Global cancer statistics 2022

Cancer is a major societal, public health, and economic issue in the 21st century, responsible for almost one in six deaths (16.8%) and one in four deaths (22.8%) from noncommunicable diseases (NCDs) worldwide. In 2022, there were close to 20 million new cases of cancer (including nonmelanoma skin cancers [NMSCs]) and 9.7 million cancer-related deaths. Cancer is currently the second leading cause of death worldwide and its impact is expected to continue growing.(Bray et al., 2024)

Global cancer statistics paint a stark picture of the immense burden that cancer places on individuals and societies worldwide. As we delve deeper into the specifics of cancer types, solid tumors emerge as a significant focus of research and clinical efforts. Solid tumors, characterized by abnormal cell growth in tissues such as the breast, lung, colon, and prostate, represent a substantial portion of cancer cases and pose unique challenges in terms of diagnosis and treatment.

The complexity of solid tumors lies not only in their diverse origins and behaviors but also in the intricate interactions between tumor cells and the surrounding microenvironment. The intricate interactions between tumor cells and the tumor microenvironment play a pivotal role in the development and progression of solid tumors. The dynamic interplay between cancer cells, stromal cells, immune cells, and the extracellular matrix within the tumor microenvironment contributes significantly to tumor growth, invasion, and resistance to therapy. (Li et al., 2007)

Cancer treatment encompasses a wide range of therapeutic approaches aimed at combating the growth and spread of cancer cells. Conventional treatment methods include surgery, chemotherapy, and radiotherapy. However, significant advances have been made in recent years, leading to the development of new and targeted therapies. Some notable breakthroughs include: Immunotherapy, CAR-T Cell Therapies, Targeted Therapies, Precision Drugs, Liquid Biopsies, Nanotechnology, Cancer Vaccines and so on.(Society, 2022)

These advances, along with ongoing research and clinical trials, are continuously improving the effectiveness and precision of cancer treatment, offering new hope for patients and advancing the field of oncology.

While there have been significant advances in cancer treatment, there are still limitations and challenges that researchers and healthcare professionals face:

Cancer cells can develop resistance to therapies over time, leading to treatment failure. This resistance can be intrinsic (present from the start) or acquired (developed during treatment).

Many cancer treatments, such as chemotherapy and radiation therapy, cause significant side effects. These side effects can range from mild to severe and may include fatigue, nausea, hair loss, immunosuppression, and organ damage.("Advancing Cancer Therapy," 2021)

Cancer treatments are expensive. Advanced cancer therapies are costly and inaccessible to patients due to financial constraints and healthcare system limitations. The high prices are affected by prohibitive costs for new treatments, expensive and often unsuccessful procedures, as well as insurance plans lack of coverage. People with cancer are also often unable to work full time or even at all, both during and after treatment, increasing the financial burden.

A systematic literature review was conducted to identify studies that estimated the out-of-pocket cost burden faced by cancer patients and their caregivers. The average monthly out-of-pocket costs per patient were reported/estimated with afflicted individuals paying up to 2600$ a month for care in the United States.(Iragorri et al., 2021)

Addressing these limitations requires ongoing research, collaboration, and innovation in the field of oncology as well as scalability of treatments to help further drive down costs.

Given the persistent challenges in cancer treatment, the Westlake team from Westlake University developed Tumor-Targeting Salmonella-Mediated Apoptosis Therapy. We chose Salmonella as the delivery vector because it can invade epithelial cells, which comprise a large portion of cancers. Notably, scientists have developed VNP20009, an attenuated strain of Salmonella with enhanced tumor-targeting capabilities(Clairmont et al., 2000). We leveraged VNP20009 to deliver our therapeutic system.

We added a small antibody to the surface of VNP20009, enabling it to recognize specific antigens on the surface of cancer cells, thereby enhancing its invasion efficacy. Upon invasion, VNP20009 undergoes self-lysis, activated by a specific promoter that is only triggered within human cells. This releases the plasmids contained within VNP20009. Among these plasmids, three form the killing system: one codes for an effector gene to induce cancer cell death, while another acts as a bio-switch to recognize specific intracellular signals and determine whether the effector gene will be expressed.(Shao et al., 2024)

This therapy offers a promising targeted treatment approach for cancers currently lacking effective treatments, such as liver cancer and metastatic breast cancer. The Salmonella delivery system is composed of three key components: (1) scFv display on the bacterial surface; (2) an auto-lysis initiation circuit triggered by bacterial internalization signals; and (3) a cancer-specific killing system regulated by a bio-switch.

To optimize our therapeutic approach and predict its efficacy, we developed a comprehensive mathematical model comprising three key components: (1) the diffusion process of engineered Salmonella following intratumoral injection, (2) the growth and secretion dynamics of Salmonella within the tumor microenvironment, and (3) the predictive modeling of the bactericidal effects on cancer cells. This model quantitatively analyzes how the bacteria spread through the tumor tissue, how they grow and release therapeutic agents upon self-lysis, and how these agents induce apoptosis in cancer cells. By simulating these interactions, the model provides valuable insights into optimal dosing strategies and timing, ultimately aiming to maximize the therapeutic efficacy of our engineered Salmonella system.

For more details, please see our Design page.

1. Low Production Cost: The gene circuits designed for this system are not influenced by individual differences, allowing for mass production of the engineered Salmonella at a low cost. This scalability makes the therapy economically viable for widespread use.

2. Safety Mechanisms: The system is designed with several built-in safeguards. No individual plasmid in the killing system can induce apoptosis by itself. The therapeutic effect is only triggered when all plasmids are present and cohesive, working together in the cancer cell intracellular environment, ensuring targeted killing while minimizing off-target effects in normal cells.

3. Precise Translational Regulation: A bio-switch is incorporated to regulate the expression of the BAX gene at the transcriptional level. This allows for finer control, as transcriptional regulation is more immediate and sensitive compared to translational control, leading to a faster and more accurate therapeutic response.

4. Enhanced Tumor Specificity: By displaying a scFv on the surface of Salmonella VNP20009, the bacteria are directed specifically to cancer cells with an increased invasion capacity allowing better colonization of tumors. This ensures that the therapy is selectively delivered to tumor sites, improving efficacy and reducing potential damage to healthy tissue.

5. Efficient Intracellular Delivery: The use of Salmonella as a delivery vehicle ensures that the therapeutic payload is effectively delivered into cancer cells. Once inside, the self-lysis mechanism releases the payload directly into the cytoplasm, increasing the efficiency of gene expression and the therapeutic effect.

6. Reduced Risk of Immune Response: Attenuated VNP20009 has been shown to have low toxicity and reduced virulence, minimizing the risk of eliciting a strong immune response from the patient. This makes the therapy safer and less likely to cause adverse immune reactions.

7. Scalability: Our T-SAT system can be adapted for the treatment of a wide range of solid tumors and even other diseases related to epithelial cells. By replacing the BAX gene with different effector genes and selecting intracellular signals specific to pathological cells, our engineered VNP20009 strain can be tailored to target various diseases. This flexibility makes the system highly scalable for diverse therapeutic applications.

Advancing Cancer Therapy. (2021). Nature Cancer, 2(3), 245-246. https://doi.org/10.1038/s43018-021-00192-x

Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), 229-263. https://doi.org/https://doi.org/10.3322/caac.21834

Clairmont, C., Lee, K. C., Pike, J., Ittensohn, M., Low, K. B., Pawelek, J., Bermudes, D., Brecher, S. M., Margitich, D., Turnier, J., Li, Z., Luo, X., King, I., & Zheng, L. M. (2000). Biodistribution and Genetic Stability of the Novel Antitumor Agent VNP20009, a Genetically Modified Strain of Salmonella typhimuvium. The Journal of Infectious Diseases, 181(6), 1996-2002. https://doi.org/10.1086/315497

Iragorri, N., de Oliveira, C., Fitzgerald, N., & Essue, B. (2021). The Out-of-Pocket Cost Burden of Cancer Care—A Systematic Literature Review. Current Oncology, 28(2), 1216-1248. https://doi.org/10.3390/curroncol28020117

Li, H., Fan, X., & Houghton, J. (2007). Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem, 101(4), 805-815. https://doi.org/10.1002/jcb.21159

Shao, J., Li, S., Qiu, X., Jiang, J., Zhang, L., Wang, P., Si, Y., Wu, Y., He, M., Xiong, Q., Zhao, L., Li, Y., Fan, Y., Viviani, M., Fu, Y., Wu, C., Gao, T., Zhu, L., Fussenegger, M., . . . Xie, M. (2024). Engineered poly(A)-surrogates for translational regulation and therapeutic biocomputation in mammalian cells. Cell Research, 34(1), 31-46. https://doi.org/10.1038/s41422-023-00896-y

Society, A. C. (2022). Cancer treatment & survivorship facts & figures 2022-2024. In: American Cancer Society Atlanta.