Development of a Small Molecule-Targeted Therapy for Mantle Cell Lymphoma

DESCRIPTION (provided by applicant): Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL) that accounts for 5- 8% of all lymphoma cases. The disease is typically found in older adults with a higher incidence in males that pre sent with advanced disease. MCL has one of the poorest prognoses of all NHL subtypes. The clinical course of MCL can be characterized by very high initial overall response rate (up to 97%) to induction therapy but a short time of progression leading to ref ractory relapse. This leads to poor overall survival with a median survival of approximately 1 to 2 years following relapse. The most recent numbers from the National Cancer Institute (2007) state that there are to be 63,190 new cases of MCL resulting in 1 8,680 deaths in the year 2007. Therefore, there is a dire need for novel agents and therapies to treat this disease benefiting a large number of cancer patients. Onconova Therapeutics, Inc is developing styryl sulfones, a new class of small molecule non-AT P competitive synthetic inhibitors. These compounds have high potency and specifically alter the regulation of the cell cycle of mantle cell lymphoma cell-lines, such as Granta 519 and Z138C. This proposal will describe the development plan for ON 013105, a new chemical entity that has many advantages over current standard therapies as well as newer agents just beginning to be tested in the clinic. The advantages of ON 013105 include: high potency and selectively towards tumor cells. activity against multi- drug resistant cell lines, synergy with many chemotherapeutic agents and ease of large scale manufacture. The IND directed acute toxicology studies have demonstrated that ON 013105 has a wide margin of safety. This compound is proprietary to Onconova Thera peutics, Inc. and is protected by patent applications. The key aim of this proposal is to employ systematic formulation development to design a shelf stable injectable formulation of ON 013105 suitable for further development and leading to an IND. Secondl y, we will utilize an animal model of efficacy in mantle cell lymphoma based on live imaging technology. Third, we will determine the appropriate combinations of ON 013105 with a number of clinically relevant therapeutic agents. The proposed work-plan will lead us to an IND application for clinical testing of a new therapeutic option for the treatment of mantle cell lymphoma. PUBLIC HEALTHE RELEVANCE: Mantle cell lymphoma is an aggressive subtype of non-Hodgkin's lymphoma that has very poor prognosis. At th e present there are no standard treatments and there are no cures for this disease. Therefore there is a dire need to develop novel agents that can provide disease free long-term survival. Onconova Therapeutics, Inc, has a novel selective anticancer compou nd, ON 013105, which is being developed to provide targeted treatment for mantle cell lymphoma patients.