Jaime R. Merchan, M.D., MMSc.

Associate Professor of Medicine

Description of Research

Dr. Merchan’s laboratory focuses on the development of strategies aimed at inhibiting angiogenesis in the laboratory and then translating these findings into clinical trials for patients with advanced cancer.

One focus of his laboratory efforts is to understand and redefine the role of plasminogen activators (urokinase) and inhibitors (PAI-1) in tumor angiogenesis and metastases using syngeneic, immunocompetent cancer models. Understanding (at a molecular and cellular level) how changes in the balance between uPA and PAI-1 regulate metastases and angiogenesis, may identify novel-yet unrecognized- mechanisms of urokinase/PAI-1 regulation of tumor progression, as well as novel targets for drug development. Dr. Merchan is completing a manuscript for submission in the next month(Dr. Merchan had previously published 2 original papers on this topic), and are planning to submit an application for extramural funding in early 2011.

As an extension of the above efforts to exploit the plasminogen activator system for cancer biotherapies, the Merchan lab has engineered a novel recombinant oncolytic measles virus (MV-uPA) fully retargeted against human (MV-huPA) or murine (MV-muPA) urokinase receptor, a clinically and biologically established tumor and vascular target. Our lab has demonstrated for the first time the ability of MV-muPA to target tumor capillaries after systemic administration. Future studies will fully characterize the stromal targeting abilities of MV-uPA and other oncolytic virus variants developed in our laboratory in immunocompetent cancer models of metastases. We have successfully applied for extramural funding (R01 grant for NCI) and expect to focus on this project for the next 5 years. In collaboration with Dr. Glen Barber, Dr. Merchan is conducting pre-clinical studies on VSV-IFNB for a first in man trial of this promising oncolytic virus in patients with advanced head and neck cancer.

As part of Dr. Merchan’s efforts to identify novel angiogenesis targets for cancer treatment and to overcome resistance to antiangiogenic therapies, his team has investigated –in a bench to bedside manner- novel combinations of antiangiogenic agents. Most of the translational studies and trials have derived from their laboratory observations. Examples of these strategies include the use of plasminogen activators as antiangiogenic/antitumor agent, and the combination of metronomic paclitaxel and COX-2 inhibitors for melanoma and prostate cancer. Current efforts include:

The evaluation of CCI-779 and Bevacizumab in RTKI refractory renal cell cancer (our reported phase I portion led to 2 large First line trials in advanced RCC in Europe and the USA), and a combination of metronomic vs. standard ixabepilone and sunitinib for advanced solid tumors. All of these studies include translational (angiogenesis biomarker studies) to correlate biological and clinical activity/toxicity.

Finally, Dr. Merchan’s laboratory is investigating the antiangiogenic activity of 2-DG. They have discovered that 2-DG potently inhibits angiogenesis in vitro and in vivo, and that the cytotoxic effects occur at concentrations of 2-DG that are below tumor cytotoxic concentrations (Revised paper is being submitted for publication). Future studies will focus on understanding the molecular mechanisms of 2-DG antiangiogenic effects, and to explore other agents that target glucose metabolism as potential novel agents to overcome tumor resistance to anti-VEGF/antiangiogenic therapies. Dr. Merchan is planning to submit a Program Project grant with Dr. Theodore Lampidis (Dr. Merchan is the project 4 leader), to extend the above findings.

Highlights

Discovered that proteases of the plasminogen activator system induced potent antiangiogenic activity in vitro and in vivo. Dr. Merchan also has demonstrated induction of an antiangiogenic state in patients with cancer, after administration of intravenous tissue plasminogen activator and captopril.
Discovered that forced overexpression of urokinase delays tumor growth, metastasis, and survival in a syngeneic, immunocompetent murine model of breast cancer. Also demonstrated that the tumor delaying effects are directly due to the protease activity of urokinase, which induces in vivo antiangiogenic and antiproliferative effects.
Discovered that endothelial uptake of taxanes is significantly higher than tumor or normal cells. This discovery provides a mechanistic explanation for the exquisite sensitivity of endothelium to low dose taxanes. Also provided insight into the finding that low dose, frequent taxane administration is more effective in several tumor types than standard (high) taxane doses.
Discovered increased endothelial expression of COX-2 enzyme after exposure to taxanes. Combining COX-2 inhibitors to low-dose taxanes significantly enhance the antiangiogenic effects of low-dose taxanes and prevent the endothelial cell’s “defense mechanism.” This discovery led to a clinical trial of metronomic paclitaxel and celecoxib in patients with advanced melanoma.
Identified novel angiogenesis biomarkers. By using a novel endothelial bioassay (endothelial tube formation) using patient’s plasma as a surrogate marker, Dr. Merchan discovered that pre-eclampsia is an antiangiogenic state, due to placental overexpression of sFLT-1. This important discovery opened a new avenue of research in pre-eclampsia, placing the disorder into the category of angiogenesis-dependent diseases. Relevant to cancer research, this discovery shed light into the understanding of common side effects of FDA-approved antiangiogenic agents (like Avastin), whose side effects (hypertension/proteinuria) mimic the antiangiogenic state of pre-eclampsia. These plasma bioassays are currently being investigated as potential biomarkers to establish surrogate endpoints for benefit in several antiangiogenesis trials.
Developed the first oncolytic measles virus fully retargeted against a tumor/angiogenesis target (MV-uPA) with the ability to target murine tissues. This significantly contributes to the field of measles virotherapy, by allowing for the first time to perform in vivo studies using non-transgenic, immunocompetent animals, for further development of retargeted oncolytic measles virotherapy for cancer treatment.

Selected Cancer-Related Publications

Talebi TN, Stefanovic A, Merchan J, Lian E, Silva O. Sunitinib-induced microangiopathic hemolytic anemia with fatal outcome. Am J Ther 19:e143-5, 2012. Read more »
Ascunce G, Ribeiro A, Reis I, Rocha-Lima C, Sleeman D, Merchan J, Levi J. EUS visualization and direct celiac ganglia neurolysis predicts better pain relief in patients with pancreatic malignancy (with video). Gastrointest Endosc 73:267-74, 2011. Read more »
Ascunce G, Ribeiro A, Rocha-Lima C, Larsen M, Sleeman D, Merchan J, Szabo D, Levi JU. Single-session endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography for evaluation of pancreaticobiliary disorders. Surg Endosc 24:1447-50, 2010. Read more »
Bhatt RS, Merchan J, Parker R, Wu HK, Zhang L, Seery V, Heymach JV, Atkins MB, McDermott D, Sukhatme VP. A phase 2 pilot trial of low-dose,continuous infusion,or "metronomic" paclitaxel and oral celecoxib in patients with metastatic melanoma. Cancer 116:1751-6, 2010. Read more »
Jing Y, Tong C, Zhang J, Nakamura T, Iankov I, Russell SJ, Merchan JR. Tumor and Vascular Targeting of a Novel Oncolytic Measles Virus Retargeted against the Urokinase Receptor. Cancer Res 69:1459-1468, 2009. Read more »

Programs

Collaborating in the Multidisciplinary Research Program(s):