Team:NEFU China/Description
Inspiration
As one of leading causes of human death, cancer is a major public threat of the human beings. Approaches of cancer treatment have changed through centuries, from humoral theory-based Greek therapies to radical surgeries, and then radiotherapies and chemotherapies. Gradually, their shortcomings are getting obvious in recent years. Here, we take chemotherapy as an example. During chemotherapies，the experience of physicians is not sufficient to apply perfect dosages of drugs，and inappropriate dosages can lead to various complications or even death. One of those typical complications is acute uric acid nephropathy. When tumor cells get dissociated by drugs, they would produce extra uric acid, which could beyond the dissolving capacity of the body fluid and then dissolve out as crystals to accumulate in kidney tubules and collecting tubules. Consequently, the nephropathy would happen when such kind of crystals substantially accumulates. Many conventional treatments for this syndrome, such as intravenous fluid infusion, urine alkalization, allopurinol and Rasburicase, have their shortages, including limited effects and high expense.
To find a better approach, we decided to precisely monitor the speed quota of tumor dissolution to control the dissolution process. Our choice for modification is E.coli Nissle 1917, a probiotic which can be used to serve as treatments for gastrointestinal illnesses and infections, as our "bacterium oncologists". As a nanoscale creature, these bacteria can easily get through the blood capillary of tumor tissues, with a better ability to colonize at tumor sites than any other species of E.coli. We can further strengthen the targeting ability of our oncologists by the interference of a magnetic field and self-elimination of these bacterium oncologists getting into healthy tissues. These bacteria would be sensitive to uric acid and produces tumor necrosis factor (TNF-α) to kill cancer cells. When the uric acid level produced from dissociated tumor cells increase, our oncologists would synthesize uricase to reduce it, while the expression of TNF-α would be restricted at this scenario. With cancer cells being gradually dispelled from the patient, our loyal bacterium oncologists can build comfortable harmony between drug dosage and patient's tolerance.
Abstract
At the stages of high-burden tumors or metastasis, cancer patients may suffer from acute uric acid nephropathy due to rapid dissolution of a large number of tumor cells caused by conventional treatments, such as radiotherapy and chemotherapy, which is one of the typical tumor lysis syndromes. To resolve this issue, we designed a novel system using E. coli Nissle 1917 that holds a controllable system to release anti-tumor agents in response to changes of uric acid levels. This can prevent the risk of manual assessment and reduce the occurrence of acute uric acid nephropathy. In this system, the engineered bacteria will regularly release anti-tumor agents when the levels of uric acid are low. With rapid tumor cell dissolution and consequent uric acid accumulation, the bacteria will slow down the agent release and start to degrade uric acid. As a result, the tumor cells can be safely dissolved under the conditions of uric acid fluctuation within a physiologically tolerable range. Simultaneously, we designed a normal tissue-specific cytosine deaminase expressing system that can eliminate the engineered bacteria in normal tissues under treatment of 5-Flucytosine. To increase tumor-specific targeting, we will engineer the E. coli Nissle to express ftnA-M (a mutant vision of the ferritin iron storage protein) that will allow the bacteria to localize at the tumor sites when they are exposed to a magnetic field to enhance tumor cell killing.
Background
Complications associated with cancer therapies represent one cause of high mortality of cancer patients. Chemotherapy is one of the most commonly used treatments for patients with their malignant tumors at the stage of a high burden or metastasis. Currently, the optimal dosage of clinically used chemotherapeutics can vary a lot depending on patients’ physical conditions and sensitivity to the agents; thus, overdosed chemotherapeutics may often cause damages to normal tissues and organs, and dampen the life quality of patients. When chemotherapeutic drugs dissolve a large number of tumor cells, a large amount of tumor contents will be released into the systemic circulation. One of the major contents is nucleic acid, which can be converted to urate through the nucleic acid metabolic pathway. Thus, with the quick dissolution of a large number of tumor cells, excessive urate will be produced, which will precipitate and deposit in renal tubules in the form of uric acid crystals, resulting in acute uric acid nephropathy accompanied by severe kidney injury and posing a serious threat to patients' lives.
For solid tumors, the risk assessment of acute uric acid nephropathy during chemotherapy is difficult. Its incidence varies due to sensitivity of tumors to chemotherapeutics, tumor growth kinetics, and renal function of individual patients.
Traditional approaches to prevent acute uric acid nephropathy also fall short. Normal therapy of acute uric acid nephropathy is intravenous infusion of NaHCO3-alkalized fluids. However, data obtained from evidence-based medicine suggested that the physiological consequence of urine alkalinization is unclear, but may rather enhance the deposition of other excess salt, while intravenous fluids showed minor protective effects. Several agents may also alleviate the syndrome. Allopurinol, with a modest preventive effect, can block the process from precursor of uric acid, xanthine, to uric acid, but cannot remove uric acid. Labradinase, with a function of removing uric acid, is considerably expensive with an estimated daily cost of about 5,000 USD for an adult.
Introduction
Cancer has become one of the leading causes of death seriously threatening the health of people worldwide. According to the latest statistics from the National Cancer Institute, in 2018, an estimated 1,735,350 new cases of cancer would be diagnosed in the United States and 609,640 people would die from the disease. Based on the data from 2011 to 2015, the annual number of new cases of cancer (cancer incidence) is 439.2 per 100,000 men and women and the annual number of cancer death (cancer mortality) is 163.5 per 100,000 men and women. All the statistics above indicated that cancer is really a challenge for our life. Now, our team wants to design a bacterium-based cancer therapy system to conquer this challenge.
Description
Based on the facts described above, an effective tumor therapeutic approach with reduced risk of acute uric acid nephropathy is urgently needed. With the rapid development of synthetic biology, bacterium-based cancer treatment has become an emerging way of cancer therapies with a great potential of clinical applications due to its reinvention and sustainability. Therefore, we decided to use engineered bacteria to deliver and release anticancer agents, and simultaneously prevent accumulation of uric acid during cancer treatment. We expect that this will lead to elimination of cancer cells and prevention of nephropathy.
We will use mice as a model to test this approach. In our system, with the engineered bacteria being systematically delivered into the mice, the bacteria in normal tissues will be eliminated in response to 5-fluorocytosine, while the majority of the bacteria will be attracted to the tumor sites to exert their anticancer activity. In this system, whether the therapeutics is releasing or elimination of tumor cells is processing depends on uric acid levels. When uric acid level at tumor sites is low, bacteria will release anti-tumor agents. However, when uric acid reaches a certain level (a threshold), the bacteria will slow down the release of anti-tumor agents and instead express uricase to reduce uric acid levels. Therefore, we will accomplish the goal of killing tumors and at the same time avoid the occurrence of acute uric acid nephropathy, which will treat cancer patients gently and safely.
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iGEM-NEFU_China2019
E-mail:nefu_igem2019@163.com
No.26 Hexing Road, Xiangfang District, Harbin, Heilongjiang Province 150040
