The dna damage response as a target for anti-cancer therapy

Lectures: 1 session / week, 2 hours / session

For proper assessment of the primary literature, students are expected to have completed: Genetics (7.03), General Biochemistry (7.05), Cell Biology (7.06), or Molecular Biology (7.28).

In 1971, President Nixon declared the "War on cancer." Over recent years we have seen the development of new armament for this war — treatment strategies that are based on unique characteristics of tumor cells. An increased propensity for mutation is a hallmark of cancer, and an increasing number of genes involved in the DNA damage response and DNA repair have been found mutated or inactivated in human cancers, thus underlining the importance of an intact DNA damage response as a critical anti-cancer barrier. Cellular responses to DNA damage constitute one of the most important fields in cancer biology. Exciting work in this area has taught us important lessons, such as: DNA damage can cause cancer; paradoxically, the induction of DNA damage is also the mechanism of action of many currently used anti-cancer therapeutics, such as radiation and chemotherapy; and DNA damage of normal tissues is responsible for most of the side effects of cancer therapy, such as hair loss.

In this class we will analyze classical and recent papers from the primary research literature to gain a profound understanding of cell cycle regulation and DNA damage checkpoints that act as powerful emergency brakes to prevent cancer. We will consider basic principles of cell proliferation and molecular details of the DNA damage response and we will discuss the methods and model organisms typically used in this field. Building on this foundation we will explore new concepts in the treatment of cancer that are based on and exploit characteristic differences in the DNA damage response between normal cells and cancer cells. While mutations in genes involved in cell cycle control and the DNA damage response allow the runaway proliferation of incipient cancer cells, it can also be seen as the "Achilles heel" of cancer. We will see that therapeutic regimens emerge that are guided by a spectrum of characteristic mutations that differ between individual patients — paving the way for personalized anti-cancer therapy. This course will not stop at discussing the research literature. We will go one step further by gathering and analyzing real data in an MIT Cancer biology laboratory.

One primary objective of this course is to introduce students to the analysis of primary research literature. To achieve this goal, we will have weekly sessions, during which we will engage in a detailed discussion of two scientific papers. Our readings will include both classic and recent breakthrough papers. With the exception of the first meeting, no lectures will be given. Instead, course participants will actively present as well as drive the discussions of the papers.

The second objective of this course is for students to gain a deeper understanding of the response mechanisms a cell puts into place when it faces DNA damage. We will learn that these defense mechanisms are crucial for cellular survival and that misregulation of these processes can lead not only to cell death but also to increased mutation frequency, thus paving the way for cancer development. The cellular mechanisms involved in the so-called DNA damage response are well-studied both at the organism level as well as at the molecular level. We will see that the core machinery of the DNA damage response consists of a highly specialized network of protein kinases and phosphatases, which are rapidly acting enzymes that can add or remove phosphates to substrates. Many different components of this cellular defense mechanism have been found mutated in different cancers. This impairment of DNA quality control and repair mechanisms allows the accumulation of mutations and the development of cancer. Over recent years we have seen the development of therapeutic regimens that are based on the impaired DNA damage response of cancer cells. During this class we will use our understanding of basic cell cycle regulatory mechanisms to understand how these new therapeutic concepts work and why they are specifically targeting cancer cells.

This course is graded pass/fail. The grading will be based on participation during presentations and discussions as well as on two assignments. Attendance at all meetings is very important. If an absence is unavoidable, instructors should be notified in advance and make-up work will be assigned.

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