New drug compounds, and old ones put to new use, offer new hope for treating and preventing cancer. Studies presented at the 2008 Annual Meeting of the American Association for Cancer Research (AACR), show promise and progress against brain, colorectal, rectal, and ovarian cancers and lymphoma.
Brain Cancer: Cediranib
The investigational drug AZD2171 (cediranib) may help shrink tumors and prolong survival of patients with a relatively common, aggressive type of brain cancer, according to results from a clinical trial conducted by Boston researchers.
In a phase II study of 31 patients with recurrent glioblastoma, researchers observed that daily treatment with cediranib decreased tumor volume by more than half in 56 percent of patients. Nearly 26 percent of patients were alive and their cancer had not progressed six months into treatment. On average, patients experienced a progression-free survival of 117 days and overall survival of 221 days. In addition, cediranib was found to alleviate brain swelling—a major cause of morbidity among these patients.
Cediranib is a selective signaling inhibitor for vascular endothelial growth factor (VEGF), which promotes formation of new blood vessels that tumors need for nourishment and growth. The drug targets all three receptors for VEGF, one of which is expressed on the endothelial cells in glioblastoma.
Abstract LB-247: A Multidisciplinary Phase II Study of AZD2171 (cediranib), an Oral Pan-VEGF Receptor Tyrosine Kinase Inhibitor, in Patients with Recurrent Glioblastoma
Rectal Cancer: Bevacizumab
Adding bevacizumab to standard chemotherapy and radiation in patients with rectal cancer fully prevented tumor spread and “normalized” tumor blood vessels enough to enable effective therapy, Harvard Medical School researchers report. Bevacizumab is currently approved for colorectal cancer, and works by destroying the blood vessels that tumors need to grow.
“This mechanism of action was a conundrum for scientists because in order for radiation and chemotherapy to work, you need blood vessels,” said Rakesh Jain, Ph.D., Andrew Werk Professor of Tumor Biology. “However, the current study adds evidence to a concept called normalization whereby restoring order to blood vessels inside a tumor opens up a window of opportunity for treatment.”
Blood vessel normalization allows the vessels that remain to perform more efficiently. “With a drug like bevacizumab, some of the tumor vasculature is pruned away immediately, but the vessels that remain become less abnormal,” Jain said. “These normalized vessels make the surviving cancer cells more vulnerable to the treatments that can now be delivered more efficiently. Cancer therapies in this environment should be maximally effective.”
Abstract LB304: Evaluation of the effects of anti-VEGF therapy in a multidisciplinary phase I/II study of neoadjuvant bevacizumab with chemoradiation therapy in rectal cancer
Follicular Lymphoma: Monoclonal Antibody
A second generation, highly targeted monoclonal antibody appears to provide benefit for some patients with follicular lymphoma for whom other treatments have failed, according to results of a phase I clinical trial. In the 16 patients evaluated so far, four have achieved either a partial or complete response with use of the novel agent AME-133v, said the study’s lead investigator, Andres Forero, M.D., associate scientist at the University of Alabama, Birmingham, Comprehensive Cancer Center.
“These first results suggest that AME-133v provides a mechanism of action that may be more potent and ultimately more effective than the treatments we have on hand for a subset of patients with this cancer,” Forero said. “Given these encouraging results, patients are currently being enrolled in a phase II study.”
The majority of patients in this study either did not initially respond or relapsed after use of rituximab, the first monoclonal antibody therapy approved for use in lymphoma treatment. AME-133v is a second-generation therapy that is believed to be a more specific treatment for follicular lymphoma in general, compared to rituximab, but is also thought to offer particular benefits for those patients who have a variant in the immune cells needed to attack the cancer, Forero says.
“Monoclonal antibodies were the first successful targeted therapy for cancer, and we have now moved on to a whole new class of second generation antibodies for the treatment of many different lymphomas,” Forero said. “This is an exciting time.”
Abstract LB-70: Preliminary results of a Phase I study of AME-133v, an Fc-engineered humanized monoclonal antibody, in low-affinity Fc?RIIIa patients with previously-treated follicular lymphoma
Pancreatic Cancer: Paclitaxel and Gemcitabine
A novel combination of nanoparticle albumin-bound (nab) paclitaxel and gemcitabine showed a significant clinical benefit in more than 70 percent of pancreatic cancer patients, according to researchers.
“Unfortunately most patients with pancreatic cancer have a very poor survival” said Daniel Von Hoff, M.D., Physician in Chief of the Translational Genomic Research Institute (TGen) and Chief Medical Officer for the Scottsdale Clinical Research Institute at Scottsdale Healthcare in Arizona.
SPARC (Secreted Protein Acidic and Rich in Cysteine) was noted to be commonly found in pancreatic cancer specimens in an ongoing Target Now Research Program being performed by Caris-MPI. This finding, also described by other investigators, was the basis for this phase I clinical trial that Von Hoff presented here. “Chemotherapy often means combining more than one drug, and we do not want to just take the next thing off the shelf. We want to know as much about a tumor as possible going in,” Von Hoff said.
In this trial, patients received escalating doses of nab-paclitaxel (which binds to a potential target SPARC in pancreatic cancer specimens) from 100 mg/m2 to 150 mg/m2 combined with 1000 mg/m2 of gemcitabine. Researchers from TGen/SHC, Johns Hopkins, University of Alabama, and South Texas Hematology/Oncology reported on the first 20 patients who received nab-paclitaxel 100 mg/m2 of what will eventually be a 42-patient trial. Investigators assessed tumor response by measuring levels of the cancer marker CA 19-9 and by PET and/or CAT scan. A drop in CA 19-9 levels had been previously linked in other research with improved survival.
Of the original 20 patients enrolled at the nab-paclitaxel 100 mg/m2 dose, 17 had levels of CA 19-9 that could be evaluated. CA 19-9 levels dropped more than 20 percent in 82 percent of patients, researchers report. Reductions in CA 19-9 of more than 70 percent were observed in 64 percent of patients. Utilizing CAT scan criteria, 9 of the 16 patients (56 percent) who had serial scans had responses. Twelve of the 16 (75 percent) had responses or stable disease for more than four months.
Abstract 4179: Promising clinical activity of an NAB paclitaxel plus gemcitabine combination in a disease-specific phase I trial in patients with advanced pancreatic cancer
Ovarian Cancer: Mifepristone
Researchers from the Sanford School of Medicine at The University of South Dakota have demonstrated that mifepristone prevents regrowth of ovarian cancer cells that survive standard chemotherapy.
“Utilizing a cell culture system, our work provides evidence that giving mifepristone between courses of cisplatin has the potential to improve treatment success,” said Carlos M. Telleria, Ph.D., the study’s senior author and assistant professor of biomedical sciences at the university. The regrowth of cancer cells between chemotherapy cycles is a major treatment challenge, Telleria says. One strategy to prevent regrowth is the use of drugs like mifepristone, which has been shown in separate studies to prevent cancer cells from multiplying.
Telleria and colleagues observed whether mifepristone would prevent ovarian cancer regrowth if administered with cisplatin. Ovarian cancer cells in culture were treated with cisplatin at 20 µM for one hour every 12 days for 36 days. Researchers assessed the number and viability of cancer cells, and how likely they were to reproduce, every four days.
Cisplatin killed the majority of cancer cells, but those that remained were able to reproduce. However, when mifepristone was added at a dose of 5, 10 or 20 µM the cells, and their ability to reproduce, decreased. The larger the dose of mifepristone the stronger the effect; at the 20 µM dose, the cultures contained no cancerous cells to test by day 12 of the study.
Abstract 1210: Mifepristone abrogates repopulation of ovarian cancer cells in between courses of cisplatin treatment
Release date: April 15, 2008
Filed Under: Drug Discovery