Glioblastoma Cancer Stem Cell Organoids for Identification of Novel sesquiterpene lactone Therapies
Summary
Glioblastoma (GBM) is the most common malignant brain tumor among adults and has a grim prognosis with a median survival of 15months with standard therapy. Standard therapy has not changed since 2005, and only one chemotherapy (i.e. temozolomide) is approved for this devastating disease. Improving therapeutic strategies for GBM is a high priority, but there is a need for model systems that allow for preclinical testing. Glioma stem cells (GSCs) in GBM can evade chemotherapy and radiation treatment and later give rise to the residual cell population that leads to recurrence. Therefore, GSCs are ideal candidates for therapeutic targeting.
In this study, we will evaluate novel bioactive compounds that have yet to be used in brain cancer. Parthenolide is a sesquiterpene lactone that has attracted considerable attention after it was discovered that it induces apoptosis of leukemia stem cells. Parthenolide has been shown to inhibit multiple types of cancer cell lines including glioblastoma. Unfortunately, despite its remarkable in vitro profile, the limited water solubility of parthenolide has precluded its clinical applicability. Synthetic efforts to improve its physicochemical profile had also failed to produce clinically useful derivatives The CMC12 library of compounds that we have assembled for this project include representatives of the various types of sesquiterpene lactones, that were discovered by bioassay directed fractionation scheme that is targeted to discover bioactive compounds with a better pharmacokinetic profile. We hypothesize that these compounds will more effectively kill GSCs in comparison to currently available chemotherapy.
We will use our high throughput patient derived GSC organoid platform to screen our panel in GBM patients. We will specifically harvest tumor cells from the subventricular zone (SVZ) during surgery which is the region within GBM tumors with the highest proportion of GSCs. Traditional preclinical models, such as patient-derived xenograft modeling in animals, can be expensive and require long engraftment periods. To overcome these limitations, three-dimensional (3D) organoids have been developed to recapitulate tumor characteristics in an in vitro setting. We have been successful in implementing a 3D organoid method to generate EC50 values from patient derived GBM cells within a week. Our preliminary data indicate we can isolate GSCs and screen multiple drugs efficiently. Our team is comprised of a neurosurgeon scientist, a cancer biologist, and medicinal chemist with expertise in patient derived GBM models, targeting cancer stem cell functionality, and the development of bioactive compounds respectively. The overall goal of our multidisciplinary team approach is to identify novel therapeutic candidates for GBM. Our specific aims are as follows: 1) Test our CMC12 library efficacy in our novel patient derived GSC 3D organoid platform. 2) Establish the structure activity relationship of our top candidates 3) Design optimized compound analogues for translational potential. Our innovative approach will result in identifying novel therapies that specifically target GSC populations and ultimately can be commercialized for brain cancer patients. Our team also plans to apply for extramural funding with the preliminary data generated from this project. Ultimately, our functional precision medicine system can be adapted for various cancer types.