10月13-16日，第14届国际妇科肿瘤学会双年会（IGCS 2012）在加拿大温哥华举行。IGCS 2012一如既往地为参会者奉上妇科肿瘤学领域最新研究进展，提供发布、讨论和争辩最新科学信息的良机。金宝搏网站登录技巧 对本届年会进行了专题报道（http://zt.cmt.com.cn/zt/igcs2012/index.html）。 

研究摘要：

Meso-TR3: A Novel TRAIL-Based Targeted Therapeutic in
Ovarian Cancer
G Garg1, WG Hawkins2, MA Powell1, DGMutch1, J Gibbs2,
P Goedegebuure2, D Spitzer2
1Division of Gynecologic Oncology, Department of Obstetrics
and Gynecology, and 2Department of Surgery, Washington
University School of Medicine, St Louis, MO.
Background: Chemoresistance limits the use of cytotoxic
agents in the treatment of ovarian cancer, as more than half of
ovarian tumors eventually acquire inactivating p53 mutations.
Tumor necrosis factorYrelated apoptosis-inducing ligand
(TRAIL) is a member of the TNF superfamily. It kills cancer
cells via the extrinsic death pathway independent of p53, thus
offering a complementary approach to conventional cancer
therapy. We have developed a novel TRAIL form, designated
TR3, which represents a fusion protein of 3 consecutive TRAIL
ectodomains that is generically extensible with stoichiometric
control and improved stability. It has been shown that tethering
TRAIL (TR3) to the surface of cancer cells enhances cell

killing. Ovarian cancer cells have been described to express
MUC16, which shows high-affinity interaction with mesothelin
protein. Therefore, we reasoned that modifying the TR3 drug
platform by attaching the mesothelin protein sequence to the
N-terminus of TR3 (generating Meso-TR3) would enhance
target cell killing compared to its nontargeted TR3 counterpart.
Methods: Human embryonic kidney cells [HEK293T] were
used for the production of soluble mesothelin, Meso-TR3,
and TR3. Fluorescence-activated cell sorter (FACS) analysis
was used to determine the expression of MUC16 on different
cancer cell lines (OVCAR-3, Jurkat-H, and HeLa) and
the binding of mesothelin to MUC16-positive cells. The
killing activity of Meso-TR3 and TR3 was compared
using a luminescence-based cell viability assay (Cell-TiterGlo).
Results:WhereasMUC16 was strongly expressed in OVCAR-
3 cells (100% positive), it was completely absent in Jurkat
cells (our reporter cells to determine antigen-independent
killing activities of Meso-TR3 and TR3). Using soluble
mesothelin alone, we were able to demonstrate strong binding
to MUC16 on OVCAR-3 cells. Furthermore, at concentrations
where Meso-TR3 and TR3 killed the same number of
MUC16-deficient Jurkat reporter cells, significantly greater
killing was seen with Meso-TR3 in the MUC16-positive
OVCAR-3 cells. Finally, to obtain evidence for the targeted
killing capacity of Meso-TR3, we challenged HeLa cells (a
native mix of MUC16-positive [80%] and MUC16-negative
cells [20%]), where treatment with Meso-TR3 resulted in a
selective reduction of the MUC16-positive population to 54%
(33% reduction), whereas TR3 alone did not change this ratio.
Conclusions: Meso-TR3, the novel tumor-targeted TRAIL,
enhances TRAIL-mediated killing in MUC16-positive ovarian
cancer via selective drug delivery to the tumor marker. The
ability to target TRAIL to a cell surface protein via a native
ligand/receptor interaction presents a unique opportunity to
create a cancer-selective drug with fewer off-site toxicities
and enhanced killing capacities.