Invited Commentary

Dear Prof. Riccardi,

I read carefully your manuscript and I am impressed. First, you have been therapeutically successful with ketotifen in a huge number of patients of any age and gender with both plexiform and cutaneous neurofibromas. Second, I am irritated by the problems you still have trying to convince the American community that neurofibromas may be cured with a preventive therapy. You propose a long term cure with a drug that is tolerated by patients and is not a chemotherapeutic drug, such as the Kit inhibitor, imatinib (Gleevec®), or other kinase inhibitors. I know them well from the molecular point of view respecting my many-years work at the Ludwig institute.

 

A number of influential investigators are producing a huge literature to sustain the “chemotherapy hypothesis.” They are supported by a “group of scientists” who still believe that, in order to find a potential molecular target for an effective drug, it is necessary to investigate the molecular processes involved in the “advanced tumor,” (e.g., malignant peripheral nerve sheath tumor, or MPNST). By contrast, another branch of serious molecular oncologists teach the alternative: there are tumors that progress through and require fibrosis and extracellular matrix (ECM) deposition, (e.g., pancreatic, lung or breast carcinomas) that have to be blocked near or at the onset.

 

I already had realized that there is a strong prejudice (in Europe, as well as elsewhere), as you clearly depicted in your paper, about the molecular mechanisms initiating and sustaining neurofibroma formation. At some point, it is true that the core of the tumor comprises Schwann cells that lose neurofibromin. These cells, however, proliferate and undergo neoplastic transformation thanks to novel expression of growth factor autocrine loops, as well as the cytokine-stimulation and probably the ECM pressure generated by fibroblasts transformed to myofibroblasts by mast cell-derived factors (mainly TGF-β). In the mouse model, neurofibromas do not develop in the absence of mast cells.

 

Further, there seem to be few investigators asking how an NF1+/- nerve functions after injury or whether NF1+/- or NF1-/- Schwann cells mature and myelinate. Anyway, this absence of an NF1-unique therapeutic approach to proceed is perplexing. In Padua, I have received dramatic testimonies from mothers who have seen their child die from a plexiform neurofibromas transformed to an MPNST without any attempted therapy… (“terapia compassionevole”)

 

In this context, I have focused on three alternative, but complementary considerations:

1) NF1 overlaps mastocytosis.
2) The onset of neurofibroma formation.
3) Topical treatments.

 

I, like you, think that the source of the problem is simply “knowledge.” However, an informative publication is not enough. We need to publish scientific work, unassailable from a scientific point of view. We also need a review summarizing molecular and clinical data, as well as an overview of ketotifen: this drug, in contrast to H1 and H2 antihistamines, is able to prevent mast cell secretion of cytokines, which probably stimulate fibroblasts to produce ECM, enable Schwann cells to proliferate and afford thereby neoplastic transformation.

 

F Chiara, PhD

images
12 Mar 2015
Padua, Italy

 

 

 

 

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