Pancreatic cancer is a devastating disease that is refractory to standard chemotherapies, as demonstrated by the low five-year survival rate of 8%. The objective of this proposal is to assess a novel, highly promising therapeutic for the treatment of pancreatic cancer, employing comprehensive in vitro and preclinical in vivo testing prior to clinical evaluation studies. The sigma-2 (S2) receptor is overexpressed in pancreatic cancer, and small molecule ligands to this receptor localize to these tumors. In addition, PDAC cancer cells rapidly internalize selected sigma-2 ligands. This finding prompted us to explore the possibility of using these ligands to deliver additional therapeutic payloads to PDAC tumor cells via chemical linkage with our ligands. We have successfully used S2 ligands to deliver structurally diverse compounds including both peptides and small molecule therapeutics (classic chemotherapeutics [rapamycin] and peptidomimetics), into the cancer cells both in vitro and in vivo. In each case, the activity profiles of the conjugates were far greater than the isolated components or their equimolar combinations. Based on this delivery concept, we combined the tumor selectivity of the S2 ligand SV119 with a promising drug cargo that induces cell death selectively in PDAC (dm-Erastin), by creating a single small molecule conjugate (SW V-49). We have shown that this conjugate efficiently kills tumor cells in stroma-rich pancreatic cancer models with only limited signs of systemic toxicity. The key tasks of this project involve pharmacology and toxicity drug testing employing PDAC cell lines in vitro (murine and human), primary patient-derived 3D organoid in vitro cultures as well as syngeneic (mouse) and patient-derived xenograft models (PDX) of pancreatic cancer.

Public Health Relevance

Pancreatic adenocarcinoma is the third most lethal cancer and notoriously resistant to standard chemotherapy. We present here a novel strategy for the delivery of a small molecule drug cargo (dm-Erastin) selectively into pancreatic cancer (using the sigma-2 ligand SV119) causing tumor-selective cell death. We propose to comprehensively characterize the novel cancer-selective drug conjugate SW V-49 and evaluate its mode of action and its pharmacologic properties in preclinical models of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA163764-06
Application #
9237745
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2012-06-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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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
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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
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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

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