Specific Projects (2)
Targeting Protein Kinase C Isoforms
Seminal work by Dr. Fields, who heads the oncology laboratory research program at the Mayo Clinic campus in Jacksonville, Fla., 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. Based on tissue culture and animal studies that confirmed the effectiveness of one of these molecules, aurothiomalate (ATM), in lung cancers driven by protein kinase C iota, an ongoing Phase I trial is examining the safety and tolerability of this molecule in the clinical setting. Efforts to identify second generation inhibitors of pertinent protein kinase C family members are ongoing in the Fields laboratory.
Targeting DNA Damage-Activated Checkpoints
The work of Dr. Karnitz and David Toft, Ph.D., a now retired member of the Program, 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 an 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.
At the same time this work was being performed, Dr. Karnitz’s laboratory identified the components of a new pathway (the Rad9-Rad1-Hus1 or “9-1-1” pathway) that is activated by cellular stresses that stall the molecules that synthesize DNA (replication stress). One of the results of signaling by the 9-1-1 pathway is activation of the Checkpoint kinase 1 (Chk1) protein, thereby leading to biochemical changes that halt cell replication until the damage or stress is resolved. In addition to elucidating the detailed pathway by which replication stress leads to Chk1 activation, 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.
Overcoming Blocks to Programmed Cell Death
Dr. Kaufmann’s laboratory has extensively studied the process of programmed cell death (apoptosis) and the manner in which it is triggered by anti-cancer 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 anti-cancer agents that damage DNA.
Dr. Kaufmann’s earlier work showed that the protein encoded by the myeloid cell leukemia 1 (MCL-1) gene is over-expressed in over half of acute leukemia specimens at the time of relapse. More recent studies from the Kaufmann lab have demonstrated that this protein serves as a buffer, sequestering various pro-apoptotic molecules when cells are exposed to various stresses. In collaboration with Keith Bible, M.D., Ph.D., and Gregory Gores, M.D., who are members of this Program, and Alex Adjei, M.D., Ph.D., a former member of the Program, the Kaufmann laboratory demonstrated that Mcl-1 can be down-regulated by inhibition of specific signal transduction pathways. As might be predicted, this Mcl-1 down-regulation sensitizes cells to various drugs and death-inducing cytokines. Because some of the signaling pathways leading to Mcl-1 up-regulation are targets of established or investigational anti-cancer drugs, these results have led to ongoing preclinical and early clinical studies of combinations examining the effects of selected signal transduction inhibitors in combination with death-inducing cytokines or apoptosis inducing chemotherapy.
Tumor Cell Activation of Drugs
Dr. Ames has a long-standing interest in the metabolism of anti-cancer 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 a National Cancer Institute-sponsored Phase I clinical trial of this agent in Mayo Clinic Cancer Center.
Chemotherapy Targeted at a Signaling Pathway Combined with Radiation Therapy
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.
More recently the Sarkaria laboratory has utilized the same mouse model to assess the action of temozolomide, a DNA damaging agent that is currently the most effective drug available to treat GBM. These studies have not only recaptitulated the clinical situation in which GBMs become resistant to temozolomide, but have provided an opportunity for biochemically dissecting mechanisms of this resistance and testing strategies for overcoming it.
Testing the Next Generation of Anti-Cancer Drugs
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.
Read more about current efforts in this area.
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