How Many Therapeutic Options Are There for Recurrent or Metastatic Salivary Duct Carcinoma?
Authors: Laura D. Locati, Paolo Bossi, Lisa Licitra
Journal: Journal of Clinical Oncology (2012)

Piha-Paul et al 1 recently described the impres- sive response of two patients with salivary duct carcinoma (SDC) who were treated with temsirolimus and bevacizumab within a phase I study.Their article follows another recent report about the promising activity of androgen deprivation therapy in the same disease. 2The rationale of this latter approach is based on the well-reported overexpression of androgen receptors (ARs) in SDC, 3,4 which explains the consistently documented activity of androgen deprivation therapy in patients with AR-positive SDC. 2,5In the article by Piha-Paul et al, 1 the combination of mammalian target of rapamycin (mTOR) inhibition and bevacizumab was seen to be efficacious in two patients, although the authors seem to attribute all of the benefit to mTOR inhibition.Indeed, one of the two patients had an aberration of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway (PTEN loss), whereas the other responding patient did not demonstrate a PI3K mutation or PTEN loss.SDC is a rare tumor and its molecular profile and suitability for drug targeting have not been well investigated.However, in the absence of data on the molecular profile of SDC, we speculate that SDC could be mutated from prostate cancer (PCa).In PCa, which is typically AR positive, there is substantial evidence that indicates that the activity of the AR can be regulated not only by androgen but also by the cross talk with the protein kinase signal transduction, such as the PI3K/AKT/mTOR pathway. 6The PTEN gene negatively regulates the PI3K/AKT/mTOR pathway, thereby acting as a tumor suppressor gene.PTEN deletions are frequently found in PCa tumor specimens (77%); moreover, this has been determined to be correlated with pAKT and AR expression. 7These data are corroborated by preclinical models wherein PTEN-deficient xenografts, ARs, and the PI3K/AKT/ mTOR pathway cross regulate each other by a reciprocal negative feedback, so that inhibition of one of them results in tumor cell survival maintenance, 8 although PI3KA inhibition has been reported to be dominant over AR signaling. 9In this context, the administration of BEZ235, a dual inhibitor of PI3K and mTOR, as a single agent resulted in tumor growth arrest only.On the contrary, the inhibition of PI3K and the AR pathway resulted in tumor regression, which suggests that the combined approach that is based on AR and PI3K/ AKT/mTOR inhibition could be therapeutically appealing for PCa. 8 Several compounds that target angiogenesis are under study in advanced PCa.Bevacizumab, in particular, has demonstrated activity in combination with docetaxel plus prednisone. 10n the basis of these premises, we hypothesize that the treatment effect observed with temsirolimus and bevacizumab in this ARexpressing disease could have been obtained through the AR modulation; thus, we encourage the authors to examine the AR expression in the tumor specimens.In this context, if this hypothesis is confirmed, a novel treatment strategy should be investigated in SDC.