Difference between revisions of "Team:ETH Zurich/Description"

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<p>This is the story about how we developed the idea of CATE. To skip to story and jump directly to how CATE is designed to treat tumors, see <a href="https://2017.igem.org/Team:ETH_Zurich/Applied_Design">CATE in Action.</a></p>
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<p><em>This is the story about how we developed the idea of CATE. To skip to story and jump directly to how CATE is designed to treat tumors, see <a href="https://2017.igem.org/Team:ETH_Zurich/Applied_Design">CATE in Action.</a></em></p>
  
 
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Revision as of 08:24, 31 October 2017

Story of CATE

This is the story about how we developed the idea of CATE. To skip to story and jump directly to how CATE is designed to treat tumors, see CATE in Action.

Introduction

In 2015, cancer claimed the lives of 8.8 million people and still remains the second leading cause of death. The majority of these cases are due to cancers originating from malignant solid tumors - tumors developing in solid tissues such as breast and liver. In 2013, WHO launched the Global Action Plan for the Prevention and Control of Non-Communicable Diseases 2013-2020, aiming at reducing the global mortality due to diseases such as cancer by 25% by 2020. To fulfill this goal, safe and effective treatment options are required. [1]

Figure 1. Cancer in 2013.

Current Cancer Treatments

Today, there are several approaches to treating cancer and in general, they can be divided into two main groups: local and systemic treatment options. Local treatment options include surgery and radiation therapy, while systemic options refer to chemotherapy, targeted therapy and immunotherapy. Typically, the patient will receive a combination of different treatments extended over several weeks to months. [2]

Surgery

Surgery is a local treatment modality that includes removal of the visible tumorous tissue along with a margin of healthy tissue of a variable size.

PRO

  • usually a one time procedure
  • well established
  • great for large and isolated solid tumors

CONS

  • locally invasive and damaging
  • can be contraindicated in patients with comorbidities (e.g. older patients with cardiovascular diseases might be unable to undergo anesthesia)
  • not available for all sites
  • not suitable for curing a metastatic disease
  • can't guarantee the removal of invisible "micrometastases" in the vicinity of the primary tumor site
  • can be difficult to repeat if initial procedure fails
Radiotherapy

Radiotherapy includes using ionizing radiation to cause lethal mutations in cancer cells. It relies on the fact that normal tissue repairs damage faster and more efficiently than cancerous tissue.

PROS

  • not locally invasive
  • includes a large safety margin to ensure destruction of micrometastatic spreading

CONS

  • conventional regimen takes several weeks to complete
  • normal tissue between the skin and the tumor is always affected
  • long-term mutagenic and carcinogenic effects (that are stochastic and therefore do no depend on the dose)
  • short-term acute damages
Chemotherapy

Chemotherapy is the treatment of cancer with conventional anti-cancer drugs. These are not specifically targeted, but tend to inflict more damage to rapidly-dividing cells.

PROS

  • systemic treatment that can destroy all cancer cells in the body
  • cheap

CONS

  • dose and therefore efficiency of killing limited by severe systemic side effects due to lack of targeting
  • usually involves several treatments extended over weeks or months
Targeted Therapy

Targeted therapy involves a group of drugs that are more specific than typical chemotherapeutics. It includes small molecules that target mutations in cancer cells that let them grow, divide and spread. A group of monoclonal antibodies that inhibit growth of cancer by targeting and blocking specific surface receptors that are overexpressed on cancer cells also belong in this type of therapy. On the other hand, monoclonal antibodies that work by labelling the target cells for immune destruction are considered to be a part of Immunotherapy (see below).

PROS

  • in theory, only damaging to the tumor and not the healthy tissue

CONS

  • requires a specific, ideal target and currently, these are unknown for most of the tumors
  • systemic side effects still occuring
Immunotherapy

Immunotherapy is one of the most recent approaches to treating cancer and involves helping the patient's own immune system to fight the tumor through different strategies. CAR-T cells, the most promising form of immunotherapy, involve genetically engineering patient's own immune cells to target individual cancers specifically

PROS

  • tailored to an individual
  • potentially offering long lasting protection against the cancer
  • autologous (patient-derived) cells and therefore not immunogenic
  • specific for the cancer and can avoid normal tissue

CONS

  • unpredictable systemic side effects seen in clinical trials
  • specific targets/antigens still need to be found for every type of tumor, especially for solid tumors
  • expensive
  • complicated to produce

Some of the therapeutic options mentioned above are well established and have been used for decades, while others represent pioneering treatments developed thanks to advances in biological engineering. However, as seen from the list of pros and cons, no strategy is perfect. Therefore, complete removal of cancer without inflicting damage on the healthy tissue remains a challenge. [3]

Bacteria in Cancer Therapy

To tackle the challenge of treating cancer, we decided to look beyond these classical approaches and from the point of view of a synthetic biologist. Our search led us to the concept of bacterial cancer therapy - a strategy for treating cancer that actually dates back to the beginning of the 20th century but has since changed significantly. In the beginnings, different species of unmodified bacteria were given intravenously to cancer patients and were shown to accumulate preferentially in the tumorous tissue. This attractive inherent feature has been investigated since and is thought to be due to a combination of mechanisms, including:

  • entrapment of bacteria in the chaotic vasculature of the tumor,
  • production of chemotactic agents in the tumor microenvironment and
  • protection from the immune system that the microenvironment, as an immuno-privileged site, offers. [4]

Although native cytotoxicity of the bacteria was shown to inhibit tumor growth to a certain extent, simply administering unchanged bacteria intravenously has been connected to severe side effects and limited efficacy. To overcome this, engineering efforts have been made and different modifications have been implemented and are currently being tested in clinical trials. However, full potential of bacteria as an anti-cancer agent has not yet been fulfilled. [5]

Our vision

The ideal bacterial cancer therapeutic should be:

  • a tiny programmable robot factory that specifically targets tumors,
  • selectively cytotoxic to cancer cells,
  • self-propelled,
  • responsive to external signals,
  • able to sense the local environment and finally,
  • externally detectable. [5]
Figure 1. Features of ideal bacterial cancer therapeutic as implemented into our design. E. coli Nissle inherently finds and colonizes tumors. Once in this special surrounding, it is designed to recognize the environment (1. Environmental sensing), produce an MRI contrast agent (2. External detectabilty) and accummulate a cytotoxic agent it will later deliver. After confirmation of the correct colonization done by a physician, an external signal is sent via focused ultrasound (3. Response to external signal). This leads to selective delivery of the cytotoxic agent to the tumor (4. Selective cytotoxicity).

CATE, the cancer-targeting E. coli that we have engineered, represents our vision of the ideal bacterial cancer therapeutic. With the combination of autonomous targeting, visualization and externally controlled toxin release, we believe our project provides a novel non-invasive, quick and safe approach to treating cancer (Figure 1).

CATE in Action

We decided to work with the probiotic E. coli Nissle 1917, due to its inherent tumor targeting capabilities and lack of pathogenicity, which make it the ideal chassis for development of precisely controllable features that we decided to integrate into the therapeutic. [5][6]

We envision the treatment to follow the strategy described below. A short duration, enhanced safety and overall effectiveness are expected to be decisive factors for choosing to treat with CATE instead of conventional therapies.

The procedure revolves around two safety Checkpoints, unique to our design. Checkpoint 1 is an internal checkpoint where the bacteria identify the tumor and decide if they can proceed with the treatment, while Checkpoint 2 represent and external checkpoint manipulated by the physician. With the combination of the two, we believe to have designed a system of superior security.

The following steps will guide you through the treatment. To find out more about how each of the described steps works, click on the links below that will guide you to a detailed description of each function implemented in CATE.

1. Administration of the Bacterial Therapeutic

Following diagnostic procedures and the decision to use CATE, the patient will receive a soluble formulation of CATE in an intravenous injection. This is a quick and easy step for both the patient and the doctor.

2. Colonization of the Tumor Tissue

CATE distributes throughout the body and specifically populates the tumor tissue. Only in this special microenvironment, rich in nutrients and hidden from the immune system, CATE can grow to a high cell density. [5][6]

3. Tumor Sensing
CHECKPOINT 1

CATE is designed so that the two conditions necessary to pass the safety Checkpoint1 are only present in the tumor tissue and not in the healthy tissue.

  • The first condition is the high cell density of the bacteria, that CATE can only reach in tumors because of their unique microenvironment. [6]
  • The second condition is the presence of a high concentration of lactate, a molecule typically overproduced by cancer cells. [7]

Only if both of these conditions are fulfilled, CATE will pass Checkpoint 1 and proceed to the next step.

Function A: Tumor Sensor

4. Anti-Cancer Toxin Acummulation and MRI Contrast Agent Production

To pass Checkpoint 1, cell density of the bacteria in the tumor has to be high enough to kill it. Once this has been achieved, CATE will start to produce an Anti-Cancer Toxin. However, the toxin will not be released yet. It will reside in CATE until the second checkpoint has been passed. At the same time, CATE will also produce an MRI Contrast Agent. This will allow the doctor to confirm through an MRI scan that the Toxin is ready and the bacteria have indeed colonized the correct location. This additional security step is unique to our bacterial cancer therapy with CATE. Neither conventional cancer treatments that include systemically administered toxic compounds, nor modern targeted therapies with engineered immune cells have the advantage of combining an internal molecular tumor-recognition with the ability to externally verify and manipulate the treatment.

Function B: MRI Contrast Agent

Function C: Anti-Cancer Toxin

5. Focused Ultrasound

Immediately after examining the MRI scan, the doctor can apply focused ultrasound specifically to the tumor site. Focused ultrasound is an emerging medical technology that allows for high-energy sound waves outside of the audible spectrum (the same ones used by bats for navigation) to transmit their energy to a specific location on the inside of the body. [8] This results in a temperature increase in a narrowly defined area of the tumor.

6. Heat Sensing
CHECKPOINT 2

The increase in the temperature, from 37°C to 45°C, caused by the doctor via focused ultrasound, alerts CATE that Checkpoint 2 has been passed. A thermosensitive protein that has been blocking the activation of the Heat Sensing circuit until now is removed and CATE can continue with the next step of the treatment procedure.

Function D: Heat Sensor

7. Cell Lysis and Toxin Release

After successfully going through Checkpoint 2, CATE is designed to produce a special protein that originates from bacteria-killing phages. This protein interferes with the bacterial cell wall synthesis which leads to pore formation and ultimately, the breakdown of CATE. This way, the previously accumulated Anti-Cancer Toxin is released to the tumor tissue.

Function E: Cell Lysis

8. Cancer Killing

After the Anti-Cancer Toxin gets released, it enters the malignant cells. Once inside, it interferes with the cell cycle through multiple mechanisms, which include stabilization of a tumor suppresor protein and blocking of the transduction of growth signals. This interference inhibits the growth of cancer cells and ultimately results in their death. [9][10] With this, CATE’s mission is accomplished.

References

  1. "Cancer - Fact Sheet" who.int. World Health Organization, Feb. 2017, who.int/mediacentre/factsheets/fs297/en/.
  2. "Types of cancer treatment." cancer.gov. National Cancer Institute, Feb. 2017. cancer.gov/about-cancer/treatment/types.
  3. Miller, Kimberly D., et al. "Cancer treatment and survivorship statistics, 2016." CA: a cancer journal for clinicians 66.4 (2016): doi: 10.3322/caac.21349
  4. Felgner, Sebastian, et al. "Bacteria in cancer therapy: renaissance of an old concept." International journal of microbiology 2016 (2016). doi: 10.1155/2016/8451728
  5. Forbes, Neil S. "Engineering the perfect (bacterial) cancer therapy." Nature reviews. Cancer 10.11 (2010): 785. doi: 10.1038/nrc2934
  6. Stritzker, Jochen, et al. "Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice." International journal of medical microbiology 297.3 (2007): 151-162. doi: 10.1016/j.ijmm.2007.01.008
  7. Hirschhaeuser, Franziska, Ulrike GA Sattler, and Wolfgang Mueller-Klieser. "Lactate: a metabolic key player in cancer." Cancer research 71.22 (2011): 6921-6925. doi: 10.1158/0008-5472.CAN-11-1457
  8. Ebbini, Emad S., and Gail Ter Haar. "Ultrasound-guided therapeutic focused ultrasound: current status and future directions." International Journal of Hyperthermia 31.2 (2015): 77-89. doi: 10.3109/02656736.2014.995238
  9. Yamada, Tohru, et al. "Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer." Proceedings of the National Academy of Sciences 99.22 (2002): 14098-14103. doi: 10.1073/pnas.222539699
  10. Bernardes, Nuno, et al. "Modulation of membrane properties of lung cancer cells by azurin enhances the sensitivity to EGFR-targeted therapy and decreased β1 integrin-mediated adhesion." Cell Cycle 15.11 (2016): 1415-1424. doi: 10.1080/15384101.2016.1172147