (RF)-capacitive heating apparatus (Thermotron-RF 8; Yamamoto Vinita Co. Ltd., Osaka, Japan) once a week (on days one, eight, and 15) for approximately 60 minutes immediately after irinotecan administration.

We speculated that the remarkable efficacy may have been due to an intrinsic effect of hyperthermia or a synergistic effect of the hyperthermia-chemotherapy combination. Hyperthermia is known to be directly cytotoxic to cancer cells:

• Cellular response to combinations of hyperthermia and radiation.
• Potential for hyperthermia and radiation therapy.
• The response of human and rodent cells to hyperthermia.

When cells are exposed to elevated temperatures, damage is inflicted at multiple sites; the predominant molecular target appears to be proteins such as heat shock proteins (HSPs):

• The heat shock response: life on the verge of death.

Roth et al. reported the effects of heat stress on HSPs. It was noted that hyperthermia induced the downregulation heat-stress-induced Hsp40 and Hsp70 expression and reduced the survival of mesothelioma cells:

• Mesothelioma cells escape heat stress by upregulating Hsp40/Hsp70 expression via mitogen-activated protein kinases

Some clinical reports have also reported the benefits of hyperthermia. Matsuzaki et al. reported on intra-pleural chemotherapy perfusion with hyperthermia to induce MPM cell apoptosis. MPM cells obtained from pleural effusions showed apoptotic action, peaking at 24 hours after perfusion:

• Induction of apoptosis by intrapleural perfusion hyperthermo-chemotherapy for malignant pleural mesothelioma

Xia et al. reported significant prolongation of MST by hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for MPM. Although a complete response was not achieved, MST was 27.1 months without any severe side effects. These reports suggest that hyperthermia may have a special effect on MPM cells, and that the combination of hyperthermia and chemotherapy may act synergistically:

• Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma.

Peritoneal mesothelioma is a rare disease that requires early diagnosis and can be effectively treated by cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy in selected group of patients.

Median duration of surgery, median length of hospital stay, and median follow-up duration were 7.04 hours, 11 days, and 15 months respectively. One postoperative morbidity relating to chemical peritonitis required exploratory laparotomy with good outcome. There were no mortality. All patients are alive at the last follow-up with no evidence of recurrences at 4 to 31 months from the time of their surgery.

Kurkumin

• Curcumin: A Double Hit on Malignant Mesothelioma„Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anti-carcinogenic properties through its anti-inflammatory effects.
  Curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of High Mobility Group Box1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the Nuclear Factor kappaB (NF-κB) pathway. Furthermore, curcumin’s cytotoxicity in MM cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death
  Our data indicates that curcumin has a double effect on MM cells through induction of pyroptosis while subsequently protecting against inflammation.“
• Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis„Curcumin inhibited MPM cell growth in a dose- and time-dependent manner while pretreatment of MPM cells with curcumin enhanced cisplatin efficacy. Curcumin activated the stress-activated p38 kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and apoptosis. In addition, curcumin treatments stimulated expression of novel transducers of cell growth suppression such as CARP-1, XAF1, and SULF1 proteins. Oral administration of curcumin inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating apoptosis. Thus, curcumin targets cell cycle and promotes apoptosis to suppress MPM growth in vitro and in vivo“
• Spice May Trigger Mesothelioma Cell Breakdown„Curcumin has a damaging effect on human mesothelioma cells in the lab, as well as on live mesothelioma cells in mice. In that study, conducted at the John D. Dingell VA Medical Center in Detroit, curcumin was found to disrupt the cell cycle and promote apoptosis (cell death) whether added to cells in a dish or fed to mice that had mesothelioma.“

Kvercetin

• The Investigation of Effects of Quercetin and Its Combination with Cisplatin on Malignant Mesothelioma Cells In Vitro„Our experiments showed that Quercetin significantly reduced the proliferation of cell lines, altered the cell cycle distribution, and increased the level of Caspase 9 (C9) and Caspase 3 (C3) in concentration and time-dependent manner. Additionally, the combination of QU + CIS was found more effective when compared with individual treatment of agents.“
• Role of transcription factor Sp1 in the quercetin-mediated inhibitory effect on human malignant pleural mesothelioma„In the present study, it was found that MSTO-211H mesothelioma cell viability was reduced and apoptotic cell death was increased by Quercetin (20-80 µM). In addition, Qu increased the sub-G₁ cell population, and was found to interact with specificity protein 1 (Sp1) and significantly suppressed its expression at the protein and mRNA levels. Furthermore, Qu modulated the levels of Sp1 regulatory genes, such as cyclin D1, myeloid cell leukemia (Mcl)-1 and survivin in MSTO-211H cells.
  Our results strongly suggest that Sp1 be considered as a novel molecular target of Qu in human malignant pleural mesothelioma.“

Bromelain

• Pineapple Extract Enhances Chemo Effectiveness on Mesothelioma Cells„The research focused on the ability of the bromelain enzyme to break down the protein MUC-1 in mesothelioma cell lines through a chemical decomposition process. The MUC-1 protein is what helps the cancer cells metastasize and allows it to resist the toxicity of chemotherapy.
  The Bromelain significantly increased the toxicity of the cisplatin on the tumor cells.“
• Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells
  http://www.prweb.com/releases/2014/01/prweb11455232.htm
  „The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines.
  Bromelain appears to have the ability to break down MUC-1 in mesothelioma cells through a chemical decomposition process called hydrolyses.“
• Anticancer property of bromelain with therapeutic potential in malignant peritoneal mesothelioma„Antitumor properties of bromelain have been demonstrated in both, in vitro and in vivo studies, along with scanty anecdotal human studies.
  Further, the efficacy of cisplatin and 5-FU are enhanced by adjuvant treatment with bromelain, indicating that the barrier function of MUC1 may be affected.
  Further, bromelain in combination with either 5-FU or cisplatin, the efficacy of the chemotherapeutic drug is enhanced. Hence, current evidence indicates that bromelain may have the potential of being developed into an effective anticancer agent for MPM.“

EGCG

• Negative modulation of mitochondrial oxidative phosphorylation by epigallocatechin-3 gallate leads to growth arrest and apoptosis in human malignant pleural mesothelioma cells
  „The EGCG-dependent negative modulation of mitochondrial energy metabolism, selective for cancer cells, gives an important input for the development of novel pharmacological strategies for MMe.“
• EGCG induces human mesothelioma cell death by inducing reactive oxygen species and autophagy
  „We found that EGCG induced apoptosis in all five mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism. EGCG induced reactive oxygen species (ROS), and impaired the mitochondrial membrane potential. As treatment with ROS scavengers, catalase and tempol, significantly inhibited the EGCG-induced apoptosis, ROS is considered to be responsible for the EGCG-induced apoptosis. Further, we found that EGCG induced autophagy, and that when autophagy was suppressed by chloroquine, the EGCG-induced cell death was enhanced. Taken together, these results suggest that EGCG has a great potential for the treatment of mesothelioma by inducing apoptosis and autophagy.“

Vitamín C

• High dose of ascorbic acid induces cell death in mesothelioma cells
  „High dose of ascorbic acid induced cell death of all mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism that ascorbic acid induced reactive oxygen species and impaired mitochondrial membrane potential. In vivo experiment, intravenous administration of ascorbic acid significantly decreased the growth rate of mesothelioma tumor inoculated in mice. These data suggest that ascorbic acid may have benefits for patients with mesothelioma.“

Salvestrol

• Incurable Mesothelioma Responds to Salvestrols
  „Amanda prescribed a range of herbal treatments to build up his immune system and improve his breathing, pulse and liver function. She also recommended a long-term course of Salvestrols. And to get the maximum benefit from this medicine, she advised him to follow a completely organic diet. Alan also has a mistletoe injection three times a week to boost his immune system’s ability to fight cancer cells.
  The results were dramatic. Within three months Alan’s tumour was receding. He was less breathless, had more energy, a healthy appetite and his pulse rate had come down to normal.
  In October 2009, Alan’s oncologist was so astounded by the results of a scan, he sent him back for another one, just to make sure.“
• Lorraine’s Journey with Mesothelioma
  „Before beginning the treatment, Dr Wang asked if I would consider also taking a new supplement called Salvestrol. In the 6 months that I have been away between treatments, Dr Wang has been using Salvestrol with patients and has had a lot of success in increasing the effectiveness of the cancer fighting treatments.
  The main feature of Salvestrols is that they target a specific enzyme called CYP1B1 found only in diseased cells of the human body.“

Resveratrol

• Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53
  „Resveratrol, in combination with clofarabine, time-dependently induced a strong cytotoxic effect with the nuclear accumulation of phospho-p53 (p-p53) in MSTO-211H cells, but not in normal mesothelial MeT-5A cells.
  Gene silencing with p53-targeting siRNA attenuated the sensitivity of cells to the combined treatment of two compounds. Analyses of p53 DNA binding assay, p53 reporter gene assay, and RTP-CR toward p53-regulated genes, including Bax, PUMA, Noxa and p21, demonstrated that induced p-p53 is transcriptionally active.
  Taken together, these results demonstrate that resveratrol and clofarabine synergistically elicit apoptotic signal via a p53-dependent pathway, and provide a scientific rationale for clinical evaluation of resveratrol as a promising chemopotentiator in MM.“
• Synergistic inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation
  „The combination treatment showed a marked growth-inhibitory effect, which was accompanied by suppression of Nrf2 activation and decreased expression of heme oxygenase-1 (HO-1).
  Pretreatment with Ly294002, a PI3K inhibitor, augmented the decrease in HO-1 level by their combination, whereas no obvious changes were observed in Nrf2 levels. Altogether, these results suggest that the synergistic cytotoxic effect of clofarabine and resveratrol was mediated, at least in part, through suppression of Nrf2 signaling.“
• Synergistic anti-cancer effects of resveratrol and chemotherapeutic agent clofarabine against human malignant mesothelioma MSTO-211H cells
  „The inhibition of phosphoinositide 3-kinase using Ly294002 augmented a decrease in the p21 level induced by their combination, but it showed no significant effects on expression of Sp1 and cyclin D1. Taken together, the data provide evidence that the synergistic antiproliferative effect of resveratrol and clofarabine is linked to the inhibition of Akt and Sp1 activities, and suggest that this combination may have therapeutic value in treatment of malignant mesothelioma.“

Withania somnifera

• Withaferin A Inhibits the Proteasome Activity in Mesothelioma In Vitro and In Vivo
  „Withania somnifera (WA) is the major and the most active component of dietary supplement Ashwagandha. Recent preclinical studies have revealed that WA targets multiple molecules for mediating cell death in a variety of cancer cells. WA exhibited anti-angiogenesis effects through NF-κB inhibition, and the ubiquitin-proteasome pathway was thought to be involved
  WA potently inhibited cell proliferation in all tested cell lines.
  Taken together, our in vitro studies strongly suggest that WA suppressed growth of human and murine MPM cells by attenuating proteasomal activity and stimulating apoptosis.
  WA inhibited growth of MPM cells transfected with scrambled siRNAs, whereas CARP-1 knock-down interfered with WA-dependent suppression of MPM cell growth.
  Together our in vitro and in vivo studies suggest that WA suppresses MPM growth by targeting multiple pathways that include blockage of proteasome activity and stimulation of apoptosis, and thus holds promise as an anti-MPM agent.“

Sulforafan

• Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells
  „Sulforaphane treatment decreased cell viability and triggered a rapid and transient increase in the intracellular ROS levels.“

Agaricus blazei Murill Kyowa

• Mesothelioma Patient Cures Self with Mushroom Extract
  „A 73-year old malignant pleural mesothelioma patient in Japan has demonstrated that alternative therapies can result in the complete disappearance of a mesothelioma tumor. He refused continuance of chemotherapy and radiation treatments. The patient instead began taking a mushroom extract containing Agaricus blazei Murill Kyowa (ABMK) in addition to alternative parasympathetic nerve stimulation therapy. Four months after the start of the alternative treatments the tumor began to decrease. Over the next two years the tumor completely disappeared.“

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