Abstract 5359: Antitumor efficacy of EC1456 in patient derived xenograft models of ovarian, endometrial, NSCLC and TNBC

Abstract

EC1456, a potent folate-targeted tubulysin conjugate, is currently being evaluated in a phase 1 dose escalation study in patients with advanced solid tumors. To assist in upcoming cancer indication selection decisions for advanced trials, we tested EC1456 against eight patient-derived xenograft (PDX) cancer models. Thus, EC1456 was evaluated as a single agent or in combination with standard of care (SOC) treatments against two folate receptor (FR)-positive models each of ovarian, endometrial, non-small cell lung (NSCLC) and triple negative breast (TNBC) tumor models. Nude mice engrafted subcutaneously with PDX tumors received 4 μmol/kg/week EC1456 for two weeks, following a once a week (SIW) or two times a week (BIW) schedules, either alone or in combination with 15 mg/kg, SIW x 2 Paclitaxel (ovarian and endometrial), 1 mg/kg SIW x 2 eribulin mesylate (TNBC) or 15 mg/kg, SIW docetaxel (NSCLC). EC1456 alone demonstrated tumor growth suppression or stasis in most of the tumor models and significantly greater anti-tumor activity (including cures) with no detectable increase in toxicity when tested in combination with the SOC agents. Overall, EC1456 significantly augmented the growth inhibitory effects of SOC treatments against all four PDX cancer indications examined, thus lending support to future clinical development of this novel FR-targeted agent. Citation Format: Joseph A. Reddy, Alicia Bloomfield, Christina Taylor, Katherine Hargett, Melissa Nelson, Christopher Leamon. Antitumor efficacy of EC1456 in patient derived xenograft models of ovarian, endometrial, NSCLC and TNBC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5359. doi:10.1158/1538-7445.AM2015-5359

Comparison of folate-conjugated rapamycin versus unconjugated rapamycin in an orthologous mouse model of polycystic kidney disease

“…However, biodistribution studies with EC20, a folatetargeted, technetium-based imaging agent, in human patients reveals very little uptake by the choroid plexus and no uptake in the lung and it has been proposed that the specific polarized location of FR␣ in epithelial tissues (i.e., apical or basolateral) may determine whether the receptor would be accessible to an intravenous injection of an FR-targeted conjugate (4,25). Furthermore, it is important to point out that to date minimal toxicity has been observed with folate-targeted lead small molecule drug conjugates in both animal models (22)(23)(24) and human subjects (7,11,12,14). In addition to the polarized nature and relative accessibility of FR␣, as discussed above, this may in part be due to the expression of the reduced folate carrier, which is the primary mediator of folate transport in most normal epithelial cells and for which FR-targeted conjugates do not serve as substrates.…”

A Scalable Method for Squalenoylation and Assembly of Multifunctional 64Cu-Labeled Squalenoylated Gemcitabine Nanoparticles

“…In addition, pancreatic tumors can quickly develop resistance to gemcitabine, and chemical modification of gemcitabine with squalene alters gemcitabine's transport on the cellular level, bypassing one mechanism of gemcitabine resistance 3 , 18 , 19 . Further, the squalenoylation of gemcitabine, a hydrophilic molecule, creates amphipathic chemicals capable of self-assembly into squalenoylated gemcitabine (SqGem)-based nanoparticles (NPs), which are cytotoxic in a variety of human tumor cell lines 15 , 20 . The ability of SqGem to form NPs extends the plasma half-life and allows for active drug targeting, controlled drug release, and co-delivery of multiple therapeutic or imaging agents 3 , 4 , 8 , 9 , 17 .…”