Abstract
A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases.
Highlights
Prostate cancer is the most commonly diagnosed malignancy worldwide and is the second leading cause of cancer death among men [1]
We interrogated gene expression profiles that we have previously generated in the Transgenic Adenocarcinoma of the Mouse Prostate model [TRAMP [15]], comparing the transcriptome of adenocarcinoma and NEPC occurring in TRAMP mice either spontaneously [18] or following pharmacologic inhibition of mast cells (MCs) with cromolyn [9]
Treatment with Androgen deprivation therapy (ADT)/ARPI in patients with castration-resistant prostate cancers (CRPC) fails, due to mechanisms of resistance associated with cellular plasticity and the emergence of treatment-related NEPC [4, 6], and the diagnosis of patients with advanced prostate cancer remains dismal
Summary
Prostate cancer is the most commonly diagnosed malignancy worldwide and is the second leading cause of cancer death among men [1]. Patients with CRPC may be treated with agents inhibiting the androgen receptor pathway (ARPI), such as the AR antagonist enzalutamide These treatments can delay tumor progression despite the failure of ADT, but resistance eventually occurs. Treatment-related NEPC is characterized by few genomic alterations, including N-Myc expression, Rb loss and p53 mutations, and by de-regulation of several epigenetic and transcription factors [2, 6]. This aggressive variant of prostate cancer can very rarely occur in untreated patients and in this case it is called de-novo NEPC [7]. No definitive therapeutic options are available for NEPC, and further study of the molecular mechanisms that stimulate its emergence is necessary to identify novel targets
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