Honorary Investigator Radiation Oncology, Mass General Research Institute

collagen synthesis inhibition; large therapeutic agents; matrix metalloproteinases; multiphoton laser scanning microscopy; oncolytic viruses; relaxin; tumor cell migration; vascular extravasation; viral transport

Delivery of Oncolytic Viruses and Large Therapeutic Agents in Tumors

As part of the Edwin L. Steele Laboratory for Tumor Biology, the Boucher Laboratory analyzes delivery of oncolytic viruses and large therapeutic agents in tumors and tumor cell migration and metastasis.  The therapeutic success of oncolytic viruses and other large anti-cancer agents 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 fibrillar collagen degradation. Bacterial collagenase or mammalian collagenases - matrix metalloproteinase-1 or -8 can also improve the intratumoral penetration and anti-tumor efficacy of oncolytic viruses. Ongoing and future studies will determine how matrix metalloproteinases and inhibition of collagen synthesis (e.g. losartan, halofuginone, inhibition of TGFb) affect the composition and transport in the tumor interstitial space.

The narrow spacing between cancer cells is also a major barrier hindering the movement of oncolytic viruses. To bypass the cellular barrier, we tested the hypothesis that void space produced by cancer cell apoptosis improves the initial spread and efficacy of oncolytic herpes-simplex virus (HSV). 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 the therapeutic efficacy of oncolytic HSV injected intratumorally. In order to improve the systemic efficacy of oncolytic virotherapy targeted both at primary and metastatic tumors, it is also essential to identify agents (e.g., cytotoxic agents) or strategies that will improve the vascular extravasation and interstitial transport of viruses injected intravenously. We are testing if the targeting of tumor blood vessels, cancer cells or both improves the extravasation and delivery of viral vectors and large particles, and the anti-tumor efficacy of oncolytic HSV. The tumor vasculature is targeted with cytotoxic agents known to induce endothelial cell apoptosis and remodel the vasculature.

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 chambers 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.