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26 juanuari 2019: Lees ook dit artikel: https://kanker-actueel.nl/dendritische-celtherapie-heeft-succes-bij-patienten-met-mesothelioma-asbestkanker-erasmus-doet-oproep-dat-meer-patienten-zich-aanmelden-voor-de-studie.html

1 april 2017: Lees ook ditt artikel: 

https://kanker-actueel.nl/NL/pembrolizumab-een-anti-pd-medicijn-geeft-uitstekende-resultaten-bij-zwaar-voorbehandelde-patienten-met-mesothelioma.html

1 april 2017: lees ook dit studierapport, een meta analyse bij mesothelioma - asbestkanker: Diagnostic value of microRNAs in asbestos exposure and malignant mesothelioma: systematic review and qualitative meta-analysis over welke aanpak bij mesothelioma eventueel zou kunnen werken. Met ook hier een interessante referentielijst. Tekst gaat onder beeld verder.

mesothelioma asbestkanker grafiek(2)

Schematic drawing illustrating summary findings

En lees onderstaand artikel over ranpirnasse.

Ook in dit studierapport met interessante referentielijst: Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer bewijst tetrakis-ranpirnase ook effectiviteit bij triple negatieve borstkanker. In alle studies met ranpirnase komt naar voren dat dit middel werkt bij bepaalde mutaties en tumorenexpressie TROP-2 expressie. Er is best veel ondezoek naar gedaan, zie ook referentielijst onderaan dit artikel. En heel belangrijk het lijkt een medicijn te zijn dat weinig bijwerkingen geeft.

18 januari 2012:

Nu Nederlandse onderzoekers hebben aangetoond dat een chemo behandeling bij zowel buik mesothelioma als long mesothelioma geen positief effect hebben op de mediane overleving is de aanpak met niet toxische enzymen onder de naam ranpirnase - onconase nog belangrijker geworden. Wie hier klikt kan een volledig studierapport inzien over ranprinase - onconase bij mesothelioma dat bijzonder positief oordeelt over dit niet toxische middel. Hier de conclusie van deze review en daaronder een studie abstract met ranpirnasse uit 2002 met bijzonder goede resultaten op de mediane overlevingstijd. Mocht u mesothelioma hebben neem dit studierapport aub mee naar uw oncoloog - arts.

Ranpirnase is a ribonuclease endowed with potent antitumor properties; its mechanism of action is completely novel since, by degrading tRNA, it acts both as a cytotoxic and a cytostatic drug; furthermore, owing to both its in vitro synergy with other cytotoxic agents, and its tolerability as a single agent, it is amenable to combination with traditional chemothera-peutic drugs, eg, doxorubicin and cisplatin.
Since its early clinical development, it has held great promise for the treatment of MMe, where it seems to act mainly as a cytostatic agent, thus stabilizing the disease. Indeed, ranpirnase proved to be superior to doxorubicin within a phase III trial, while preliminary results of another large, phase III trial suggest that the combination of ranpirnase and doxorubicin could be more effective than doxorubicin alone
Ranpirnase appears to be generally well tolerated with predicable and reversible toxicity, and with very few serious adverse events; furthermore, dose modifications are usually required only for changes in renal function.
Unfortunately for the development of the drug, during the course of its phase III development, the combination of pemetrexed and a platinum derivative emerged as the standard first-line treatment for MMe patients in. This led to a slowing of the recruitment into the P30–302 protocol and clearly reduced the interest for its use as a first-line treatment.
Thus, while waiting the final results of the above study, it appears clear that ranpirnase may find its niche (in combination with doxorubicin) for second-line therapy of MMe (Pavlakis and Vogelzang 2006) where, at present, no standard of care exists.
However, the current understanding of its mechanism of action, coupled with its favorable toxicity profile, characterized by a lack of major toxicities, especially in terms of hematology, make ranpirnase an appealing drug to use in combination with other anticancer agents, as well as with radiotherapy. This could clearly open a new frontier for the use of this novel drug in tumor types other than MMe.

2002: 

In een Phase II trial bleek het medicijn ranpirnase (onconase) maar liefst bij 41 van de 81 deelnemende patiënten de tumorgroei tot stilstand te brengen. De overlevingstijd werd verlengd tot gemiddeld 18,5 maanden, een verbetering van 6-8 maanden in vergelijking met de overlevingtijd die normaal staat voor een mesothelioma patiënt. Dit resultaat was nog opmerkelijker omdat een derde van de patiënten helemaal niet had gereageerd op eerdere chemobehandeling. Ranpirnase wordt gehaald uit de eieren van kikkers en de patiënten vertoonden geen bijwerkingen zoals normaal gesproken voorkomen bij een behandeling met bv. chemo.

A promising drug for mesothelioma
Results of a Phase II multicentre trial indicate that the ribonuclease-based drug ranpirnase (Onconase) shows promise as a treatment for patients with inoperable malignant mesothelioma. This asbestos-related cancer of the inner lining of the chest and abdomen will kill over 250,000 people in Europe alone in the next 35 years. As reported in the Journal of Clinical Oncology, the tumours either shrank or stopped growing in 41 of the 81 patients that were assessable for tumour response. The median survival time for these patients was 18.5 months — a dramatic improvement over the 6–8-month life expectancy for the average mesothelioma patient. The results were especially encouraging in light of the fact that over one-third of these patients did not respond successfully to prior systemaic therapy. Ranpirnase — a ribonuclease that was developed from the eggs of the frog, Rana pipiens — interrupts protein synthesis, resulting in the inhibition of cell growth and the induction of apoptosis in cancer cells. The drug has been shown to be well tolerated in most patients, and has not been associated with the toxicity that is typically associated with chemotherapy. A randomized, controlled Phase III trial of the combination of ranpirnase with doxorubicin in patients with inoperable malignant mesothelioma, compared with doxorubicin therapy alone, is also underway in the United States and Europe. 
ORIGINAL RESEARCH PAPER
Mikulski, S. M. et al. Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J. Clin. Oncol. 20, 274–281 (2002). | PubMed | 

 

A new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.

Mol Cancer. 2014; 13: 53.
Published online 2014 Mar 10. doi:  10.1186/1476-4598-13-53
PMCID: PMC4015355

Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer

Donglin Liu,corresponding author1,2 Thomas M Cardillo,2 Yang Wang,2 Edmund A Rossi,1,2 David M Goldenberg,corresponding author1,2,3 and Chien-Hsing Chang1,2
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Abstract

Background

Ranpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC).

Methods

The DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model.

Results

(Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50 ≤ 1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose.

Conclusions

A new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.

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Articles from Molecular Cancer are provided here courtesy of BioMed Central

The qualitative meta-analysis and functional investigation confirmed the early diagnostic value of two miRNA signatures for MM. Large-scale, standardized validation studies are needed to assess their clinical relevance, so as to move from the workbench to the clinic.

Oncotarget. 2016 Sep 6; 7(36): 58606–58637.
Published online 2016 Jun 1. doi:  10.18632/oncotarget.9686
PMCID: PMC5295457

Diagnostic value of microRNAs in asbestos exposure and malignant mesothelioma: systematic review and qualitative meta-analysis

Luigina Micolucci,1,2 Most Mauluda Akhtar,1,2 Fabiola Olivieri,2,3 Maria Rita Rippo,2 and Antonio Domenico Procopio2,3
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Abstract

Background

Asbestos is a harmful and exceptionally persistent natural material. Malignant mesothelioma (MM), an asbestos-related disease, is an insidious, lethal cancer that is poorly responsive to current treatments. Minimally invasive, specific, and sensitive biomarkers providing early and effective diagnosis in high-risk patients are urgently needed. MicroRNAs (miRNAs, miRs) are endogenous, non-coding, small RNAs with established diagnostic value in cancer and pollution exposure. A systematic review and a qualitative meta-analysis were conducted to identify high-confidence miRNAs that can serve as biomarkers of asbestos exposure and MM.

Methods

The major biomedical databases were systematically searched for miRNA expression signatures related to asbestos exposure and MM. The qualitative meta-analysis applied a novel vote-counting method that takes into account multiple parameters. The most significant miRNAs thus identified were then subjected to functional and bioinformatic analysis to assess their biomarker potential.

Results

A pool of deregulated circulating and tissue miRNAs with biomarker potential for MM was identified and designated as “mesomiRs” (MM-associated miRNAs). Comparison of data from asbestos-exposed and MM subjects found that the most promising candidates for a multimarker signature were circulating miR-126-3p, miR-103a-3p, and miR-625-3p in combination with mesothelin. The most consistently described tissue miRNAs, miR-16-5p, miR-126-3p, miR-143-3p, miR-145-5p, miR-192-5p, miR-193a-3p, miR-200b-3p, miR-203a-3p, and miR-652-3p, were also found to provide a diagnostic signature and should be further investigated as possible therapeutic targets.

Conclusion

The qualitative meta-analysis and functional investigation confirmed the early diagnostic value of two miRNA signatures for MM. Large-scale, standardized validation studies are needed to assess their clinical relevance, so as to move from the workbench to the clinic.

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