Pancreatic cancer is a devastating disease, with an estimated 43,140 new cases in the United States in 2010, and represents the fourth highest mortality overall amongst all cancers. The objective of our research efforts is to develop novel therapeutics for the treatment of pancreatic cancer. Sigma-2 (S2) ligands are small molecules that are under clinical investigation as imaging agents because their receptors are overexpressed in pancreatic cancer, which is the reason why they selectively localize to these tumors. In addition, S2 ligands are pursued as therapeutics because they have an intrinsic ability to cause cancer-selective cell death. The rapid and cancer-selective uptake mechanism in combination with their intrinsic killing capacity puts sigma-2 ligands into a strategic position for drug development evaluations. XIAP is a key molecule for the inhibition of apoptosis by blocking the activation of caspases-3/7 and caspase-9. As such, XIAP controls induction of apoptosis through the extrinsic as well as the intrinsic apoptosis pathway. Recent X-ray crystallography and NMR studies have identified the structural interactions between XIAP and its natural inhibitor, SMAC. Of note, preliminary data using a sigma-2 ligand conjugated to a SMAC mimetic showed robust killing of pancreatic cancer cells. Here, we propose the synthesis and functional analysis of several novel SMAC mimetics conjugated to sigma-2 ligands with the ultimate goal of selecting the best drug candidate(s) for a phase I clinical trial in patients with pancreatic adenocarcinoma. We hypothesize that tumor-selective targeting of SMAC mimetics through chemical linkage to sigma-2 ligands will prove efficacious in the treatment of pancreatic adenocarcinoma.
In Aim 1, we propose the synthesis and in vitro characterization of a series of novel S2/Smac conjugates focusing primarily on their ability to induce tumor cell apoptosis.
In Aim 2, we will assess our current S2/Smac conjugate and the top few new compounds for their ability to selectively target and kill pancreatic cancers in vivo. In summary, we present here a novel concept for the cancer-selective, sigma-2- mediated co-delivery of apoptosis-inducing cargo. Once inside the cell, these drug conjugates mediate enhanced killing via the combined activities of both moieties (dual-domain therapeutics). As a result, the cytotoxic activity of the delivery agent is augmented following the signaling pathway of its cargo. This new concept represents an innovative opportunity for the development of future small molecule drugs with dual functionality combined in a single reagent.

Public Health Relevance

Pancreatic adenocarcinoma is the fourth most lethal cancer and notoriously resistant to standard chemotherapy. We present here a novel strategy for delivery of small molecules selectively to pancreatic cancer that induce tumor cell death. We propose the rational design and functional validation of several candidate compounds in vitro and in a mouse model of human pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163764-01
Application #
8219912
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2012-06-01
Project End
2017-03-31
Budget Start
2012-06-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$375,271
Indirect Cost
$122,703
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Garg, Gunjal; Vangveravong, Suwanna; Zeng, Chenbo et al. (2014) Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer. Mol Cancer 13:50
Hashim, Yassar M; Spitzer, Dirk; Vangveravong, Suwanna et al. (2014) Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134. Mol Oncol 8:956-67
Zeng, C; Vangveravong, S; McDunn, J E et al. (2013) Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer. Br J Cancer 109:2368-77