Our Science – Capala Website

Jacek Capala, Ph.D.

Radiation Oncology Branch Investigator National Institutes of Health 10 Center Drive, MSC 1682 Building 10 CRC, Room B2-3561 Bethesda, MD 20892 Phone:   301-496-5457 Fax:   301-480-5532 E-Mail:   CapalaJ@mail.nih.gov

Biography

Dr. Capala graduated from the Jagiellonian University, Krakow, Poland with a M.Sc. in medical physics in 1986. After a year spent on a positron emission spectroscopy project at the Instiute of Nuclear Physics in Krakow, he escaped the communistic regime to Uppsala, Sweden, where he received his Ph.D. in physical biology from Uppsala University in 1991. His Ph.D. thesis work included one of the first published reports on using epidermal growth factor (EGF) receptors as targets for delivery of radioactivity to tumor cells. Between 1992 and 1994, Dr. Capala continued to study the feasibility of EGF conjugates as tumor targeting agents for imaging and therapy, including boron neutron capture therapy (BNCT), at the Ohio State University, Columbus, OH. Then, he moved to the Brookhaven National Laboratory, Upton, NY, were he participated in the design of clinical trials of BNCT for glioblastoma multiforme (GBM) and was responsible for medical physics aspects of those trials. He also contributed to the development and testing of boron delivery agents for BNCT. At that time he held joined appointments as a medical physics research associate at the Department of Radiation Oncology, Beth Israel Medical Center, New York, NY and the Department of Radiology, State University of New York at Stony Brook, NY. In 1999, Dr. Capala was invited to become the Director of Medical Physics at Studsvik, AB, Nykoping, Sweden, where he helped to design a BNCT facility and established pre-clinical and clinical research. He also became an Associate Professor of biomedical radiation sciences at Uppsala University and established a national consortium for mixed high- and low-LET radiation research. Dr. Capala joined Radiation Oncology Branch of NCI in June 2004.

Research

I. Multitarget Approach to Targeted Therapy Aimed Against EGF and IGF Signaling Pathways

Advances in basic tumor biology have resulted in the identification of molecules associated with regulation of cellular proliferation, migration, apoptosis, differentiation, and angiogenesis. All theses processes are influenced by the EGF receptor family (ErbB1 thought 4), which has been identified as the main target for therapeutic intervention. Recent pre-clinical and clinical studies indicated that EGFR blockade can inhibit the growth and progression of malignant cells and to potentiate the activity of conventional chemo- and radiotherapeutic approaches. However, it is unlikely that blockage of only one receptor on even whole family of receptors will be enough. It has been shown that blockage of HER-2 by monoclonal antibody (Trastuzumab) has limited affect on tumor cells expressing IGF1-R and IGF1-R signaling has to be prevented as well in order to reduce cell proliferation [Lu et al., 2001 & 2004]. Therefore, cocktails of inhibitors will be needed to block both receptors or/and their signaling pathways. There are many questions to be addressed regarding the regiment of such combined treatment.

The major goal of this project is to develop a multi-target approach to molecular therapy combining methods developed for blocking of various growth factor signaling pathways to enhance the effectivness of conventional therapy. In the initial phase, we will investigate effects of simultaneous blockage of EGFR, HER-2, and IGF1-R combined with the current chemo- or radiotherapies on tumors in vitro and in vivo. The specific aims are:

1. To investigate the interactions between signaling pathways of different growth factor receptors: how blockage of one pathway influences others (including receptor expression and activation).
2. To visualize simultaneously the expression of different receptors in vivo (using multiple optical dyes, or different radionuclides, or combination of thereof including MRI contrast)
3. To investigate effect of therapy on receptor expression and acivity
4. To investigate the effects of receptor expression (combined, not individual as it has been dose so far) on tumor sensitivity to conventional therapies.
5. To investigate how blocking of the relevant pathways influences the outcome of chemo- and radiotherapy in order to identify optimal combination

II. Development and Characterization of Affibody®-Based Bioconjugates for Molecular Imaging and Targeted Therapy of HER2-Positive Cancers

We are developing an innovative strategy for individualized treatment of HER2-positive cancers by combining a non-invasive method for monitoring of HER2 in vivo and HER2-specific delivery of therapeutic agents. Affibody molecules obtained from our CRADA partner in Sweden (http://www.affibody.com) are used as the targeting agent. These very stable and highly soluble a-helical proteins are relatively small (8.3 kDa) and can be readily expressed in bacterial systems or produced by peptide synthesis. The His6-Zher2:324 binds to HER2 receptors with high affinity (22 pM) and is available with cysteine at the carboxy-terminal to facilitate conjugation. For imaging purposes, these molecules are labeled with optical beacons or radionuclides. For therapy, the His6-Zher2:324 are conjugated with thermo- or radio-sensitive liposomes, labeled with beacons for in vivo imaging, and loaded with therapeutic agents (e.g., toxins, radiosensitizers, or kinase inhibitors) that will allow local drug release defined by real-time monitoring of their distribution. These nanoparticles will provide means for HER2-specific delivery of a variety of tumoricidal agents, including those whose application is currently limited due to their hydrophobicity and, thereby, complement current therapeutic strategies. This approach, involving assessment of target presence and distribution in an individual patient followed by optimized, target-specific drug delivery, should significantly improve the efficacy of cancer treatment while reducing side effects.

This page was last updated on 6/11/2008.