Breakthrough Therapies for Malignant Brain Cancer from the Perspective of Tumor Stem Cells
Breakthrough Therapies for Malignant Brain Cancer from the Perspective of Tumor Stem Cells
Tumor stem cells possess a high capacity for self-renewal and differentiation, and are believed to be key drivers of tumor growth, recurrence, and therapy resistance.
Cancer Stem Cells (CSCs) possess the unique ability to self-renew and differentiate, and are considered the main drivers of tumor growth, recurrence, and resistance to therapies. They are a rare subset of cells within the tumor, often referred to as the “root” of cancer, and they exhibit significant similarity to normal stem cells. Their inherent characteristics, such as resistance to chemotherapies and their ability to remain dormant (G0 phase), allow them to evade the immune system and regenerate tumors even after most of the tumor cells are eliminated by standard treatments like chemotherapy and radiotherapy.
Treatments Targeting Tumor Stem Cells
The Relationship Between Cancer Stem Cells and Malignant Brain Cancer In highly aggressive cancers like glioblastoma multiforme (GBM), which has a median survival time of only 15-18 months, cancer stem cells (CSCs) are thought to be a key factor in recurrence and treatment resistance. While conventional treatments may initially shrink the tumor, CSCs can persist, giving rise to new, more heterogeneous, and often treatment-resistant cancer cells.
CSCs display two key features:
- Self-renewal: The ability to divide and produce more CSCs, ensuring the survival and continued growth of the tumor.
- Multilineage differentiation: CSCs can differentiate into various types of tumor cells, leading to the tumor’s heterogeneity and complicating treatment efforts.
For example, while traditional alkylating chemotherapy drugs, such as temozolomide, target and kill cancer cells, they often fail to eradicate CSCs. Once chemotherapy ceases, these stem cells can differentiate and regenerate the tumor, potentially producing treatment-resistant cancer cells due to their asymmetric division.
Advancements in Treating Cancer Stem Cells in Brain Tumors In recent years, novel treatment options that target both the cancer cells and CSCs have shown promise. For example, Cerebraca® Wafer, an experimental anti-brain cancer drug developed by Changhong Biotechnology, has shown the potential to kill both tumor cells and CSCs. This dual action may offer a more complete eradication of tumors and reduce the risk of recurrence.
Cerebraca® Wafer is More Effective in Overcome Cancer Stem Cells in Recurrent GBM
- As below Table shows, seven out of eight primary glioma lines acquired in this clinical trial revealed high expression of the cancer stem cell markers, CD133 and SOX2, suggesting that tumor recurrence presents high cancer stem cell generation.
- The IC50 of BCNU (active ingredient in Gliadel Wafer) in T1, a non-tumor stem cell line, was approximately 1200 µM. We further showed that GBM cells with high stem cell marker expression had higher IC50 when treated with BCNU (≥1600 µM). This result possibly correlates to the limited therapeutic effects of the BCNUloaded Gliadel wafer.
- However, the IC50 of BP (EF-API-001) in patient-derived primary glioma cell lines was lower than that of BCNU, indicating that the API of the Cerebraca® wafer was more efficient than that of the Gliadel wafer. We further demonstrated that the IC50 of BP was around four times lower than that of the BCNU.
- Additionally, the difference in drug loading between the Cerebraca® and Gliadel wafers was almost 10-fold (75 vs. 7.7 mg per wafer), which makes the cancer cell killing possible
- For more detailed information, please refer to Cancers 2022, 14(4), 1051; https://doi.org/10.3390/cancers14041051
Precision Medicine: New Strategies Targeting Cancer Stem Cells
Several strategies are under development to more effectively target CSCs and increase treatment success. Among the most promising are targeted therapies and immunotherapies:
Targeted therapies aim to disrupt the critical signaling pathways responsible for CSCs’ survival and self-renewal, such as the Notch, Wnt, and Hedgehog pathways.
Immunotherapies, including CAR-T cell therapies, are being designed to target and eliminate CSCs. CAR-T cells can be engineered to specifically recognize and attack CSCs, reducing the chances of harming healthy cells.
Another promising approach is the development of tumor vaccines, which train the patient’s immune system to recognize and attack CSCs. Similarly, exosomes derived from mesenchymal stem cells show potential for treating various brain cancers, offering a new avenue for therapeutic development.
Future Challenges and Opportunities
Despite the progress, treating CSCs presents significant challenges due to their heterogeneity and ability to evade many current therapies. Developing more precise drugs that specifically target the molecular mechanisms of CSCs remains a priority. Continued research into the biology of CSCs will also aid in crafting more effective therapies. However, advancements in precision medicine, clinical trials, and experimental drugs offer hope that targeting CSCs will become a major breakthrough in brain cancer treatment.
Investigational Drug
CEREBRACA® WAFER <Phase IIa> >>more
- Cerebraca® Wafer developed by Everfront Biotech Inc. is a therapeutic drug wafer that can be used to treat highly malignant glioblastoma (malignant brain cancer). It can be directly implanted into the brain and slowly releases drugs at a high concentration, high penetration, and long duration for about 1 month, exerting a multi-target effect (EF-API-001) that helps to treat cancer and make cancer cells more susceptible to chemotherapy or immune cell killing.
- Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor that can grow up to 16 times its original size within a month. It has a high rate of recurrence after surgical resection, and there are currently no effective treatment options available.
- EF-API-001, the small molecule active pharmarceutical ingredient in Cerebraca® Wafer, has the following characteristics:
- Targeting Axl-1 receptor tyrosine kinase: effectively inhibits the growth and metastasis of brain tumor stem cells.
- Inhibiting the PD-L1 immune checkpoint: reduces the immune suppressive nature of the tumor microenvironment, thus preserving the activity of immune cells to kill tumor cells.
- Inhibition of MGMT DNA repair enzyme: overcomes resistance to Temozolomide (chemotherapy drug) and enables cancer cells to be killed again by chemotherapy.
- Cerebraca® Wafer, its small molecule active ingredient and biodegradable polymer are all manufactured by internationally renowned PIC/S GMP pharmaceutical companies in Taiwan to ensure high quality and reliable aseptic manufacturing processes.
