Targeting Cancer Cells With pH-Responsive Transmembrane Peptides

Major goals in oncology include the development of approaches to target cancer cells and deliver therapeutics specifically. Biologics and, more specifically, transmembrane peptides (TMPs) have emerged as promising tools. TMPs can penetrate cell membranes and specifically bind to tumor-associated receptors. However, poor solubility in aqueous solution, the need for a delivery vehicle (i.e., detergent micelles), lack of insertion directionality, and indiscriminate insertion in healthy and cancer cells limit their efficacy and applications.

In this presentation, I will discuss our efforts to develop pH-responsive TMPs that exploit a conserved and major vulnerability of solid tumors: their inherent extracellular acidity. Indeed, rapidly expanding cancer cells share a feature that distinguishes most malignant tumors from surrounding normal tissues in that they create an acidic micro-environment. I will present our work on developing the pH(Low) Insertion Peptide (pHLIP) family of peptides to deliver therapeutics to cancer cells and its potential in immunotherapy. I will also discuss the design and testing of a first-in-class pH-responsive TMP agonist of a member of the receptor protein-tyrosine phosphatase (RPTPs) family, PTPRJ. This peptide promotes PTPRJ activity by disrupting its oligomerization and inhibits receptor tyrosine kinase-driven signaling, migration, and proliferation. Developing tumor-selective and TM-targeting peptide binders of critical RPTPs could afford a potentially transformative approach to studying RPTP's selectivity mechanism without requiring less specific inhibitors and represent a novel class of therapeutics against receptor tyrosine kinase-driven cancers.

Bio:
Prof. Damien Thévenin earned his B.S. in Structural Biochemistry from Université Paul Sabatier in Toulouse, France, followed by an M.S. in Biology and Biotechnology at the Institut National des Sciences Appliquées, where he focused on lipase catalysis in organic solvent. He completed his Ph.D. in Chemistry and Biochemistry at the University of Delaware, studying G-protein Coupled Receptors (GPCRs) folding and interaction. He then pursued postdoctoral research at Yale University under Prof. Donald Engelman, investigating the biophysical properties and anti-cancer therapeutic potential of the pH-Low Insertion Peptide (pHLIP).
Damien subsequently joined Lehigh University to establish his independent research group, concentrating on interdisciplinary studies in cell biology, peptide chemistry, membrane protein biochemistry, and biophysics. The Thévenin Group focuses on developing strategies for selectively targeting cancer cells and examining the role of oligomerization in receptor function. Notably, they have advanced the understanding of receptor protein-tyrosine phosphatases (RPTPs), demonstrating how specific transmembrane interactions influence receptor tyrosine kinase (RTK) signaling and identifying novel pH-sensitive peptides that modulate RPTPs activity.

Zoom link for attending remotely: https://epfl.zoom.us/j/67439985599