Targeting STAT3 for Lymphoma Project

Project: Novel Nucleotide-based Approaches Targeting the STAT3 Pathway for the Treatment of Lymphoma
Project Leaders: Hua Yu, Ph.D. and Marcin Kortylewski, Ph.D.

This project will conduct experiments to optimize the design and delivery of therapeutic oligonucleotide agents targeted to the STAT3 pathway. STAT3 is a transcription factor central to the up-regulation of many genes involved in lymphoma cell survival, proliferation and resistance to therapy. STAT3 inhibition will both directly target tumor cells as well as curtail the suppression of the normal anti-tumor immune response in the cells of the tumor microenvironment. One agent, pG-STAT3siRNA, is currently being tested for animal toxicology to prepare for human clinical trials.

The specific aims of this project are as follows:

Aim 1: Develop anti-lymphoma targeting of oligonucleotide-conjugated STAT3 siRNA delivery systems.

  1. Manufacturing development and production of CpG-STAT3siRNA for required IND toxicity studies.
  2. Preclinically evaluate the anti-lymphoma effects of CTLA-4apt-STAT3siRNAs, as well as effects on tumor angiogenesis and immunologic microenvironment.

Aim 2: Optimize CpG-STAT3dODN strategy for targeting B cell lymphoma cells

  1. Preclinically assess the direct cytotoxic and immune-mediated effects of CpG-STAT3dODN on B cell lymphoma.
  2. Evaluate pharmacokinetic (PK) and pharmacodynamic (PD) properties of CpG-STAT3dODN delivered by different routes (intradermal vs. intravenous).