A Second Generation 2-Methoxyestradiol Prodrug Is Effective Against Barrett's Adenocarcinoma in a Mouse Xenograft Model

This is the author's accepted manuscript. The original is available at http://mct.aacrjournals.org/content/12/3/2552-Methoxyestradiol (2-ME2) is an endogenous metabolite of estradiol. In preclinical models, 2-ME2 is effective against different types of tumors. Unfortunately, only low systemic concentrations of 2-ME2 can be achieved following oral administration, even after very high doses are administered to patients. In an effort to solve this problem we have now synthesized and tested a new prodrug of 2-ME2 that is water soluble due to a bio-reversible hydrophilic group added at the 3-position and more effectively resists metabolic inactivation due to an ester moiety added to mask the 17-position alcohol. We are reporting here for the first time that this double prodrug of 2-ME2 is effective as an antiproliferative and anti-cancer agent for both in vitro and in vivo studies against Barrett's esophageal adenocarcinoma (BEAC), and provided greater potency than 2-ME2 in inhibiting the growth of BEAC xenografts. Finally, studies indicate that, like 2-ME2, the 2-ME2-PD1 exhibits anticancer effect through possible disruption of microtubule-network

RRx-001 Priming of PD-1 Inhibition in the Treatment of Small Cell Carcinoma of the Vagina : A Rare Gynecological Tumor

Small cell carcinoma of the vagina is rare, so rare in fact that the total number reported in English-language journals is less than 30. Due to this extremely low incidence, no specific treatment guidelines have been established, and most of what is clinically known is derived from a handful of single case reports. However, as befitting its highly aggressive histologic features, which are reminiscent of small cell lung cancer (SCLC), first-line treatment is modeled after SCLC. Herein is reported the case of a 51-year-old African-American patient with metastatic biopsy-proven small cell carcinoma of the vagina that progressed through multiple therapies: first-line cisplatin and etoposide (making it platinum-resistant) and radiotherapy, followed by the tumor macrophage-stimulating agent RRx-001 in a clinical trial called QUADRUPLE THREAT, which per protocol preceded a mandated rechallenge with cisplatin and etoposide. RECIST v.1.1 tumor progression on both RRx-001 and cisplatin/etoposide was accompanied by central necrosis in several of the enlarged lymph nodes and hepatic metastases, which may have been evidence of pseudoprogression, accounting for her ongoing longer-than-expected survival, since the necrotic tissue may have primed the activity of the PD-1 inhibitor. The lack of response to RRx-001 is hypothesized to have correlated with sparse tumor macrophage infiltration, seen on pre-and post-treatment biopsies, since the mechanism of action of RRx-001 relates to stimulation of tumor-associated macrophages. (C) 2017 The Author(s) Published by S. Karger AG, BaselPeer reviewe