HSP90 Inhibitor Drug Conjugates (HDCs): A Novel Drug Delivery Strategy to Selectively Target NF2 Tumor Cells
Abstract
We propose to evaluate the potential of a new class of therapeutic molecules for the treatment of tumors in neurofibromatosis type 2 (NF2) patients. Synta Pharmaceuticals (Lexington, MA) developed and patented new molecules called HSP90 inhibitor Drug Conjugates (HDCs). The innovation of these molecules is that they are designed to increase the killing of tumor cells while reducing collateral damage to normal cells. We will first perform in vitro tests on a panel of cellular NF2 models to analyze the efficacy of the compound, to understand the mechanism of action and if it induces apoptosis of the targeted cells. We will test the selectivity by comparing the effect of the compound on tumor cell lines versus normal cells. Then we will evaluate the in vivo effect of the compound in a NF2 xenograft model where mouse schwannoma cells are growing under the skin of mice. This model will give us a proof-of-concept for the use of the compound in NF2-associated tumors. Finally, we will use our genetically modified NF2 schwannoma mouse model, which develops slow-growing Schwann cell lesions similar to NF2 patients. We previously demonstrated the predictive properties of this model by obtaining comparable results in the mice and in an index patient. By treating the mice at different ages, this model will allow us to evaluate the efficacy of the new compound to prevent and/or treat tumor growth. We will also perform hearing tests on the mice to assess the effect of the compound on hearing function. The innovation of these compounds relies on the structure designed to target tumor cells based on intrinsic properties that we verified NF2 tumor cell also arbor. They are composed of three parts: the first one targets the compound into the tumor cells, the middle part allows cleavage of the compound inside the tumor cells, and the third part is a potent chemotherapy drug. Once in the tumor cell, the compound will be cleaved and the combined effect of two drugs will kill the tumor cell. The selectivity of these compounds toward tumor cells versus normal cells makes it safer and more efficient than traditional chemotherapy drugs. It will be the first time these molecules are evaluated in the context of NF2 tumors. This project will evaluate a promising new class of therapeutic molecules showing a strong efficacy on other cancer models. The specific targeting of tumor cells will improve the safety and efficacy of the compounds for the patients. This is of particular interest for NF2 patients requiring long-term treatments with reduced drug toxicity and adverse effects to treat multiple occurring, benign tumors. The success of this project will give a proof-of-concept for the use of such molecules in NF2 patients and ultimately add a new therapeutic option for NF2 patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510172
Entities
People
- Jeremie Vitte
Organizations
- United States Army
- University of California, Los Angeles