The proposed studies focus on the development of a new paradigm for targeted cancer therapy. Our approach is based on the development of small molecules that possess the functional properties of antibodies;these functions include the ability to bind antigens with high affinity and selectivity, and the ability to trigger the action of professional phagocytic and killer cells (e.g., natural killer cells, macrophages, and dendritic cells). Such materials would combine the many advantages of antibody-based therapeutics with those of traditional small-molecule-based approaches. Here we propose to develop small molecule antibody mimics (SAMs) that bind selectively to cancer cells that overexpress the prostate-specific membrane antigen (PSMA), and induce immune-mediated cytolysis through the Fc-gamma receptor type 1 (Fc?RI). Fc?RI triggers immune cells to release cytotoxic contents only upon multivalent binding to an appropriate cell-surface-immobilized ligand. PSMA is a cell surface enzyme that is overexpressed both in prostate cancer cells and in tumor neovasculature for a wide variety of cancers (including pancreatic ductal carcinoma, colon adenocarcinoma, glioblastoma multiforme, and non-small cell lung carcinoma). Preliminary data suggests that formation of complexes between the small molecule, cancer cells, and immune cells will lead to highly selective immune-mediated cancer cell destruction. The strategy proposed here is not limited any one particular disease - the therapeutic action is determined simply by which cell type is targeted by antibody mimics. As such, we believe that the proposed research is highly significant, and constitutes a critical step toward improving the lives of patients suffering with cancer and other diseases.

Public Health Relevance

The proposed studies focus on the development of an innovative strategy for targeted cancer therapy involving small molecules that possess the functional properties of antibodies. These compounds will selectively target cancer cells and induce immune-mediated destruction. The proposed research is significant in that it constitutes a critical step toward improving the lives of patients suffering with cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM100283-03
Application #
8663289
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Gautam, Samir; Gniadek, Thomas J; Kim, Taehan et al. (2013) Exterior design: strategies for redecorating the bacterial surface with small molecules. Trends Biotechnol 31:258-67