Research Project
9342631
Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive brain tumor with a dire unmet therapeutic need. It has an overall incidence of 0.47 per 100,000 person-years and is regarded as an orphan disease with potential for fast track approval. Our group made a discovery via gene expression analysis that osteopontin (OPN) is the most upregulated gene in PCNSL compared to its non-CNS counterpart. By immunohistochemistry analysis, OPN is expressed heavily by all the lymphoma cells in 92% of PCNSL cases. Functional genomic studies identified OPN as an important pro-tumorigenic driver with multifaceted role in CNS lymphoma including intracerebral tumor growth, invasion, and dissemination via a unique mechanistic activation of NF-?B signaling. High OPN expression in PCNSL patients has a strong correlation with poor progression-free and overall survival. To target OPN, we have developed a novel compound, Chloro-ethyl agelastatin A (CEAA), with excellent CNS penetration (~27%), which demonstrates robust therapeutic activity against CNS lymphoma in a cell line-derived murine model. We have secured a patent for composition of matter of agelastatin A analogues and their therapeutic use in primary and secondary brain tumors such as primary and secondary CNS lymphoma, glioblastoma multiforme, and metastatic breast cancer of the brain. We are proposing to further develop CEAA for PCNSL with two specific aims. In Aim 1 (Copland/Hazlehurst, Modulation Therapeutics Inc.), the dose limiting toxicity (DLT) of CEAA will be determined in rats. In Aim 2, the Tun Laboratory will evaluate the therapeutic activity of CEAA against PCNSL in two novel patient derived xenograft (PDX) mouse models with high OPN expression in comparison to two control groups ? standard of care control with high-dose Methotrexate and no-treatment vehicle control. The dose and frequency will be varied, as guided by results from Aim 1, to inform the Phase I clinical trial design. The generated dataset will provide the necessary data to i) initiate a pre-IND meeting with the FDA ii) design of the GLP studies required for the IND application and iii) design of the phase I clinical trial. CEAA represents a first in class agent, which targets a specific molecular abnormality in PCNSL. We believe that due to high penetrance to the brain, and robust in vivo activity of CEAA that further pre-clinical development of CEAA for the treatment of PCNSL is warranted. As OPN is ubiquitously over-expressed in many aggressive cancers including other brain tumors, we anticipate that the study results will have ramifications and applications for many other cancers.
