SBIR-STTR Award

The long-term goal of this project is to develop an anti-cancer drug, based on the prototype compound suramin that would allow widespread use in humans with a variety of cancer types. Clinical studies with suramin in hormone refractory prostate cancer have shown significant response rates through Phase II studies. However, severe toxicities have been observed that are treatment limiting and the narrow window between active and toxic drug levels precludes suramin use in some cancers or in combination with other anti-cancer agents. We plan to overcome these problems with suramin by identifying derivatives that maintain the anti- cancer activity but have reduced toxicity. Preliminary studies have identified a set of five compounds that have increased potency in growth factor inhibition and prostate tumor cell growth. These compounds will be assessed for tumor growth inhibition in vivo with human tumor cell xenografts in mice. In addition, a preliminary assessment of toxicity will be determined in order to evaluate the therapeutic index. Successful completion of this project may lead directly to a new clinical candidate for treatment of prostate and other solid tumors. PROPOSED COMMERCIAL APPLICATION: The work may lead to an improved treatment for hormone refractory prostate cancer. This would potentially also provide a new treatment for other cancers currently without any effective therapy

The long term objective of this program is to identify and develop an angiostatic compound useful in cancer treatment. The rationale is to develop a dual inhibitor of the heparin binding endothelial growth factors bFGF and VEGF. Phase I goals were to validate methods to synthesize and identify growth factor-heparin binding antagonists which block endothelial cell proliferation. Phase I work not only identified a dual bFGF and VEGF inhibitor from a pilot heparin mimetic combinatorial library, but showed the compound to be active in vitro and in vivo to block endothelial proliferation. Thus, the primary goal was achieved and methods were validated for continuing the objective of discovering optimal growth factor antagonists that have angiostatic activity. Current studies are focused on identifying additional antagonists so that medicinal chemistry (analog synthesis) can be based on multiple active structures. Current methods for combinatorial compound synthesis allow rapid iterative compound improvements and scale-up for in vivo testing in both mechanism and disease based models. The application proposes to use these validated synthesis and screening methods, together with toxicity and tumor models in vivo to complete the identification of optimal compounds suitable for development as treatments for cancer and related proliferative disorders