*** FACULTY CANDIDATE ***

Erik Dreaden, Ph.D.*

Koch Institute for Integrative Cancer Research,

Massachusetts Institute of Technology

A Tale of Two Particles: Engineering Rational Combination Therapies Against Metastatic Tumors

ABSTRACT

Drugging tumors with combinations of nucleic acids or small molecules can be challenging when cellular colocalization is required for efficient cell killing. Unlike conventional pharmaceuticals, polymer nanotechnologies can tailor the combined delivery of drugs to tumors in a manner that maximizes synergistic or synthetic lethal interactions while minimizing off-target effects. Here, I’ll describe recent progress from our laboratory in the synthesis and preclinical development of two modular nanoscale therapeutics based on (i) layer-by-layer (LbL) polymer self-assembly and (ii) N-carboxyanhydride polymerization, and their application towards interventions for breast, lung, and ovarian cancers. (i) I’ll show that LbL nanoparticles can be engineered to heterogeneous tumors and deliver synergistically toxic combinations of small molecules that block MAPK and PI3K pathway signaling in vitro and in vivo, eliciting disease stabilization in the absence of dose-limiting toxic effects from the free drug combination. (ii) I’ll also demonstrate the rational design of an amphiphilic nucleic acid delivery vehicle that sensitizes metastatic lung and ovarian tumors to frontline chemotherapy in vitro and in vivo. Here, we find that loss of the kinase, MK2, is synthetic lethal in combination with p53 deficiency in solid tumors and that nanoparticle-mediated silencing of the checkpoint kinase dramatically sensitizes metastases to chemotherapy currently used in the clinic. This work demonstrates how polymer nanotechnologies can exploit new insights in cancer cell signaling to address unmet needs in current clinical interventions for breast, lung, and ovarian cancer. Following the seminar, I’ll briefly introduce the ways in which my future research will leverage these and related technologies to facilitate immune surveillance of tumors in a tissue-specific and patient-personalized fashion.

Host: Shuming Nie, Ph.D.

Thursday, Feb. 23

10:30 a.m.

HSRB Auditorium,  

Emory University

Videoconference:

Georgia Tech, McIntire Rm 3115 and TEP 104