Current Projects

The Developmental Therapeutics Program brings together researchers from a variety of disciplines whose goal is to develop new, more effective cancer treatments. Investigators in this program focus on research in four areas:

• Elucidation of the signaling pathways that contribute to cancer cell survival and proliferation.
• Laboratory evaluation of small molecule inhibitors that target these pathways and others implicated in resistance to current chemotherapeutic approaches.
• Performance of innovative clinical trials designed to assess the effectiveness and safety of new agents as well as their ability to inhibit their intended targets in the clinical setting.
• Study of how a patient’s genetic makeup affects the response to and side effects of chemotherapy.

Each of these areas is described in greater detail in the following paragraphs.

SIGNALING PATHWAYS INVOLVED IN CELL SURVIVAL

Cell signaling pathways are fundamental to the understanding of cancer. A complicated series of signals tells cells when to divide and when to stop growing. Cells divide and duplicate their DNA over and over again with remarkable precision. Sometimes – perhaps once in a billion times – there is a malfunction that may damage 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 process of self-destructionknown as apoptosis (programmed cell death). In cells where the signaling pathways for DNA repair and/or programmed cell death are not functioning properly, cells continue to divide and become cancerous.

Many cancer drugs kill cancer cells by damaging DNA or other cellular components, ultimately producing signals that trigger apoptosis. As a result, alterations in the same signaling pathways that contribute to the development of cancer initially can also affect the sensitivity of cancer cells to chemotherapeutic agents and radiation.

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

Elucidation of Signaling Pathways that Contribute to Breast and Ovarian Cancer
Junjie Chen, Ph.D.

Dr. Chen works on the signaling pathways involving BRCA1 and BRCA2, the products of the two genes that are most frequently mutated in familial breast and ovarian cancer. His studies have not only demonstrated that these two proteins are involved in signaling pathways that are activated by DNA damage, but also identified additional components of these pathways and demonstrated a new mechanism by which the proteins in this pathway communicate with each other.

Dr. Chen’s findings have provided new understanding of the mechanism by which alterations in these signal transduction pathways can contribute to development of cancer. In addition, they provide new insight into the role of these same pathways in determining how cancer cells respond to radiation therapy and chemotherapeutic agents that damage DNA.

Identification of Specific Genes that Contribute to Pancreatic Cancer Cell Growth
Daniel Billadeau, Ph.D.

Dr. Billadeau works with signaling pathways usually found to be active only in blood cells. However, he recently demonstrated that that this pathway is present and activated in 50% of pancreatic tumors, but not in the normal pancreas. Further experiments have suggested that this pathway contributes to the processes that cause normal pancreatic cells to become cancerous.

Dr. Billadeau’s findings are exciting because they provide a new potential chemotherapeutic target against a malignancy that is highly resistant to chemotherapy. He is currently examining the effect of various anticancer agents on genes in this signaling pathway and developing strategies to design new agents specifically targeted at proteins in the pathway. One of his studies forms the basis for a project that is part of the Specialized Programs of Research Excellence (SPORE) grant in pancreatic cancer, recently awarded by the National Cancer Institute to the Mayo Clinic Cancer Center.

DEVELOPING THE NEXT GENERATION OF ANTICANCER DRUGS

The delineation of critical cellular pathways involved in malignant transformation and cancer progression has yielded detailed understanding on the proteins involved in these cellular processes, many of which are potential targets for chemotherapeutic agents. For the first time, drugs are being developed to target specific molecular abnormalities in tumor cells. There is considerable optimism in the anticancer drug development community that targeting these specific abnormalities will result in potent anticancer drugs that lack the high level of toxic side effects observed with previous drugs.

Members of the Developmental Therapeutics Program are working to identify and study the next generation of chemotherapeutic agents in their laboratories.

Targeting Protein Kinase C Isoforms
Alan Fields, Ph.D.

Seminal work by Dr. Fields, who heads the oncology laboratory research program in Jacksonville, has established a critical role for several members of the protein kinase C family of signaling molecules in the development of cancer. More recent studies in the Fields laboratory have validated a novel strategy for inhibiting signaling by these molecules and then identified small drug-like molecules that can actually inhibit this signaling. Ongoing studies are designed to confirm the effectiveness of these molecules in animals bearing tumors that arise as a consequence of increased protein kinase C signaling. Once these animal studies are complete, further laboratory evaluation will be undertaken to develop these agents as potential anticancer drugs.

Targeting DNA Damage-Activated Checkpoints
Larry Karnitz, Ph.D., and David Toft, Ph.D.

The work of Drs. Karnitz and Toft is an important demonstration of the collaborative efforts within the Developmental Therapeutics Program. The experimental agent 17-allylamino-17-demethoxygeldanamycin (17-AAG) is one member of and important new class of drugs that interrupt critical cellular processes involving protection or “chaperoning” of certain cellular proteins. Dr. Toft, a nationally recognized expert in these protein chaperone pathways, helped establish the mechanism of action of these new agents.

More recently, Dr. Karnitz and colleagues established that heat shock protein 90, the chaperone that is targeted by 17-AAG, plays a critical role in one of the cell’s responses to DNA damage. Joint studies between the Karnitz and Toft laboratories have demonstrated that the checkpoint kinase Chk1 depends upon intact heat shock protein 90 for its stability. When heat shock protein 90 is inhibited by 17-AAG, Chk1 decreases; and cells are no longer able to respond to replication inhibitors such as gemcitabine or cytarabine in the usual fashion. As a result, tumor cells become more sensitive to gemcitabine- or cytarabine-induced cell death. Collectively, these studies led to the design and implementation of several recently completed or ongoing clinical trials examining the ability of heat shock protein 90 inhibitors to enhance the antitumor properties of gemcitabine, cisplatin, cytarabine and topoisomerase I inhibitors.

Stimulators of Programmed Cell Death
Scott H. Kaufmann, M.D., Ph.D. and Yuan-Ping Pang, Ph.D.

Dr. Kaufmann’s laboratory has extensively studied the process of programmed cell death (apoptosis) and the manner in which it is triggered by anticancer drugs. To avoid accumulation of excessive DNA damage after exposure to UV light or other sources of DNA damage, normal cells undergo programmed cell death when dangerous levels of DNA damage occur, thus protecting against conversion of cells to a cancerous state. Cancer cells frequently contain alterations that reduce the effectiveness of programmed cell death pathways. According to current understanding, these alterations not only contribute to the development of cancer, but also contribute to resistance to important anticancer agents that damage DNA.

In collaboration with Dr. Pang, who has developed a highly powerful computational-based screen for small drug-like molecules that interact with any target of interest, Dr. Kaufmann has identified small molecules that reverse one of the death pathway alterations frequently observed in breast cancer cells. These small molecules increase the efficiency of programmed cell death activity in tumor cells and enhance the effectiveness of a variety of anticancer agents in vitro. Further studies are under way to determine whether these agents can successfully enhance the efficacy of chemotherapy in vivo.

Tumor Cell Activation of Drugs
Matthew M. Ames, Ph.D.

Dr. Ames has a long-standing interest in the metabolism of anticancer agents by normal and tumor tissues. For the past several years, Dr. Ames has been investigating a family of drugs that work through a novel mechanism of action involving a specific drug metabolism pathway in tumor cells. The drug induces production of a specific protein in sensitive tumor cells that in turn metabolizes the drug to a DNA-damaging product that is lethal to tumor cells. Production of the toxic metabolite directly in tumor cells may result in reduced normal tissue toxicity, and may allow individualized patient selection by assessing patient tumor cells for the drug induction prior to therapy. This work has led to selection of this agent for study in clinical trials by the National Cancer Institute, and those studies will be performed in the Mayo Clinic Cancer Center.

Chemotherapy Targeted at a Signaling Pathway Combined with Radiation Therapy
Jann Sarkaria, M.D.

Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor. Currently the standard therapy for GBM is surgery followed by radiation therapy. Unfortunately even after surgery and radiation the tumors invariably recur and the prognosis is bleak. Dr. Sarkaria theorized that a combination of a new chemotherapeutic agent targeted at a signaling pathway and radiation treatment would have a beneficial effect on this type of brain tumor.

Researchers know that the epidermal growth factor receptor (EGFR) signaling pathway is important in the development of malignancy in multiple tumor types. Several classes of new chemotherapeutic agents have been developed to specifically target EGFR. In studies with tumor-bearing mice, Dr. Sarkaria tested a combination of one of these new drugs with radiation therapy and found that the combination of the drug and radiation therapy has a greater effect than either therapy alone. Dr. Sarkaria’s exciting results in this very resistant tumor have led to the initiation of clinical trials at Mayo Clinic Cancer Center to evaluate this regimen.

TESTING THE NEXT GENERATION OF ANTICANCER DRUGS

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. The Phase I Group of the Mayo Clinic Cancer Center 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. The involvement of members of the Phase I Group in the design and performance of these more advanced trials helps speed the most promising treatments into more widespread testing.

Inhibiting Signal Transduction Pathways in the Clinic
Alex Adjei, M.D., Ph.D.

Dr. Adjei, the director of the Mayo Clinic Phase I Program, has a long-standing interest in the development of signal transduction inhibitors as potential anticancer drugs. His phase I trial of a new class of agents called farnesyl transferase inhibitors not only identified a dose that could be safely administered in subsequent trials, but also provided the first evidence that these agents actually inhibit their target at therapeutically achievable concentrations. His subsequent laboratory and clinical studies of these agents have demonstrated that they can be safely and, in some cases, highly effectively combined with conventional anticancer drugs. More recently Dr. Adjei’s studies have also focused on agents that inhibit other components of the signal transduction pathways that contribute to cell survival and proliferation.

Inhibiting the function of molecular chaperones
Charles Erlichman, M.D.

As past director of the Mayo Clinic Phase I Program and current director of the Mayo Phase 2 Consortium, Dr. Erlichman has a long-standing interest in the development of novel chemotherapeutic agents. For the past several years he has collaborated with Drs. Toft and Karnitz in testing an agent that inhibits the molecular chaperone HSP90. In a recent phase I trial, Dr. Erlichman, along with Drs. Toft, Ames and Goetz not only identified a dose that could be safely administered in subsequent trials, but also identified a new marker of HSP90 inhibition and provided evidence that HSP90 has been inhibited in the clinical setting. Dr. Erlichman’s subsequent laboratory and clinical studies of these agents have demonstrated that they can be safely and, in some cases, effectively combined with conventional anticancer drugs. Several of the combinations are currently being tested in phase I and phase II trials.

Targeting cyclin-dependent kinases and more
Keith C. Bible, M.D., Ph.D.

Dr. Bible has a long-standing interest in the development of flavopiridol, a small molecule kinase inhibitor originally identified by investigators at the National Cancer Institute. Dr. Bible’s laboratory work provided the first evidence that this agent could kill cancer cells, identified additional targets of flavopiridol and demonstrated how difficult it is to combine this agent with established chemotherapeutic agents. Over the past several years he has completed phase I trials of flavopiridol alone and in combination with selected anticancer agents. Phase II trials of this agent are ongoing.

PHARMACOLOGY, PHARMACOGENETICS AND PHARMACOGENOMICS

Pharmacology is the science of characterizing the fate of drugs in the body following administration to patients and the study of how drugs work. Determining key features of a drug, such as concentrations in the blood, how long the drug remains in the body, and conversion of the parent drug to other molecules that might be involved in drug effects, is an important element in learning how to optimally use new drugs in the treatment of disease. Understanding drug behavior is particularly important for anticancer drugs because these agents must be used very carefully to maximize benefit and minimize side effects. Defining the pharmacology of new anticancer agents during their evaluation in early clinical trials is a major emphasis of the Developmental Therapeutics. This information is then used to develop optimal doses and schedules of administration to most effectively utilize new anticancer agents in our patients.

Pharmacogenetics is the study of the role of inheritance in the individual variation in drug response. We now recognize that an important component in the variable response of patients to anticancer agents, including side effects and antitumor effects, is due to genetic variation in specific genes that are responsible for drug metabolism and drug activity. Program investigators routinely study the relationships between genetic variability and patient responses to new anticancer agents in early clinical trials at the Cancer Center. Based on studies by program investigators, treatment regimens for several important agents are individualized based on genetic data for each patient. At the same time, Program investigators are constantly studying additional genes at a fundamental level to identify new gene variants in populations, and to define the effects of those variants on drug responses. These fundamental pharmacogenomic studies are constantly adding to our repertoire of genetic variants to study in patients in order to optimize chemotherapy.

The Pharmacogenetics of Irinotecan
Matthew M. Ames, Ph.D. and Matthew P. Goetz, M.D.

Dr. Ames’ laboratory now routinely tests for the presence of more than 40 genetic variants of genes important in determining clinical responses to anticancer agents. These studies are incorporated into many Cancer Center clinical trials. One agent being extensively studied in this manner is Irinotecan, an important anticancer agent used in a variety of malignant diseases. Early pharmacologic studies determined that the parent drug was converted in the blood to the active cancer cell-killing derivative, and that subsequently a protein in the liver converted that active derivative to an inactive molecule readily excreted by the kidneys. Further, it became apparent that a subset of patients were much more prone to drug side effects at doses not affecting most patients. Dr. Goetz incorporated pharmacogenetic studies conducted in Dr. Ames’ laboratory into several irinotecan clinical trials conducted at the Cancer Center. These studies examined the sequence of part of the gene responsible for producing the inactivating protein, since one major genetic variant was known to be much less efficient at inactivating irinotecan. Results of these studies confirmed that patients carrying the genetic variant were at much greater risk for side effects. Drs. Ames and Goetz designed current studies that test patients for this genetic variant before receiving the drug and adjust the dose of irinotecan based on the genetic test results.

The Pharmacogenomics of Gemcitabine
Richard M. Weinshilboum, M.D. and Matthew M. Ames, Ph.D.

Dr. Weinshilboum is one of the world’s leading authorities and investigators in identifying new genetic variants of important genes. One of his major contributions has been to determine that a genetic variant is responsible for the serious side effects that occur in a small subset of children following administration of 6-mercaptopurine, an important drug in the treatment of childhood leukemia. He developed a simple genetic test now widely used to identify those children before therapy.

Gemcitabine is a relatively new anticancer agent that has improved the therapy of a number of malignancies that were previously very difficult to treat. A series of studies have defined the precise pathway by which this drug is taken up into cancer cells, converted into active cell-killing derivatives, and inactivated by cancer cells as well as other tissues in the body. The genes involved in producing the proteins responsible for each of these steps are now well known. Drs. Weinshilboum and Ames are currently defining the genetic variation in each of those genes, determining how the variant proteins produced by those variant genes differ from the normal or “wildtype” proteins, and then determining if genetic variability plays a role in differences in individual patient responses to gemcitabine. Dr. Weinshilboum has identified a number of genetic variants in the genes involved in gemcitabine antitumor activity. His laboratory also produces quantities of the variant proteins arising from those genes; and Dr. Ames’ laboratory has determined how those variant proteins differ in activity towards gemcitabine activation or inactivation in cancer cells. In aggregate, these studies may play an important role in gemcitabine chemotherapy by allowing optimal use of these agents in each patient.