Gleevec and the cell cycle problem
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Summary
Students are given a problem about a relatively new treatment for cancer, Gleevec, and asked to apply and synthesize what they have learned about cell signaling and the eukaryotic cell cycle to explain why this targeted treatment works to prevent cell division with fewer side effects than traditional chemotherapeutic agents. The Gleevec problem is synthetic and contextually rich in nature, and gives students the opportunity to review key aspects of translation and the genetic code.
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Learning Goals
The Gleevec problem is an example of a context-rich problem that requires students to synthesize what they have learned about the eukaryotic cell cycle and cell signaling. The problem provides background on the genetic cause of one type of cancer and a drug that treats this cancer; in our experience, questions related to health have high interest for the students. The problem asks the students to explain why a drug that inhibits a kinase could prevent cell division, and to compare/contrast the drug to other more general chemotherapeutic treatments.
Concepts and content- the connection between growth factor receptors, cell signaling pathways, and regulation of the eukaryotic cell cycle
- kinase inhibitors as drugs
- an understanding of how unregulated cell division can lead to cancer
- application of concepts in a new context
- analysis
- synthesis
Context for Use
This problem is used in an undergraduate introductory biology course, but could also be used in upper level courses, e.g. Cell or Genetics. The problem was designed for students to solve in-class in small groups, with faculty present to provide feedback and coach as needed (as described in the accompanying module). It was part of a handout that included other problems related to the eukaryotic cell cycle. Prior to receiving this set of problems, students had learned about cell signaling involving kinases, growth factors and their receptors, and the eukaryotic cell cycle in interactive lectures, and had worked several problems related to these topics. They had also just completed a related problem that outlined the side effects and targets of nonspecific chemotherapeutic agents. The Gleevec problem asks the students to use their knowledge of cell signaling and to apply it to control of the cell cycle. Because Gleevec targets a fused protein, students should also have covered translation and the genetic code.
Description and Teaching Materials
Student problem on Gleevec and the cell cycle
In 2001 Novartis began to market the drug Gleevec® as a therapy for one type of cancer, chronic myelogenous leukemia. Gleevec inhibits a kinase that is normally activated in response to growth factor binding to its receptor (remember that a kinase is an enzyme that transfers a phosphate group from ATP to a target protein).
A. Why would Gleevec be a successful anticancer treatment?
Chronic myelogenous leukemia is one type of cancer of the white blood cells, and is caused by a translocation between chromosomes 9 and 22. A translocation is the interchange of chromosome segments between nonhomologous chromosomes. The gene for the kinase that is normally activated in response to growth factor signaling is translocated to a new place on another chromosome. The translocation results in the fusion of two genes, as the translocated kinase gene fuses with a gene at the new location. Remarkably, the gene fusion event results in a fused protein; following fusion, the codons remain in frame and are able to be translated by the ribosomes to produce a functional protein. These cells now synthesize a new protein that has kinase activity. However, rather than being switched on or off in response to growth factor, the fused kinase remains in the "on" position, and is not regulated. Cells containing the fused protein gain the ability to divide in the absence of growth factor, and this activity contributes to the development of cancer. Gleevec only binds to, and inhibits, the fused version of the kinase. Gleevec does not bind or inhibit the unfused version of the kinase.
B. Explain why Gleevec differs from radiation or general cell cycle inhibitors often used for cancer therapies. What do you predict about side effects in an individual treated with Gleevec as compared to a more traditional anticancer treatment?
A. Why would Gleevec be a successful anticancer treatment?
Chronic myelogenous leukemia is one type of cancer of the white blood cells, and is caused by a translocation between chromosomes 9 and 22. A translocation is the interchange of chromosome segments between nonhomologous chromosomes. The gene for the kinase that is normally activated in response to growth factor signaling is translocated to a new place on another chromosome. The translocation results in the fusion of two genes, as the translocated kinase gene fuses with a gene at the new location. Remarkably, the gene fusion event results in a fused protein; following fusion, the codons remain in frame and are able to be translated by the ribosomes to produce a functional protein. These cells now synthesize a new protein that has kinase activity. However, rather than being switched on or off in response to growth factor, the fused kinase remains in the "on" position, and is not regulated. Cells containing the fused protein gain the ability to divide in the absence of growth factor, and this activity contributes to the development of cancer. Gleevec only binds to, and inhibits, the fused version of the kinase. Gleevec does not bind or inhibit the unfused version of the kinase.
B. Explain why Gleevec differs from radiation or general cell cycle inhibitors often used for cancer therapies. What do you predict about side effects in an individual treated with Gleevec as compared to a more traditional anticancer treatment?
Teaching Notes and Tips
The Gleevec problem is part of a hand-out composed of multiple problems related to the eukaryotic cell cycle. The time required to answer the questions is dependent on that student's understanding of the concepts and will be variable. There have been times when we have taught the course where Gleevec and the cell cycle has been designated as a "challenge" problem (this decision is dependent upon both the students in the course and the time we have had to discuss regulation of the cell cycle that particular year). Challenge problems are provided for those students who work through all problems quickly and are ready to learn additional material and to be challenged with more sophisticated ideas. Because our course involves daily, collaborative problem solving, we have found that having challenge problems available helps keep all students engaged, on task, and learning at their level. Prior to seeing the first challenge problem, we explain to the students that all answer keys will be posted, so everyone will have access to the "correct" answer for the challenge problems, but we also let them know they will not be asked specifically about new topics raised in a challenge problem on the exam. Students who did not have time in class to work through the challenge problems are not penalized on the exam.
Key Gleevec problem
A. The goal of the anticancer therapy is to inhibit cell division. Gleevec prevents activation of the kinase that would in turn activate the cyclin dependent kinase and cyclin complex. The active cyclin-cyclin dependent kinase is necessary for moving the cell through the cell cycle, i.e. from G1 to S phase.
B. Gleevec is a very SPECIFIC form of chemotherapy. It has a specific target in cells, the abnormally fused kinase protein. This abnormally fused kinase protein is only present in cancer cells. In the cancer cells, the kinase is inhibited and the cells are stopped from dividing. In non-cancer cells the fused kinase protein doesn't exist, therefore, Gleevec has nothing to bind to and has NO EFFECT. This specificity of Gleevec spares other rapidly dividing cells in the body, minimizing side effects. Other, more general chemotherapy drugs used to treat cancer work by targeting and destroying all dividing cells. The human adult has stem cells located in the skin, gut, and bone marrow that retain the ability to continuously divide and produce new cells throughout our lifetime. For example, the epithelial lining of our small intestine is continuously being shed at a rate of up to one billion cells per hour. These drugs don't distinguish between the DNA synthesis of a cancer cell and that of a gut epithelial cell. It is for this reason that chemotherapy results in unfortunate side effects including nausea, hair loss, and immune suppression.
B. Gleevec is a very SPECIFIC form of chemotherapy. It has a specific target in cells, the abnormally fused kinase protein. This abnormally fused kinase protein is only present in cancer cells. In the cancer cells, the kinase is inhibited and the cells are stopped from dividing. In non-cancer cells the fused kinase protein doesn't exist, therefore, Gleevec has nothing to bind to and has NO EFFECT. This specificity of Gleevec spares other rapidly dividing cells in the body, minimizing side effects. Other, more general chemotherapy drugs used to treat cancer work by targeting and destroying all dividing cells. The human adult has stem cells located in the skin, gut, and bone marrow that retain the ability to continuously divide and produce new cells throughout our lifetime. For example, the epithelial lining of our small intestine is continuously being shed at a rate of up to one billion cells per hour. These drugs don't distinguish between the DNA synthesis of a cancer cell and that of a gut epithelial cell. It is for this reason that chemotherapy results in unfortunate side effects including nausea, hair loss, and immune suppression.
Assessment
We assess this activity in class as the students work, but it is not graded. Ungraded problems emphasize formative assessment instead of evaluation (Hanson, 2004). The focus shifts, at least somewhat, away from writing down the correct answer for a grade. Students are not punished for making mistakes and may be able to learn from them before the exam. Faculty check in with each student group to make sure they are understanding the problem, and explicitly remind the students to think about what they've already learned (e.g. how kinases are activated by growth factors binding to growth factor receptors). Informal discussions with students help faculty uncover student understanding of which cells in the body divide, how DNA replication fits in to the cell cycle, and the role of specific signals in triggering eukaryotic cells to divide.
References and Resources
A figure of the structure of Gleevec, a history of its development, and details of its mechanism of action can be found at the Wikipedia entry for Gleevec.