Boucher, Yves, PhD
Delivery of Oncolytic Viruses and Large Therapeutic Agents in Tumors
The therapeutic success of oncolytic viruses and other nanotherapeutics is severely limited by their poor diffusion and distribution through the tumor interstitial space. We have shown that collagen fibers in the tumor interstitial matrix hinder the diffusion of large molecules, and the penetration of viral particles. We used relaxin – a small hormone which stimulates the secretion of matrix metalloproteinases and inhibits collagen synthesis – to improve the diffusion of large molecules in collagen-rich tumors. Multiphoton laser scanning microscopy (MPLSM) and second harmonic generation (SHG) imaging of collagen fibers in living tumors demonstrated that relaxin enhances collagen degradation. We also found that bacterial collagenase or mammalian collagenases – matrix metallo-proteinase-1 or -8 – can improve the intratumoral penetration and anti-tumor efficacy of oncolytic viruses. We recently tested if losartan – a clinically approved angiotensin II receptor blocker (ARB) with noted anti-fibrotic activity – can enhance the penetration and efficacy of nanomedicine. We found that losartan led to a dose-dependent reduction in stromal collagen in several tumor models in mice. Furthermore, losartan improved vascular perfusion, the distribution and therapeutic effectiveness of oncolytic viruses, Doxil and small cytotoxic agents. Based on our experimental results with losartan, we initiated a clinical trial at Massachusetts General Hospital that will determine in patients with pancreatic cancer if losartan improves the effectiveness of small cytotoxic agents.
The narrow spacing between cancer cells is also a major barrier hindering the movement of oncolytic viruses and other nanotherapeutics. To bypass the cellular barrier, we tested the hypothesis that void spaces produced by cancer cell apoptosis improve the initial spread of oncolytic virus. In mice with mammary tumors, cancer cell apoptosis – induced by doxycycline-regulated expression/activation of caspase-8 or cytotoxic agents – enhanced the viral spread and therapeutic effectiveness of oncolytic virus injected intratumorally. In order to improve the systemic efficacy of nanotherapeutics targeted both at primary and metastatic tumors, it is also essential to identify agents that will improve the vascular extravasation of large therapeutics injected intravenously. We are testing if targeting tumor blood vessels, cancer cells, or both improves the delivery and effectiveness of nanotherapeutics.
Tumor Cell Migration and Metastasis
We are studying how the genetic modulation of matrix metalloproteinases or transcription factors affects cancer cell migration, fibrillar collagen and vascular basement membrane remodeling, lymph and blood vessel invasion, and lymph node and distant metastasis. We use MPLSM and tumors in transparent mammary windows to assess tumor cell migration phenotypes (e.g. amoeboid, mesenchymal) and velocity, and SHG imaging to visualize the interaction of cancer or stromal cells with collagen fibers.