Project Description

Background

According to Development Goals (SDGs) Target 3.4, every country in the world is required to reduce by one-third premature mortality from non-communicable diseases (NCDs)¹ NCDs are diseases not passed from person to person (not spread through acute infection) and result in long-term treatment and care². NCDs, including cardiovascular disease (CVDs), diabetes mellitus (DM), chronic respiratory diseases (CRDs), and cancer (CA), kill 41 million people each year or equivalent to 74% of all deaths globally³.

Among NCD diseases, cancer is the second leading cause of death worldwide after CVDs⁴. Based on GLOBOCAN statistics produced by International Agency for Research on Cancer (IARC) and World Health Organization (WHO), there were 19.292.789 new cancer cases and 9.958.133 cancer deaths in 2020⁵ As the world population increases over time, the number of cancer deaths have also increased. In 2040, the number of new cancer cases per year and cancer-related deaths are expected to rise to 29.5 million (47% rise from new cancer cases in 2020) and 16.4 million (64% rise from number of cancer deaths in 2020).

Cancer is a disease in which certain body cells grow and divide uncontrollably and spread to other body parts (metastasis). Cancerous cells or malignant tumors have abilities to spread and invade nearby tissue or other organs in the body, while benign tumors do not. Normally, damaged cells break down and then grow and proliferate to form new cells⁶. In contrast to cancer cells, dysfunctions occur in proteins that inhibit cell cycle progressions and stimulate cell proliferation⁷.

Cancer incidence is increasing in low- and middle-income countries (MIC)⁸. According to the World Bank, low-income countries are countries having GNI (Gross National Income) per capita of $1,085 per year. Middle-income country is classified into lower-middle-income (GNI per capita between $1,086-$4,255) and upper-middle-income (GNI per capita between $4,256-$13,205)⁹. Many factors affect the high number of cancer incidences in MICs, such as less effective, affordable, or feasible detection strategies and treatments. In 2020, there are four highest-burden cancers in MICs⁸

Cervical Cancer in Indonesia

As a lower-middle-income country, Indonesia faces many challenges in achieving SDGs, especially Target 3.4. Cervical cancer is the second leading cancer type in Indonesia¹⁰. Prof. Dr. dr. Andrijono, Sp.OG(K)-Onk, oncology gynecology consultant and the chairman of the advisory council of Indonesia Oncology Gynecology Association (HOGI), said that94% of cervical cancer patients in Indonesia died within two yearsbased on data from Cipto Mangunkusumo Hospital (RSCM)¹¹. The low survival expectancy of cancer patients is mainly caused by the late detection of cervical cancer. The majority of cervical cancer patients are detected at advanced stage, stage IIIB (50%) and stage IIB (45%)¹².

The progression from pre-cervical cancer to cancer isrelatively long, around fifteen years (based on our discussion with Prof. Dwiana Ocviyanti). Furthermore, carcinogen proteins, carcinogen-carrying vectors (HPV virus), and stages were discovered¹³. Regarding great opportunities for cervical cancer to be prevented and the number of cervical cancers in Indonesia being relatively high, the Indonesia government provides free cervical cancer screeningsto Indonesian women such as pap smear, IVA test (acetic acid visual inspection test), and HPV DNA (Human Papilloma Virus DNA)14. Nevertheless, manyIndonesian women are still too reluctant to do the screening because of the procedures¹⁵. In addition, the perception that someone who checks cervix condition is labeled as a 'problematic woman' discourages them from doing the screening. Because prevention efforts that have been carried out are still less effective in reducing the number of cases, an alternative treatment method is needed.

The management of cervical cancer treatment in Indonesia is carried out such as cancer treatments in general, through surgery, chemotherapy, radiotherapy, or a combination of three previous methods. Nevertheless, conventional methods have not cured cervical cancer disease effectively. Thesurgery method is not suitable for all cancer types. Many factors, such as the size and location of the cancers and patient health, influence the surgery method¹⁶. Chemotherapy, using anti-cancer drugs injected into patient's bloodstream,causes side effects such as hair fall and thinner, change of organ works, vomiting, and infertility. Furthermore, high cases of cancer cell resistance to chemotherapy drugs cause this treatment method to be less sensitive17. Radiotherapy uses high-energy radiation to kill cancer cells. Radiotherapy is also less sensitive because its method can not distinguish between cancer and healthy cells and affect nearby cells18. Therefore, efficient alternative treatment for cervical cancer is needed in terms of price, ease of drug access, and solutions to the existing treatments' problems

How We Solve the Problems?

Drug delivery systems can be designed to deliver drugs specifically to disease sites in patient's bodies. The system can prevent the drugs from interacting with healthy cells. One of the methods being developed is bacterial-mediated cancer therapy. The bacteria used for drug delivery are certain weakened strains, both naturally and through genetic engineering. These strains of bacteria can generally work directly to infect cancer cells and destroy cancer cells using the mechanism of the infection of congenital host cells.

Salmonella is one of the superior bacterial candidates that can be used as cancer therapy. Besides having natural anti-tumor properties, Salmonella can also specifically target cancer cells rather than healthy cells. Furthermore, Salmonella can also survive in the environment of cancer cells, which generally can not be done by conventional treatments, overcome cancer resistance to chemotherapy drugs, and improve immune response to cancer cells.

One of the bacterial strain that can be used is Salmonella typhimurium A1-R. This strain is a mutant strain from Salmonella enterica serovar Typhimurium, which is selected from the viability test on cancer cells. This strain has random mutations due to methylation, thus losing the ability to produce amino acid arginine and leusine. This mutation causes changes in flagella-forming proteins, making them weaker than other Salmonella strains. Furthermore, these cells are able to detect cancer through aspartate, serine, and galactose/ribose receptors so that they can form colonies in cancer cells.

Nevertheless, Salmonella typhimurium A1-R has been unable to infect cancer cells effectively. The testing of Salmonella typhimurium A1-R to cancer cells relies on activation of antitumor immunity during bacterial infections so that cancer cells can die normally. However, cancer cells can not be effectively killed in clinical testing because the death of cancer cells due to bacteria can not occur effectively.

Because of the need for alternative treatment for cervical cancer, iGEM UI 2023 team made a project titled CerveX. In the project, Salmonella typhimurium A1-R will be combined with toxic peptide carrier plasmids to help kill cancer cells. Therefore, iGEM UI 2023 team intends to test the effectiveness of the recombination of toxic peptides to Salmonella typhimurium A1-R to kill cervical cancer cells.