Expansion of TGF beta Program
The Scientific Directorate has announced that the TGF-beta Program, directed by Dr. Carl-Henrik (Calle) Heldin, is set to receive further resources to develop and validate specific TGF-β antagonists (see end of page) and explore their possible clinical utility.
Contributors to the TGF beta Program over the years have included investigators from the Uppsala, Stockholm, Melbourne and Brussels and two key LICR Affiliates (and former Uppsala Branch staff): Dr. Kohei Miyazono (Tokyo University) and Dr. Peter ten Dijke (Leiden University Medical Center, and formerly at the Netherlands Cancer Institute in Amsterdam). According to Dr. Richard Kolodner, Executive Director for Laboratory Science and Technology, the research successes of the TGF-beta Program have long been recognized by the Executive Directorate. “There’s no mistaking the excellence of the research in TGF beta and Smad signaling in the Ludwig Institute, and Calle has done a great job to build such a wealth of knowledge.”
“The next, logical step is to harness the Institute’s resources to programmatically move the research firmly into the preclinical arena,” says Dr. Andrew Simpson, the Executive Director for Programs and Operations. “Programs are the process by which the LICR transitions knowledge acquired through its basic research towards clinical utility. The growing evidence for a tumorigenic role for TGF-β, the strong expertise that we possess in this area and the strong IP (intellectual property) position held by LICR certainly justify an increase in resources to procure and integrate the diverse resources and expertise for expediting the evaluation of potential clinical opportunities.”
The leaders of the principal groups to be involved in the development and validation of TGF-beta antagonists are Drs. Aristidis Moustakas and Serhiy Souchelnytskyi (Uppsala Branch), Kohei Miyazono and Peter ten Dijke. Program members have already developed assays for screening and validating TGF-beta signaling antagonists at both the cellular and animal levels, and some work with small molecule inhibitors and monoclonal antibodies has begun.
Targeted Antibodies
To date, monoclonal antibodies have been made to different domains of murine and human targets at the James R. Kerr Program laboratory in the Ukraine, which is under the direction of Dr. Ivan Gout. The mouse antibodies are expected to be of value in target validation in mouse models, and may become the direct forerunners of a therapeutic antibody. These antibodies are designed to serve as reagents for immunohistochemical analysis. Both sets of antibodies have recently been delivered to Dr. ten Dijke’s laboratory and analysis is now beginning. The next round of antibody generation, also in the Ukraine, will involve the generation of antibodies to the human TGF beta receptors expressed on the surface of transfected NIH3T3 cells. This approach, as opposed to production of antibodies to recombinant protein, led to the generation of the Institute’s very successful 806 antibody, which recognizes a specific conformational form of the epidermal growth factor receptor (EGFR). The experiences and results from the LICR’s Antibody Targeting Program have indicated that this is the best approach to generate a potential therapeutic antibody and is to be adopted as a standard method of antibody generation for surface-associated targets within LICR Programs.
Small Molecule Inhibitors
Obtaining access to small molecule inhibitor libraries and/or a chemical synthesis laboratory are being actively pursued as both academic and commercial collaborations. The latter are being negotiated and managed by the LICR’s Office of Intellectual Property.
Expression Analyses
The expression and signaling of the targets of the TGF-beta antagonists will also be thoroughly explored in human tumor samples within the Program. This will be done by collaboration with the Clinical Genomics Initiative established in Brazil by Dr. Simpson.
TGF beta
The TGF-beta superfamily regulates the growth, proliferation, differentiation, motility and apoptosis of many cell types, and appears to play a key role in angiogenesis. Defects in TGF-beta signaling have been associated with cancer, wound healing and certain fibrotic diseases. TGF-beta acts initially as a tumor suppressor through growth inhibition and apoptosis, and then as a tumor promoter stimulating epithelial to mesenchymal transition (EMT), increased invasiveness, immune suppression and angiogenesis. TGF-beta binds to heteromers formed by type 1 TGF-beta receptors (TGFBR1) and type 2 TGF-beta receptors (TGFBR2), serine-threonine kinases that activate the SMAD family of transcriptional regulators. The TGFBR2s include the ALK family, ALKS1-6 , all of which were discovered at the Uppsala Branch.
Left to right: Aristidis Moustakas and Carl-Henrik Heldin (Uppsala Branch) and Affiliates Peter ten Dijke (Amsterdam) and Kohei Miyazono (Tokyo). Absent: Serhiy Souchelnytskyi (Uppsala Branch).