# On the path to the clinic: Lead optimization and pathway analysis of the pancreatic cancer-selective drug conjugate SW V-49

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $381,250

## Abstract

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.

## Key facts

- **NIH application ID:** 9899938
- **Project number:** 5R01CA163764-09
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** WILLIAM G HAWKINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2012-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899938

## Citation

> US National Institutes of Health, RePORTER application 9899938, On the path to the clinic: Lead optimization and pathway analysis of the pancreatic cancer-selective drug conjugate SW V-49 (5R01CA163764-09). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/9899938. Licensed CC0.

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