Evaluation of Procaspase-Activating Compound-1 in Combination with Chemotherapy, MEK Inhibition, and/or Radiotherapy for Malignant Peripheral Nerve Sheath Tumors
Abstract
Neurofibromatosis type 1 is a complex genetic disorder characterized by the development of benign tumors along with the nervous, called neurofibromas that can cause disability and progress into malignant tumors. About 1 in 10 patients will have a benign neurofibroma become cancerous. These malignant tumors, known as malignant peripheral nerve sheath tumors (MPNST), are refractory to conventional treatments. Consequently, there is an urgent need to develop more efficient therapy for NF 1 patients. These incurable peripheral nerve tumors result from loss of Neurofibromin 1 (NF1) tumor suppressor gene function, causing constitutive activation of MAPK signaling. For patients not qualified for surgery resection, cytotoxic therapy is often employed as treatment. However, acquired resistance is often observed in patients treated with cytotoxic chemotherapy, and additional drug combinations are required to induce tumor regression. The acquired drug resistance occurs due to the selective pressure in cancer cells and the lack of specificity of these drugs. Therefore, one fundamental question is how to optimize drug combinations that induce tumor regression and preferentially target NF1 mutant cancer cells. The present research plan addresses these questions using a combination of therapies. Cancer cell death induction is a clinically relevant strategy, and we helped launch phase 1 clinical trials with a novel drug for cancer therapy, procaspase activating compound-1 (PAC-1). This procaspase-3 activator induces apoptosis and extends survival in several cancer models, including rodents and dogs. Therefore, PAC-1 drug combinations will likely have a synergistic effect with the most promising therapy used for NF-1-associated MPNST. Our hypothesis states that PAC-1 combined with radio/chemotherapy will impair MPNST growth in mouse models. In this hypothesis-driven and exploratory project, we aim to optimize combinations of PAC-1 with chemo/radiotherapy that would be effective for treating MPNSTs harboring NF1 mutation in vivo. We believe that with successful results in this project, the innovative data could guide translational research from bench to bedside.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310214
Entities
People
- Gregory Riggins
Organizations
- Johns Hopkins University
- United States Army