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.
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.
|Pati, Maria Laura; Niso, Mauro; Spitzer, Dirk et al. (2018) Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (?2) receptor and P-gp protein in the cytotoxic action: In vitro and in vivo activity in pancreatic tumors. Eur J Med Chem 144:359-371|
|Pati, Maria Laura; Hornick, John R; Niso, Mauro et al. (2017) Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer. BMC Cancer 17:51|
|Hashim, Yassar M; Vangveravong, Suwanna; Sankpal, Narendra V et al. (2017) The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer. J Exp Clin Cancer Res 36:14|
|Su, Yang; Tatzel, Katharina; Wang, Xuejun et al. (2016) Mesothelin's minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane. Oncotarget 7:31534-49|
|Ohman, Kerri A; Hashim, Yassar M; Vangveravong, Suwanna et al. (2016) Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic. Oncotarget 7:33529-41|
|Makvandi, Mehran; Tilahun, Estifanos D; Lieberman, Brian P et al. (2015) The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer. Biochem Biophys Res Commun 467:1070-5|
|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|
|Mach, Robert H; Zeng, Chenbo; Hawkins, William G (2013) The ýý2 receptor: a novel protein for the imaging and treatment of cancer. J Med Chem 56:7137-60|
|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|
Showing the most recent 10 out of 11 publications