New Agents in the Management of Advanced Mesothelioma

doi:10.1053/j.seminoncol.2005.02.010

Seminars in Oncology

Volume 32, Issue 3, June 2005, Pages 336-350

https://doi.org/10.1053/j.seminoncol.2005.02.010 Get rights and content

Malignant pleural mesothelioma (MPM) is a seemingly uncommon tumor whose incidence has in fact increased steadily and progressively over the last 30 years. Indeed, an actual “epidemic” is expected in Europe over the next 20 years. Despite unquestionable improvement in the diagnostic methods at our disposal and the availability of new treatment strategies, the prognosis of MPM patients remains dramatically poor (12 to 18 months’ median survival from diagnosis), although exceptional cases of long-survivors are reported in all literature series. The current review will cover the dramatic improvements in the treatment of this rare disease that have been recently achieved, as well as the promise that new, molecular-targeted therapies, such as bortezomid, mTOR (mammalian target of rapamycin) inhibitors, and Met inhibitors, seem to offer for the next few years. With pemetrexed we now have a drug that is able to impact patient survival. Together with the newer drugs, rapidly emerging from the laboratory to be applied in the clinic, we have the hope of making further advances in the struggle against this disease.

Section snippets

Host and Tumor Prognostic Factors for Response

Pathologic stage (tumor size, nodal status, etc, determined at the time of surgery) and performance status of the patient usually define prognosis. The limitations of pathologic staging are well known, but a pathologic/surgical staging system for MPM has been proposed and validated⁴ and the poor prognosis of cancer-containing lymph nodes has been confirmed.⁵ However, pathologic staging is rarely performed in patients receiving only chemotherapy, and thus two cancer cooperative groups that have

Status of Medical Treatment of Mesothelioma Before Pemetrexed

In the last two decades of the previous century, a multitude of cytotoxic drugs were tested in MPM, both as single agents and within combination regimens; from these earlier studies, mainly small phase II trials enrolling a limited number of poorly staged (due to inadequate imaging procedures) patients, it had become clear that there was a limited, if any, advantage of using a combination of chemotherapy compared to single agents.⁴⁸

More recently, however, the combination of two drugs, usually

New Agents for Therapy of Mesothelioma: Pemetrexed

Pemetrexed is a new agent whose novel mechanism of action (Fig 1) is the inhibition of glycinamide ribonucleotide formyl transferase (GARFT), which, in turn, leads to purine depletion.⁶⁰ Although developed as an inhibitor of dihydrofolate reductase (DHFR) (similar to methotrexate) it also inhibits thymidylate synthase (TS) (similar to 5-fluorouracil and the antifolate raltitrexed).⁶¹ These other effects of pemetrexed lead to pyrimidine depletion. The combination of purine and pyrimidine

New Agents for Therapy of Mesothelioma: Ranpirnase

Ranpirnase (Onconase; Alfacell, Bloomfield, NJ) is an antineoplastic ribonuclease derived from frog eggs,⁸¹ which has antitumor activity in mesothelioma. Indeed, in a multicenter trial of ranpirnase (480 μg/m² IV weekly) in 105 patients, four of 81 patients with evaluable disease had a PR, two had a minor response, and 35 had stabilization of previously progressive disease.⁸ For the entire group, the median survival duration was 6 months, and the 1- and 2-year survival rates were 34% and 22%,

Epidermal Growth Factor Receptor Pathway Inhibitors

The epidermal growth factor receptor (EGF-R) is a transmembrane glycoprotein belonging to the ErbB family of tyrosine kinase proteins.83, 84 This family includes four members: the EGFR (also known as ErbB1/HER1), ErbB2/neu/HER2, ErbB3/HER3, and ErbB4/HER4. Each of these proteins possesses three different domains: the extracellular domain, which is involved in recognizing and binding the ligands (epidermal growth factor [EGF), the transforming growth factor-alpha [TGF-α] for ErbB1) that are able

Conclusions

In concluding a review on new approaches for MPM treatment in 2002,¹⁵⁸ Nowak et al complained of “the lack of effective conventional modalities,” that, however, “has permitted enrollment of patients in clinical trials of novel therapies”; today, only 3 years later, the situation has changed radically.

We now have a new, active, standard of treatment—pemetrexed plus cisplatin—which improves MPM patients’ survival. Furthermore, although in its infancy, molecular-based targeted therapy holds

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The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?
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Citation Excerpt :
The use of 6 cycles of cediranib (a multikinase inhibitor of VEGFR and PDGFR) in combination with cisplatin and pemetrexed in chemo naïve patients followed by maintenance therapy with only cediranib showed a PFS of 10 months and an OS of 16 months (Tsao et al., 2013). There is a high expression of PDGF receptors in mesothelioma cells (Vogelzang et al., 2005). The increase in the secretion of PDGF appears to be related to thrombocythemia, which is considered an unfavorable prognostic factor occurring in many MPM patients (Filiberti et al., 2005; Edwards et al., 2001).
Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleura with a poor prognosis. The most active first-line regimens are platinum compounds and pemetrexed. There is no standard second-line treatment in MPM. Advances in the understanding of tumor molecular biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. Unfortunately none of the explored targeted treatments can currently be recommended as routine treatment in MPM.
We reviewed the biological pathways involved in MPM, the clinical trials about targeted therapy, and possible related mechanisms of resistance. We suggest that specific genetic markers are needed as targets of selective therapy. By this way the selection of patients based on the molecular profile may facilitate a therapeutic strategy that allows the use of the most appropriate drug for each patient.
MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma
2011, European Journal of Cancer
Citation Excerpt :
This suggests a beneficial role for this cytotoxic drug in slowing disease progression. Whilst gemcitabine has not been tested in the phase III setting, cisplatin and pemetrexed, have shown improvements in survival with a similar magnitude in phase III trials.43,44 We think that MexTAg mice could also be used to test the interactions of combinations of therapies and to investigate the optimal dosing and scheduling of such combinations.45
Animal models provide an important tool for investigating the biology of cancer and for testing the efficacy of novel treatments. Here we describe several aspects of the transgenic MexTAg mouse that develops asbestos-induced mesothelioma. Targeted expression of the TAg transgene causes mesothelioma to develop more rapidly after asbestos exposure in wild-type mice with 100% incidence compared to 30% incidence in wild-type mice. MexTAg mice do not develop spontaneous mesothelioma and exhibit a very low incidence of other tumours. Here we show that TAg does not affect the aggressiveness or rate of progression of the mesotheliomas, suggesting that the oncogene alters only the rate at which disease is initiated. The instillation of an alternative inflammatory agent, thioglycollate, did not induce mesotheliomas, demonstrating acute inflammation is not sufficient for tumour development in MexTAg mice. We found that neither the age of a mouse at the time of exposure nor its gender were prognostic factors. MexTAg mice with mesotheliomas respond to treatment with a cytotoxic drug in a similar way to that of patients with mesothelioma, demonstrating the validity of the model. We also show that long-term treatment with a COX-2 inhibitor prior to the development of disease does not have a survival benefit, suggesting that this is not a useful cancer prevention therapy for asbestos-exposed individuals. The model is robust and suitable for testing a wide variety of protocols and a range of translational studies.
COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines
2010, Lung Cancer
Citation Excerpt :
Currently the recommended systemic therapy for mesothelioma is cisplatin plus pemetrexed based on the phase III EMPHACIS trial which achieved a response rate of 41% with a median survival of 12.1 months in 456 patients [8,9]. Pemetrexed (LY 231514) is a structural analogue of methotrexate and lometrexol which is retained at high concentrations within the cell by irreversible polyglutamation [10,11] and demonstrated activity in MPM as a single agent in Phase II trials [12]. It is a multitargeted antifolate that acts by inhibiting thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase.
Although malignant pleural mesothelioma is a rare tumour, its incidence is increasing. The prognosis remains very poor with an average survival of 10 months from diagnosis. The choice of chemotherapy regimens for mesothelioma patients is limited and new approaches are required. COX-2 inhibition induces apoptosis in a variety of tumour cell lines. The cytotoxic effect of conventional drugs may be enhanced by the addition of a COX-2 inhibitor. In order to identify possible new therapeutic approaches we aimed to determine whether the addition of COX-2 inhibitors would enhance the cytotoxic effect of chemotherapeutic agents in mesothelioma cell lines.
Three mesothelioma cell lines MSTO-211H, NCI-H2052 and NCI-H2452 were utilised. Using the COX-2 positive A549 lung cancer cell line as control, all cell lines were assayed using an MTT assay with non-specific COX-2 inhibitors (sulindac and flurbiprofen), specific COX-2 inhibitors (DuP-697 and NS-398), and chemotherapeutic agents (cisplatin, vinorelbine and pemetrexed).
All cell lines exhibited COX-2 expression by western blotting using two antibodies. The addition of either DuP-697 or NS-398 increased the sensitivity to pemetrexed in all cell lines.
These findings suggest that the design of novel pemetrexed-containing combination regimens with increased cytotoxicity may be feasible.
Ribonucleases as potential modalities in anticancer therapy
2009, European Journal of Pharmacology
Antitumor ribonucleases are small (10–28 kDa) basic proteins. They were found among members of both, ribonuclease A and T1 superfamilies. Their cytotoxic properties are conferred by enzymatic activity, i.e., the ability to catalyze cleavages of phosphodiester bonds in RNA. They bind to negatively charged cell membrane, enter cells by endocytosis and translocate to cytosol where they evade mammalian protein ribonuclease inhibitor and degrade RNA. Here, we discuss structures, functions and mechanisms of antitumor activity of several cytotoxic ribonucleases with particular emphasis to the amphibian Onconase, the only enzyme of this class that reached clinical trials. Onconase is the smallest, very stable, less catalytically efficient and more cytotoxic than most RNase A homologues. Its cytostatic, cytotoxic and anticancer effects were extensively studied. It targets tRNA, rRNA, mRNA as well as the non-coding RNA (microRNAs). Numerous cancer lines are sensitive to Onconase; their treatment with 10–100 nM enzyme leads to suppression of cell cycle progression, predominantly through G₁, followed by apoptosis or cell senescence. Onconase also has anticancer properties in animal models. Many effects of this enzyme are consistent with the microRNAs, one of its critical targets. Onconase sensitizes cells to a variety of anticancer modalities and this property is of particular interest, suggesting its application as an adjunct to chemotherapy or radiotherapy in treatment of different tumors. Cytotoxic RNases as exemplified by Onconase represent a new class of antitumor agents, with an entirely different mechanism of action than the drugs currently used in the clinic. Further studies on animal models including human tumors grafted on severe combined immunodefficient (SCID) mice and clinical trials are needed to explore clinical potential of cytotoxic RNases.
Comparison of semiquantitative fluorescence imaging and PET tracer uptake in mesothelioma models as a monitoring system for growth and therapeutic effects
2008, Nuclear Medicine and Biology
Various techniques are available for in vivo imaging, and precise understanding of their characteristics is essential for effective use of the imaging results. We established human mesothelioma cell lines expressing red fluorescent protein (RFP) and examined their fluorescence intensity and uptake of positron emission tomography (PET) tracer analogs to compare their characteristics and assess their usefulness in the evaluation of therapeutics.
A human mesothelioma cell line was stably transfected to express RFP. Fluorescence, cell number and protein amount were measured during cell growth and treatment with cytotoxic reagents. In in vivo experiments, RFP-expressing cells were injected subcutaneously or into the pleural cavity of nude mice, and fluorescence images were taken with or without pemetrexed treatment. The uptake of [³H]3′-deoxy-3′-fluorothymidine ([³H]FLT) and [¹⁴C]2-fluoro-2-deoxy-d-glucose ([¹⁴C]FDG) under treatment with the above reagents in vitro and in vivo were examined.
Strong correlation was observed between fluorescence intensity and total cell number with or without cytotoxic treatment. The uptake of [³H]FLT and [¹⁴C]FDG decreased rapidly after the initiation of treatment with actinomycin D or cycloheximide. When treated with pemetrexed, the uptake of [³H]FLT temporarily increased. The cells formed subcutaneous and orthotopic tumors, with fluorescence intensity correlating with tumor volume. The correlation was sustained under pemetrexed treatment. The uptake of [³H]FLT in vivo increased significantly early after pemetrexed treatment.
Fluorescence imaging could be used to semiquantitatively monitor tumor size, whereas PET could be used to monitor tumor response to therapeutic treatments, and especially, FLT might be a good marker of the response to anti-folate chemotherapeutics.
Trimethylamine N-oxide: role in cell senescence and age-related diseases
2023, European Journal of Nutrition

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New Agents in the Management of Advanced Mesothelioma

Section snippets

Host and Tumor Prognostic Factors for Response

Status of Medical Treatment of Mesothelioma Before Pemetrexed

New Agents for Therapy of Mesothelioma: Pemetrexed

New Agents for Therapy of Mesothelioma: Ranpirnase

Epidermal Growth Factor Receptor Pathway Inhibitors

Conclusions

Lung Cancer

Chest

Lung Cancer

Lung Cancer

Ann Oncol

Lung Cancer

J Radiol

Chest

Ann Oncol

Lung Cancer

Ann Oncol

Semin Oncol

Clin Lung Cancer

Adv Enzyme Regul

Ann Oncol

Semin Oncol

Semin Oncol

Chem Biol

Biochem Biophys Res Commun

Cancer Treat Rev

Adv Cancer Res

Biochim Biophys Acta

Biochem Pharmacol

Malignant pleural mesotheliomaA disease unaffected by current therapeutic maneuvers

J Clin Oncol

A proposed new international TNM staging system for malignant pleural mesothelioma

Chest

Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma

J Clin Oncol

Prognostic factors in patients with pleural mesotheliomaThe European Organization for Research and Treatment of Cancer experience

J Clin Oncol

Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma

J Clin Oncol

Prognostic factors for malignant mesothelioma in 142 patientsValidation of CALGB and EORTC prognostic scoring systems

Thorax

Phase III randomized trial of Onconase (ONC) vs. doxorubicin (DOX) in patients (Pts) with unresectable malignant mesothelioma (UMM)Analysis of survival

Proc Am Soc Clin Oncol

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma

J Clin Oncol

Multiple regression analysis of prognostic variables for survival from the phase III study of pemetrexed + cisplatin vs. cisplatin in malignant pleural mesothelioma

Proc Am Soc Clin Oncol

Using gene expression ratios to predict outcome among patients with mesothelioma

J Natl Cancer Inst

Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma

Cancer Res

Gene expression profiling of malignant mesothelioma

Clin Cancer Res

Body CT and oncologic imaging

Radiology

Response rate accuracy in oncology trialsReasons for interobserver variability

J Clin Oncol

New guidelines to evaluate the response to treatment in solid tumors

J Natl Cancer Inst

Measurement of mesothelioma on thoracic CT scansA comparison of manual and computer-assisted techniques

Med Phys

Malignant pleural mesotheliomaEvaluation with CT, MR imaging, and PET

Radiographics

The role of new imaging techniques in diagnosis and staging of malignant pleural mesothelioma

Curr Opin Oncol

Is there a role for pre-operative contrast-enhanced magnetic resonance imaging for radical surgery in malignant pleural mesothelioma?

Eur J Cardiothorac Surg

Semiquantitative analysis of dynamic contrast enhanced MRI in cancer patientsVariability and changes in tumor tissue over time

J Magn Reson Imaging

Magnetic resonance spectroscopy in clinical oncology

Onkologie

Role of 18F-FDG PET for evaluating malignant pleural mesothelioma

Cancer Biother Radiopharm

Evaluation of patients with known mesothelioma with 18F-fluorodeoxyglucose and PET. Comparison with computed tomography

Clin Positron Imaging

Prognostic value of FDG PET imaging in malignant pleural mesothelioma

J Nucl Med

Prognostic value of FDG PET imaging in malignant pleural mesothelioma