Proposed Implementation
Breast Cancer
Breast cancer is the second most frequently diagnosed cancer and the fourth most common cause of cancer-related mortality in 2022[1]. Currently, chemotherapy and surgery are the main treatment approaches for breast cancer. However, the recurrence and chemoresistance of breast cancer are obstacles to its treatment, and the molecular mechanism underlying these phenomena remains unclear [2]. Targeted therapies for breast cancer, such as HER2 inhibitors (e.g., trastuzumab) and CDK4/6 inhibitors (e.g., palbociclib) [3]. Aim to specifically disrupt cancer cell pathways. However, limitations include the development of resistance, variability in patient responses, and the need for biomarker testing to identify suitable candidates. Additionally, these therapies may not be effective in all breast cancer subtypes, particularly in triple-negative breast cancer (TNBC). Targeted therapies can affect healthy cells, leading to side effects. While they are designed to focus on cancer cells, they may also impact normal cells that share similar pathways. This can result in adverse effects such as fatigue, gastrointestinal issues, and an increased risk of infections.
The imprecision of existing breast cancer treatments, along with their harmful side effects, poses a major challenge. This situation underscores the necessity for more effective and personalized strategies that can specifically target cancer cells while reducing damage to healthy tissues.
Our Product
Breast cancer drugs, such as trastuzumab and tamoxifen, can be effective but often face limitations, including the development of resistance and variability in patient response. Side effects may also impact quality of life, and not all subtypes respond well to available therapies.
In contrast, CRISPR-Cas9 targeted transcriptional enhancer factor domain 4 (TEAD4) gene knockout offers a novel approach to understanding breast cancer by directly disrupting genes linked to tumor growth and resistance[4, 5]. This method allows for precise modification of the genome, potentially revealing new therapeutic targets and enhancing treatment effectiveness. Additionally, it may help personalize therapies based on individual genetic profiles, reducing reliance on broad-spectrum drugs and their associated side effects. This approach offers a highly specific, effective, and patient-friendly option for cancer treatment by targeting precise genetic alterations. It minimizes off-target effects and reduces the toxicity often associated with traditional therapies, leading to improved outcomes and a better quality of life for patients.
Implementation in the Real World
CRISPR-Cas9 faces stability challenges during delivery to breast cancer targets, primarily due to degradation by nucleases in the bloodstream, a short half-life that limits exposure time, and potential immune responses that can diminish effectiveness. These factors hinder the ability of CRISPR components to reach and penetrate target cells. To address the stability challenges of CRISPR-Cas9 during delivery for breast cancer treatment, several strategies can be employed. These include encapsulating CRISPR components in lipid nanoparticles or polymer-based carriers to protect against nucleases, utilizing targeted delivery systems that specifically bind to cancer cell markers, and chemically modifying RNA components to enhance resistance to degradation. Additionally, optimizing dosage regimens for repeated delivery and incorporating immune evasion techniques can further improve the efficacy and safety of CRISPR therapies in targeting breast cancer cells [6, 7].
Workflow of target therapy
Intravenous administration is often considered the preferred method for delivering CRISPR/Cas9 therapies. This approach helps protect the modified CRISPR/Cas9 from degradation and aggregation in the bloodstream, enabling it to effectively reach tumor cells through the circulatory system. Once inside the target cells, CRISPR/Cas9 can selectively bind to cancer cell markers and enter the cells to knock out the TEAD4 gene.
Our experimental data indicate that increased levels of TEAD4-targeting CRISPR/Cas9 in the MCF-7 and MDA-MB-231 breast cancer cell lines lead to decreased tumor cell proliferation and migration, as well as elevated production of reactive oxygen species (ROS). These results suggest that CRISPR/Cas9 targeting of the TEAD4 gene is a promising therapeutic approach for breast cancer treatment. The successful knockout of the TEAD4 gene highlights the potential of CRISPR/Cas9 therapy in the clinical management of breast cancer.
Figure 1: The process of CRISPR/Cas9-mediated gene knockout.
Future Prospects
CRISPR/Cas9 targeting the TEAD4 gene in breast cancer includes its potential to enhance personalized therapies by specifically disrupting cancer-promoting pathways. This approach may improve treatment effectiveness and reduce side effects. Additionally, ongoing research could lead to optimized delivery methods and combination therapies, further advancing its clinical application.
References
1. Bray, F., et al., Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024. 74(3): p. 229-263.
2. Gadag, S., et al., Combination Therapy and Nanoparticulate Systems: Smart Approaches for the Effective Treatment of Breast Cancer. Pharmaceutics, 2020. 12(6).
3. Lau, K.H., Tan, A. M., & Shi, Y. , New and emerging targeted therapies for advanced breast cancer. International Journal of Molecular Sciences. International Journal of Molecular Sciences, 2022. 23(4): p. 2288.
4. Sabit, H., et al., New insights on CRISPR/Cas9-based therapy for breast Cancer. Genes Environ, 2021. 43(1): p. 15.
5. Wu, Y., Li, M., Lin, J., & Hu, C. , Hippo/TEAD4 signaling pathway as a potential target for the treatment of breast cancer. Oncology Letters, 2021. 21(4): p. 313.
6. Chehelgerdi, M., et al., Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy. Mol Cancer, 2024. 23(1): p. 9.
7. Pont, M., et al., Applications of CRISPR Technology to Breast Cancer and Triple Negative Breast Cancer Research. Cancers (Basel), 2023. 15(17).
