National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 31, 2011 • Volume 8 / Number 11

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Cancer Research Highlights

Cabozantinib Shrinks Tumors and Bone Metastases in Prostate and Other Cancers

In a phase II clinical trial, the drug cabozantinib (or XL184) shrank tumors or halted their growth in patients with several types of solid tumors, including ovarian, liver, and prostate cancer. The drug also shrank bone metastases in patients with breast and prostate cancers and melanoma. Dr. Michael Gordon of Pinnacle Oncology Hematology in Scottsdale, AZ, presented the findings at a May 18 press briefing held in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

UPDATE: Deaths from Investigational Drug Announced

Researchers reported the deaths of six participants in the randomized discontinuation trial of the experimental agent, cabozantinib, at the 2011 ASCO annual meeting in Chicago. The cabozantinib-related deaths included patients who had breast, lung, ovarian, prostate, or pancreatic cancer and represent approximately 1 percent of the total number of trial participants.

Cabozantinib is a targeted therapy that blocks the action of the cell-signaling molecules hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and may inhibit other signaling molecules as well. MET signaling can contribute to the growth and spread of cancer cells through the body (metastasis), and VEGFR2 plays a role in tumor blood vessel growth.

Of the 483 patients that Dr. Gordon and his colleagues enrolled in the trial, 398 were evaluated for tumor response during treatment. The trial employed a design called randomized discontinuation. All of the patients received cabozantinib for 12 weeks. Patients whose disease progressed during the first 12 weeks were removed from the trial, those whose tumors shrank remained on the drug, and those whose disease remained stable were randomly assigned to continue taking cabozantinib or a placebo to determine the drug's true role in stabilizing their disease.

The best results were seen in patients with liver, prostate, and ovarian cancer: 22 of 29 patients with liver cancer, 71 of 100 patients with prostate cancer, and 32 of 51 with ovarian cancer experienced either partial tumor shrinkage or stable disease.

Fifty-nine out of 68 patients who had bone metastases had their metastases shrink or disappear during the trial. Many of these patients experienced pain relief and a reduction in the need for narcotic pain medication.

These results show the benefit of "going after not just one pathway but…going after [an] entire network" of signaling molecules, stated Dr. Mark Kris, ASCO's Cancer Communications Committee chair, who moderated the press briefing.

Dr. Gordon explained that the drug's "exceptional activity" in shrinking metastases in patients with prostate cancer and the strong response among ovarian cancer patients led the researchers to expand the study to include 150 patients with each of those cancers in a nonrandomized arm of the trial. Results from those groups will be presented at the ASCO annual meeting next month in Chicago.

Also in the Journals: Cabozantinib May Shrink Some Rare Thyroid Tumors

In a phase I trial of cabozantinib, researchers led by Dr. Razelle Kurzrock of the University of Texas M. D. Anderson Cancer Center found that the targeted drug can shrink tumors in patients with metastatic medullary thyroid cancer (MTC) or MTC that could not be removed surgically. Results from 37 patients with advanced MTC treated with cabozantinib were published online May 23 in the Journal of Clinical Oncology.

Of the 35 patients whose tumors could be measured for response to the drug, 10 had tumors that shrank (a partial response). Fifteen of the 37 patients had tumors that remained stable for at least 6 months. Ninety percent of the 85 patients in the trial experienced at least one side effect, though almost half of those side effects were mild.

The partial responses seen in 10 of the patients "is remarkable…for a disease with essentially no conventional therapeutic options," wrote Drs. Yariv Houvras and Lori Wirth of Massachusetts General Hospital in an accompanying editorial. A phase III trial testing cabozantinib in patients with MTC is currently under way.

End-of-Life Care for Lung Cancer Patients Differs in U.S. and Ontario

Researchers looking at the care received by patients with non-small cell lung cancer (NSCLC) in the United States and in Ontario, Canada, during their last 5 months of life found large differences between the two countries. For example, patients in the United States were more likely to receive chemotherapy in the months before death, and patients in Ontario were more likely to die in a hospital. Dr. Joan Warren and her colleagues in NCI's Division of Cancer Control and Population Sciences collaborated with a group of investigators in Ontario to compare end-of-life care for elderly patients. These findings appeared online May 18 in the Journal of the National Cancer Institute.

The researchers used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database and from several linked databases in Ontario, the most populous Canadian province. The study included 13,533 patients from the United States and 8,100 patients from Ontario, all of whom had been diagnosed with NSCLC and died of cancer at age 65 or older between 1999 and 2003.

After adjusting for demographic differences in the two populations, the researchers found substantial differences in patterns of care near the end of life. In addition to differences in chemotherapy use and place of death, the researchers found that the majority of U.S. patients used hospice care in the last months of life. No formal hospice programs exist in Ontario, which instead provides palliative care in the home, in outpatient clinics, and in hospitals.

For patients in both countries, the use of emergency room services and hospitalization rose near the time of death. But during the last 30 days of life, 12 percent fewer U.S. patients visited an emergency room compared with those in Ontario. And fewer U.S. patients were admitted to the hospital during the last 30 days of life.

More than 60 percent of patients in Ontario who were hospitalized during the last month of life received palliative care as an inpatient, with over 80 percent of the hospitalized Ontario patients dying in the hospital. "It appears that most [of these patients] were admitted for supportive care," wrote the authors. About the same percentage of U.S. patients were in hospice during their last month of life, allowing them to die outside of the hospital.

"Despite relatively high use of community supportive care, the rates of inpatient death are too high in the United States and much too high in Ontario," wrote Dr. David Goodman of the Dartmouth Medical School in an accompanying editorial. But he cautions against expanding enrollment in hospice programs blindly without attention to the wishes of individual patients. Currently, he concluded, patients in both countries "do not yet adequately participate in end-of-life care decisions."

Researchers Identify New Way Tumor Cells May Adapt to Stressful Conditions

Some tumor cells may use a protein normally found only in the brain to help them survive and grow under stressful conditions, according to new findings. The protein, an enzyme known as carnitine palmitoyltransferase 1C (CPT1C), enables tumor cells to generate energy using fatty acids instead of glucose, which is the chief energy source for living organisms.

An international team of researchers led by Dr. Tak Mak of the University of Toronto published its findings May 15 in Genes & Development. The study suggests that CPT1C could be a new target for cancer therapy.

Cells within solid tumors, such as breast, lung, or colon cancers, can survive and grow under conditions that would kill normal cells. Tumor cells gain this survival advantage through alterations in their metabolism, a phenomenon known as metabolic transformation. Researchers have long known of this phenomenon but only recently uncovered evidence that fatty acids might be an energy source for tumor cells.

"It's like when the pipelines are cut for Middle East oil. You've got to tap all kinds of alternative sources for energy," explained Dr. James Phang of NCI's Center for Cancer Research, who studies cancer cell metabolism but was not involved in the current study.

The first hint that CPT1C could play a role in metabolic transformation came when Dr. Mak and his colleagues found that expression of the CPT1C gene was correlated with mouse mammary tumor cells' resistance to the anticancer drug rapamycin. The drug blocks glucose entry into cells and thus creates starvation conditions.

The researchers next asked whether CPT1C gene expression is increased in human cancers. They found that in 13 of 16 patients with non-small cell lung cancer, the levels of CPT1C messenger RNA (mRNA), which is used to make the CPT1C protein, were notably higher in tumor tissue than in normal lung tissue from the same patient.

In further experiments, the researchers showed that depriving tumor cells of nutrients or oxygen led to increased levels of CPT1C mRNA. They also showed that depleting CPT1C protein from human breast and colon cancer cells impaired the cells' ability to grow under low-oxygen and low-glucose conditions. CPT1C depletion also slowed the growth of tumors formed when the cancer cells were transplanted into mice.

Taken together, the study authors wrote, the results "suggest that a CPT1C inhibitor, used either…[alone] or in combination with other anticancer agents, may be a promising new avenue of cancer treatment."

In an interview, Dr. Mak said the larger implication is that rather than targeting oncogenes to treat cancer—a task that is daunting because of the sheer number of known oncogenes—it may be "time for us to try to exploit therapeutic targets, or combinations of therapeutic targets, that are a result of metabolic adaptation by a cancer cell...because there are fewer ways to rearrange the metabolic pathways of a cancer cell than there are oncogenes."

Dr. Phang agreed and noted that targeting CPT1C in particular "is promising as an approach to treating some cancers. But how efficient that could be and under what conditions remains to be seen," he said.

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