Researchers from UCLA’s Department of Chemistry and Biochemistry and the Department of Radiation Oncology have synthesized a set of compounds for the eradication of cancer stem cells. These compounds are predicted to cross the blood brain barrier and show promise as effective interventions for glioblastoma in both in vitro and in vivo assays.
BACKGROUND: With 12,000 cases diagnosed in the United States each year, glioblastoma is the most common primary brain cancer found in adults. Because of its aggressive nature and site of origin behind the blood brain barrier (BBB), treatment of glioblastoma precludes common methods of medical interventions as the disease characteristics render most treatments ineffective. Radiotherapy, in many cases, initially shows reduction of tumor burden, but such approaches routinely exhibit a return of the disease with a more aggressive phenotype. A working theory, as with many other cancers, describes cancer stem cells and cancer initiating cells (CIC) as a small percentage of cells within the tumor with high proliferative capacity which can repopulate and regrow the tumor following intervention. Previous work has shown that these CICs possess an increased resistance to radiation; as a result, radiotherapy not only doesn’t affect CICs but also triggers a phenotype conversion of non-stem cancer cells into induced CICs, ultimately enriching the number of cells with this aggressive phenotype. Hence, there is an urgent need for the development of compounds that selectively target CICs/cancer stem cells, and which have the capacity to penetrate the blood brain barrier for treatment of glioblastoma and other brain associated cancers.
INNOVATION: Researchers from UCLA have synthesized a compound and analogs with selective targeting of CICs. Furthermore, based on in silico models and in vivo mouse assays, these compounds are predicted to possess the capacity to penetrate the blood brain barrier in humans. The development of these compounds can be traced back to a screening effort to identify compounds that repress radiation-induced phenotype conversion and kill CICs. For this purpose, 83,000 compounds were assayed through unbiased phenotypic screening which resulted in 216 hits. These were furthered narrowed to 169 compounds based on chemical characteristics (Lipinski violations (rule of five), CNS optimization score, etc.). From these, four compounds were selected based on chemical properties, efficacy, and predicted capacity to penetrate the BBB. Using these as a foundation, 114 analogs were synthesized and tested for their ability to reduce self-renewal of CIC alone or in combination with radiotherapy. Additional testing showed that the lead compound and some analogs exhibit no relevant toxicity alone or in combination with radiation in normal tissue cell-lines and prolong the median survival in mouse models of glioblastoma.
POTENTIAL APPLICATIONS:
- Treatment of Glioblastoma and glioma associated cancers
- Target cancer-initiating-cells / cancer stem cells
- Combination therapy with radiotherapy
ADVANTAGES:
- Crosses Blood Brain Barrier
- Targets CIC
- Prevents radiation-induced phenotype conversion of non-stem cancers cells into CIC
- 100+ synthesized analogs
DEVELOPMENT-TO-DATE: Phenotypic screen of 83,000 compounds finished. Four compounds selected from 169 hits for secondary screening leading to one main hit compound. From this, 114 analogues have been synthesized and assessed for therapeutic efficacy. A lead compound and two of its analogues were then selected based on their capacity to penetrate BBB, lack of toxicity, and activity in in vitro and in vivo assays.