Clinical Development of the Pancreatic Cancer Drug Conjugate SW V-49
The objective of this proposal is to clinically evaluate a novel therapeutic for the treatment of pancreatic cancer with in order to improve survival rates. 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.
Project 2: S2R ligands selectively target cancers. A) Micro PET/CT of [18F] labeled S2RS2R ligand
in a mouse bearing an implanted pancreatic adenocarcinoma (Kashiwagi et al., 2007).66 B) Transaxial 18F-ISO PET and PET/CT image of patient with breast cancer (left), head and neck cancer (middle), and lymphoma (right) increased uptake in the tumor (arrows) (Dehdashti et al., 2013). SUV = standardized uptake value; T = tumor, M = muscle.This finding prompted us to explore the possibility of using these ligands to deliver a therapeutic payload 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 mechanism, we combined the tumor selectivity of the S2 ligand with a promising drug cargo that induces cell death selectively in PDAC, to create a single small molecule conjugate (SW V-49). We have shown that this conjugate efficiently kills tumor cells in stroma-rich pancreatic cancer tumor models with limited systemic toxicity.
This project performs pharmacology and toxicity assays, and tests the conjugate in a clinical trial. We hypothesize that SW V-49 will similarly improve survival in patients with PDAC. To validate this hypothesis, we perform toxicity and pharmacology studies (PK/PD studies), hope to confirm the mechanisms of drug action, and test this promising novel therapeutic in a clinical trial.
Project 2 aims:
- Aim 1: Preclinical assessment of SW V-49 including bioavailability, toxicity, efficacy and pathway selectivity.
- Aim 2: Perform a phase 0/I/II clinical trial in patients with treatment refractory stage IV pancreatic cancer.
Creation of an effective therapeutic for PDAC is the most significant aspect of our current work. However, the proposed drug-delivery platform is broadly applicable to additional drug development because the targeting strategy can easily be applied to additional small molecules targeting other pathways. If successful, it is very likely that this research will significantly impact the field of cancer-selective drug delivery. In summary, our project is a highly innovative approach to therapeutically targeting PDAC by linking S2R ligands with an Erastin derivative. This strategy is designed to activate cell death pathways selectively in the tumors and has tremendous potential to overcome drug resistance, improve efficacy and minimize off-site toxicities.