Small Molecule Activators of Protein Phosphatase 2A (SMAPs) for the Treatment of Ovarian Cancer
Abstract
It is estimated that in the United States in 2015, approximately 21,980 women will be diagnosed with ovarian cancer and 14,270 will die from the disease. Epithelial ovarian cancer (EOC) accounts for ~90% of all ovarian cancers and is the most lethal gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most common and lethal form of EOC, primarily due to advanced stage at diagnosis and lack of effective therapies for the treatment of recurrent disease. Lack of effective early detection methods and the development of resistance to first-line chemotherapeutics leave few options for the clinical management of ovarian cancer, particularly advanced ovarian cancer. There is an urgent need for the identification of novel therapeutic targets for targeted therapy in ovarian cancer. The ultimate success of these therapies depends on the validation of the biological and functional relevance of the underlying genetic aberrations targeted by these novel approaches. Currently, there are no standard therapeutic options for patients with recurrent chemotherapy-resistant tumors. The scientific framework of this proposal is focused on validating the clinical efficacy of newly created re-engineered pharmaceutical compounds that coordinately inactivate multiple oncogenic signaling and DNA repair proteins altered in HGSOC through the activation of a major serine/threonine phosphatase, protein phosphatase A (PP2A). Our novel agents, Small Molecule Activators of PP2A (SMAPs), are first-in-class, orally bioavailable, non-toxic direct small molecule activator of a tumor suppressor phosphatase, which were discovered through the reverse engineering of the tricyclic neuroleptic chlorpromazine. We have found that one of the key mechanisms by which SMAPs induce cancer cell death is through the inhibition of PLK1, which regulates DNA integrity and cell cycle progression. Furthermore, we have found that SMAPs are able to sensitize HGSOC cells and patient-derived mouse models tumors to PARP inhibition, which is highly relevant given the recent Food and Drug Administration (FDA) approval of PARP inhibitors. Our proposed research will help women who are newly diagnosed with late-stage ovarian cancer in four major ways: (1) through the repurposing of already FDA-approved drugs with well-characterized side effect profiles and toxicology, we are starting with a compound that by definition is drug-like and the chances of unexpected and problematic findings in bioavailability, metabolism, or toxicity are ameliorated; (2) assessing whether PLK1 expression may be a novel prognostic biomarkers will provide independent prognostic and predictive information for the selection of tailored chemotherapeutic regimens in order to decrease the incidence of recurrence; (3) PLK1 may be used to stratify patients that will respond to our novel small molecules; and (4) we may have uncovered a novel method to sensitize patients to PARP inhibitors. Therefore, the data gained from the proposed studies will potentially uncover a novel molecular agent to treat ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610587
Entities
People
- Analisa DiFeo
Organizations
- Case Western Reserve University
- United States Army