Integrated Cancer Research Seminar Series
Dai Fukumura, PhD
Associate Professor of Radiation Oncology, Harvard Medical School
Associate Biologist, Edwin L. Steele Laboratory for Tumor Biology
"Targeting tumor microvasculature and microenvironment: Strategies to exploit and overcome"
Blood vessels in solid tumors have abnormal and heterogeneous organization, structure, and function (e.g., hyper-permeability, heterogeneous and compromised blood flow) resulting in abnormal microenvironment (e.g., hypoxia, acidosis, elevated interstitial fluid pressure) and hindrance of the delivery and efficacy of therapeutic agents.
However, we can exploit aberrant microenvironment in tumors for selective treatment of tumors. Enhanced permeability and retention effect of tumor vasculature allows selective delivery of relatively large size nanomedicine to tumors. Such nanoparticles not only increase therapeutic index but also allow delivering toxic agents and hydrophobic drugs to tumors. However, a crucial drawback of this approach is that these nanoparticles cannot penetrate into tumor tissues after the extravasation and are stuck in the perivascular area. We propose to solve this dichotomy by developing a multistage nanoparticle delivery system such that changes its size upon exposure to enzymes uniquely present in tumor tissues.
In addition to optimizing the delivery vehicle, we would need to modulate tumor microenvironment to overcome the barriers to drug efficacy. For example, restoring tissue balance of pro- and anti-angiogenic factors can “normalize” tumor vasculature, improve its function and microenvironment, and thus, enhance cytotoxic treatment efficacy.