Specific Projects (3)

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

As 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 David Toft, Ph.D. and Larry Karnitz, Ph.D. in testing an agent that inhibits the molecular chaperone HSP90. In a recent Phase I trial, Dr. Erlichman, along with Dr. Toft, Matthew M. Ames, Ph.D., and Matthew Goetz, M.D., 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 have demonstrated that the HSP90 inhibitors can be safely and, in some cases, effectively combined with conventional anti-cancer drugs such as cisplatin and gemcitabine. The 17-AAG/gemcitabine combination is currently in Phase II trials in pancreatic and ovarian cancer.

Inhibiting Signal Transduction Pathways in the Clinic
Primary Investigator: Julian Molina, M.D., Ph.D.

Dr. Molina, the Deputy Director of the Mayo Clinic Phase I Program, has a long-standing interest in the biology and therapy of lung cancer. He has recently completed a Phase I trial of lapatinib, an inhibitor of signaling by the epidermal growth factor receptor (EGFR) and Her2, in combination with topotecan; and that combination is currently undergoing Phase II testing in ovarian cancer. More recently Dr. Molina has been performing a Phase I trial of aurothiomalate (ATM) based on data from the Fields laboratory showing that this agent selectively inhibits proliferation of cancers that are driven by abnormal expression of Protein Kinase C iota.

Targeting the Insulin-like Growth Factor Receptor
Primary Investigator: Paul Haluska, M.D., Ph.D.

Dr. Haluska has an active laboratory and clinical interest in the development of agents that inhibit signaling by the insulin-like growth factor-1 receptor (IGF1R). Based on studies showing that IGF1R signaling is enhanced in many cancers, Dr. Haluska helped complete and report the Phase I study of CP-751871, an antibody that inhibits signaling by IGF1R. Based on work showing that inhibition of IGF1R can lead to enhanced signaling through EGFR and Her2, Dr. Haluska is leading a new clinical trial of CP-751871 along with lapatinib and capecitabine. In addition, his work is actively exploring mechanisms of resistance to IGF1R inhibition as well as the role of IGF1R activation in resistance to other agents.

Targeting Cyclin-Dependent Kinases and More
Primary Investigator: Keith 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 anti-cancer agents. Based on this work, Phase II trials of this agent in combination with cisplatin (ovarian cancer) and cytarabine plus flavopiridol (acute leukemia) 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 anti-cancer drugs because these agents must be used very carefully to maximize benefit and minimize side effects. Defining the pharmacology of new anti-cancer 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 anti-cancer 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 anti-cancer 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 anti-cancer agents in early clinical trials at the Cancer Center. Based on studies by program investigators, treatment regimens for several important agents are individualized according to genetic data from 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.

Read more about Mayo Clinic Cancer Center's ongoing pharmacogenomic research.