Protein engineering to target tumor-stroma interactions in NSCLC

2014

Targeted Therapeutics Research Award

This grant was funded in part by Upstage Lung Cancer.

Alejandro Sweet-Cordero, MD

Stanford University

Stanford

Jennifer Cochran, PhD

Stanford University

Stanford

Lung cancer cells depend on continuous cross-talk with other cells around them. Drs. Sweet-Cordero and Cochran will use decoy proteins to intercept and disable this essential molecular communications between the tumor and its environment, thereby destroying the cancer.

Research Summary

Over the last few decades, cancer biologists have discovered that one of the ways cancer cells endure is that they receive “survive and grow signals” from surrounding cells in what is called the “tumor microenvironment.” Understanding these signals could provide new ways to treat cancer. This team recently discovered a mechanism by which tumor cells and the surrounding microenvironment (also called the stroma) communicate to increase tumor cell growth. CLCF1, a protein produced by cells in the stroma, is received as a growth signal by tumors cells expressing a “receptor” for this protein (termed CNTFR). This research project will capitalize on this knowledge to develop a new drug (called a “receptor decoy”) that blocks the interaction between CLCF1 and CNTFR. This drug is not a chemical but rather a small protein. The team will develop a variant of this protein that is highly effective in blocking the CLCF1-CNTFR interaction, and will test the efficacy of this receptor decoy in primary human tumors that are propagated in mice. These tumor samples are obtained directly from patients and are better models for evaluating cancer therapeutics than established cell lines that have been grown in culture for many years and have thus adapted to artificial conditions not requiring a tumor microenvironment. The team will also develop ways to predict which lung cancer patients are likely to respond best to this protein-based therapy.

Technical Abstract

Cancer-associated fibroblasts (CAFs) support the growth of lung cancer cells in vivo by secretion of soluble factors that stimulate the growth of tumor cells. One such soluble factor is CLCF1. Functional studies in our laboratory identified an important role for CLCF1–CNTFR signaling in promoting growth of NSCLCs. NSCLC cell lines as well as patient-derived xenografts were found to express CNTFR, and knock-down of CNTFR leads to decreased proliferation. To test the use of CNTFR blockade as an anti-cancer therapy, we developed a soluble version of CNTFR (i.e., a CNTFR “receptor decoy”) that can be expressed from an adenoviral vector (Ad-sCNTFR-Fc). Preliminary experiments indicate that Ad-sCNTFR-Fc can block proliferation of a NSCLC cell line in vitro. Our proposed studies build on an established translational research program that includes intensive efforts to harvest and analyze primary tumor samples and CAFs directly from patients. In Aim 1, we will test the therapeutic efficacy of Ad-sCNTFR-Fc in a panel of patient-derived xenografts (PDX) as well as established cell lines. In Aim 2, to increase therapeutic efficacy, we will use protein engineering to develop a high-affinity sCNTFR that can more effectively block CLCF1-CNTFR interactions, and will evaluate this therapeutic candidate in PDX models. In Aim 3, we will establish the utility of using plasma CLCF1 as a biomarker for CLCF1 production in CAFs isolated directly from patient tumors. Parallel analysis of CAF and plasma CLCF1 will establish if CLCF1 in plasma correlates with CLCF1 in tumors and is thus a useful biomarker.

Key words

Biomarker or biomarker testing

Non-small cell lung cancer (NSCLC)

Targeted therapy

Tumor microenvironment

Protein engineering to target tumor-stroma interactions in NSCLC

LUNGevity Foundation

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