Ligand-targeted therapeutics is a rapidly growing class of anticancer agents. This class of therapeutics is typically bifunctional molecules that use a targeting moiety to selectively deliver potent, typically nonspecific, cytotoxic agents to cancer cells while sparing normal cells. The low-molecular-weight of ligand-targeted therapeutics allows for better tumor penetration, especially in the case of solid tumors where the size of antibodies is a limiting factor for effective treatment. Unfortunately, the poor pharmacokinetic (PK) profiles of many of these conjugates present a challenge which limits their tremendous therapeutic potential. Dose-limiting toxicity is also observed due to the need for high doses and frequent administration. The overall goal of this proposal is to develop a fundamentally new approach for reducing the toxicity and enhancing the PK properties of ligand-targeted therapeutics. The main hypothesis of this proposal is to test whether conjugation of ligand-targeted therapeutics to a selective ligand for the serum protein, transthyretin (TTR) (forming trifunctional molecules; TFMs) would allow the TFMs to reversibly bind to TTR in serum. Binding of TFMs to TTR would enhance the in vivo half-life of ligand-targeted therapeutics, and would also reduce toxicity by limiting their non-selective tissue distribution. Here we propose to develop TFMs that bind selectively to prostate cancer (PCa) cells that overexpress the prostate-specific membrane antigen (PSMA). PSMA is largely absent from healthy tissues but highly expressed on the surface of PCa cells and on the new blood vessels that supply nutrients to many other types of cancers. We have already made significant progress by designing, synthesizing, and testing three TFMs (TFM1, TFM2, and TFM3) and our preliminary in vitro and in vivo results are consistent with our hypothesis. In this proposal, we will continue evaluating TFM1-3 in PCa cell culture and in vivo (PK in rats and efficacy/toxicity in mouse tumor xenograft model). We will also synthesize additional series of TFMs. This should allow us to determine the optimal linker system and affinity of TFMs to TTR and PSMA that will provide best balance between enhanced PK, efficacy, and lower toxicity. Our proposed strategy is not limited to a particular disease and the therapeutic action of TFMs could be determined by simply switching the payload or the targeting agent. Therefore, we believe that a successful realization of our proposed studies has the potential to significantly improve the therapeutic outcome and lower toxicity for patients suffering from cancer and other diseases.
Strategies that reduce the toxicity and overcome the poor pharmacokinetic properties of targeted anticancer agents will increase their clinical success rate and decrease production cost. The goal of this project is to develop a novel strategy that will reduce the toxicity and enhance the pharmacokinetic properties of targeted anticancer agents which would decrease dosing frequency and improve the lives of cancer patients.
