Overview

For patients with cancers that are not cured by surgery or radiation, chemotherapy often represents the best hope for treatment. While chemotherapy is highly effective for some cancers, it is less effective for others.

Researchers in the Developmental Therapeutics Program are developing new, more effective cancer treatments. In many cases, these treatments also have fewer side effects than standard therapies.

Novel Therapeutic Trials
Researchers in the program perform initial clinical studies of agents that target the pathways altered in cancer cells. These trials examine the efficacy and safety of the next generation of anti-cancer drugs. Laboratory investigations designed to confirm that the targeted pathway has been affected are also built into these studies.

Once novel agents or combinations of agents are developed and tested in the laboratory, members of the Developmental Therapeutics Program help translate promising findings into clinical practice. Mayo Clinic Cancer Center's Phase I Group consists of a dedicated cadre of physicians, nurses, laboratory scientists, research assistants and statisticians who collaborate to perform early clinical testing of novel chemotherapeutic strategies developed at Mayo and elsewhere.

These trials are designed to assess the safety and efficacy of new treatments. In conjunction with these trials, blood samples or tumor biopsies are often examined to determine the impact of the treatment on the targeted signaling pathway. In addition, patients enrolled in the trials are often asked to allow examination of blood samples so that the metabolism of the novel agent can be assessed and correlated with any side effects.

Treatments that appear promising after these initial clinical trials often undergo more extensive clinical testing in Phase II and Phase III trials conducted in other programs within the Mayo Clinic Cancer Center, through the Mayo Clinic Phase 2 Consortium, or through the North Central Cancer Treatment Group.

Pharmacogenetics - The Right Drug, The Right Dose
Pharmacogenetic researchers study individual response to drugs in two ways: drug response and adverse drug reaction. For example, some patients don’t get the desired response from a therapeutic drug, while others have a strong negative reaction to it. Several factors may contribute to these reactions, such as age, gender and underlying disease. Pharmacogenetic researchers focus on the role of genetic inheritance in drug response.

One example of the power of pharmacogenetics was discovered at Mayo Clinic, and resulted in a now-standard clinical test related to a childhood leukemia drug called 6-mercaptopurine. Researchers found that as a result of genetic inheritance, 10 percent of people have a decrease in their ability to metabolize this drug, and one out of every 300 people can’t metabolize the drugs at all. In effect, their bodies cannot handle normal doses of the drug.

People who cannot metabolize the drug become very sick when treated with standard doses, because the standard dose is 10 times too much for these people. Researchers then developed a blood test to determine a patient’s enzyme activity, which allowed them to tailor the dose of the drug to the patient’s inherited ability to metabolize it.

Pharmacogenetics research translates very quickly to changes in treatment; new genomic information is very rapidly being converted into information that will have an impact on clinical care.

Pre-Clinical Studies
Alterations in signaling pathways involved in DNA repair and apoptosis (the process in which a damaged cell recognizes that it is defective and self-destructs) might not only contribute to the development of cancer, but also affect the ability of tumor cells to be killed by certain chemotherapeutic approaches. With this in mind, members of the Developmental Therapeutics Program are evaluating the possibility that alterations in these pathways might contribute to drug resistance.

Members of the Program are also developing and/or evaluating inhibitors of these pathways. In some cases these inhibitors appear to trigger apoptosis and reverse the cancer phenotype of cells with altered pathways. In other cases, the inhibitors themselves do not directly kill cancer cells but nonetheless sensitize those cells to killing by existing chemotherapeutic agents.

In addition to examining known pathways as potential targets for future therapy, members of the Developmental Therapeutics Program are also investigating the action of a number of agents that exhibit anti-cancer activity in model systems through mechanisms that are currently unclear. These studies often provide insight into new, previously unsuspected alterations in cancer cells as well as improved understanding of the action of the agents under investigation.

Sending the Right Signals
Cells divide and duplicate their DNA over and over again with remarkable precision. A complicated series of signals tells cells when to divide and when to stop growing. Sometimes – perhaps once in a billion times – there is a malfunction that damages a cell. When the signaling pathways are working correctly, the damaged cell recognizes that it is defective and either undergoes repair (usually of damaged DNA) or triggers a suicide process called apoptosis (programmed cell death).

These responses to damage can become defective in several ways. First, cells might lose the ability to sense the damage. Second, even if the damage is detected, the repair pathways might be altered. Finally, cells might lose the ability to trigger cell death after sensing the damage. Any of these changes can contribute to the development of cancer.

Many chemotherapeutic drugs kill cancer cells by damaging DNA or other cellular components, resulting in signals that trigger apoptosis. Therefore, alterations in signaling pathways that contribute to cancer development can also affect cancer therapy.

The study of signaling pathways involved in proliferation, repair and apoptosis has been a major emphasis of the Developmental Therapeutics Program. In addition to providing new insight into the nature of malignant cells, this research provides opportunities to better understand the nature of cellular responses to anti-cancer agents, to identify potential new targets for chemotherapy and to take advantage of these targets for more targeted therapies.

For additional information, see Current Projects.