The last decade has seen a major expansion in the cancer drug pipeline and studies are continually underway to advance the arsenal of drugs and create more effective treatments and targeted therapies for patients.
To highlight results of more recent research, the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference will host a press briefing on "Drugs in the Pipeline." Sara A. Courtneidge, Ph.D., D.Sc., professor and director of the Tumor Microenvironment Program, and director of academic affairs at the Burnham Institute for Medical Research, will moderate this press briefing.
"Conferences such as the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference play a very important role in advancing translational cancer research. Here, one can learn about the newest breakthroughs across the continuum of cancer research," said Courtneidge.
Breakthroughs to date have been made in the development of anti-angiogenesis inhibitors that target the tumor vasculature and of modulators of gene expression and protein stability, according to Courtneidge. Many more agents have been added to the pipeline of cancer drugs, including inhibitors that target the BCR-ABL fusion protein and other kinases. Cytotoxic agents remain a mainstay of cancer therapy, and inhibitors of DNA repair and cancer stem cells show great promise.
The press briefing will take place on Monday, Nov. 16, 2009, from 1:00 p.m. to 2:00 p.m. ET, in Room 202 of the Hynes Convention Center in Boston, Mass.
Reporters who cannot attend in person may call using the following information:
U.S./Canada: (888) 282-7404
International: (706) 679-5207
Access Code: 36170264
Topic: AACR
Leading researchers will present new and exciting data on the role of hsp70 as a novel therapy for breast cancer; various drug compounds that kill leukemia stem cells and yet spare normal stem cells; tolerability results of cediranib for use in children with recurrent or refractory solid tumors; and sensitivity study results of olaparib for colorectal cancer cells containing a specific DNA repair defect.
"This research spans studies on the genetic makeup of cancer cells, validation studies on the roles of key signaling proteins and pathways, the development of novel agents, and the testing of those agents in a variety of pre-clinical and clinical settings," Courtneidge added.
The following abstracts will be presented during this press briefing:
# B21. Targeting autophagy induced by pan-HDAC inhibitor panobinostat and promoted by acetylated hsp70: A novel therapy for breast cancer
Targeting heat shock response protein with panobinostat, combined with an autophagy inhibitor, is an effective treatment strategy against growing stress cells in breast cancer.
"Clearly this points to a very new approach of targeting heat shock response in combination treatment," said Kapil Bhalla, M.D., director of the Medical College of Georgia Cancer Center, professor of medicine in the Department of Medicine, Division of Hematology-Oncology at the Medical College of Georgia, and vice president for cancer research at the Medical College of Georgia.
Panobinostat is a potent histone deacetylase (HDAC) inhibitor that has been shown to induce cell death of tumor cell lines, but not the normal cells. In breast cancer cells where programmed cell death is inhibited, pan-HDAC inhibitor treatment induces autophagy, which allows the breast cancer cells to escape elimination.
Bhalla and colleagues evaluated the stress phenotype of breast cancer cells in the mammary fat pad of mice when mediated by two heat shock proteins — hsp90 and hsp70, which help to promote cancer survival. The researchers wanted to determine how these inhibitors that deacetylate proteins and histones affect the cell's function.
"Basically we forced the cancer cell to have autophagy and then pulled the rug from under it by having an autophagy inhibitor take that away," said Bhalla.
Treatment with panobinostat induced acetylation of amino acid lysine in the hsp70 protein. With growing tumor size they found an increase in hsp70, heat shock response and autophagy.
"Panobinostat accentuates stress, causes autophagy, and sets up the cell to be eliminated by autophagy inhibitors," Bhalla said.
Panobinostat is not FDA approved for use in breast cancer.
# A51. Identification of compounds targeting human leukemia stem cells
Researchers at the University of Michigan, Ann Arbor, and the University Health Network, Toronto, have found a new paradigm for screening against leukemia stem cells that can target them and spare blood-forming stem cells at the same time.
The researchers identified small molecules, potentially novel or those currently known, that kill leukemia stem cells, but not normal blood-forming hematopoietic stem cells, which are multipotent stem cells that give rise to all blood types. Three of the 10 compounds they studied targeted leukemia stem cells: ciclopirox olamine, etoposide and kinetin riboside.
"Treatment with these compounds, at the appropriate doses, would kill the leukemia cells and potentially minimize blood system side effects, such as anemia," said Sean McDermott, Ph.D., research investigator in the Department of Internal Medicine, Hematology-Oncology at the University of Michigan Medical School.
In total, the researchers screened a collection of 4,000 small molecules using two novel leukemia cell lines that have properties of leukemia stem cells. Compounds that killed these leukemia cells were further tested on normal hematopoietic stem cells to remove toxic compounds.
"Overall, to find three compounds that target the leukemia stem cell, all with vastly different mechanisms, is extremely surprising and bodes well for future drug discovery efforts," said McDermott.
Cells from 51 patients with acute myeloid leukemia (AML) and 12 patients with chronic myelogenuous leukemia (CML) were screened with one of the drugs, etoposide. The researchers were surprised by the etoposide results, which showed that the drug may target the leukemia stem cell in 30 percent of patients with AML and 67 percent of those with CML. These patients might benefit from treatment with this chemotherapeutic drug.
"Screening of larger libraries hopefully will identify even more agents for the cancer pipeline," he added.
Follow-up studies are currently planned for ciclopirox olamine and it would be beneficial in evaluating low-dose etoposide as a single agent. Kinetin riboside may be tested in a clinical setting in the future, according to McDermott.
# A5. Phase I trial and pharmacokinetic study of cediranib in children with recurrent or refractory solid tumors
Results of a new study show that cediranib can be administered safely to children and adolescents with cancer, and that the side effects are tolerable. Preliminary evidence further showed that the drug may have activity in childhood sarcomas.
"There are a number of antiangiogenic agents, like cediranib, in development for adult cancers," said researcher Elizabeth Fox, M.D., M.S.C.R., staff clinician in the Pediatric Oncology Branch at the National Cancer Institute. "Encouraging results seen in this trial provide a rationale for future clinical trials of cediranib and other antiangiogenic agents in childhood cancer."
Cediranib is an oral drug that inhibits vascular endothelial growth factor receptor. The recommended dose in adults is 20 mg to 30 mg administered daily every day for 28 days.