Targeting Tumor Metabolism in Papillary Kidney Cancers
Name of the Trial
Phase II Study of Bevacizumab and Erlotinib in Subjects with Advanced Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) or Sporadic Papillary Renal Cell Cancer(NCI-10-C-0114). See the protocol summary.
Dr. Ramaprasad Srinivasan, NCI Center for Cancer Research
Why This Trial Is Important
Papillary renal cell cancer is an aggressive type of kidney cancer that accounts for approximately 15 percent of kidney cancer cases in the United States. Most cases of papillary kidney cancer develop in the absence of inherited gene mutations (sporadic cases), whereas some result from inherited disorders associated with the mutation of specific genes. One of these disorders is hereditary leiomyomatosis and renal cell cancer (HLRCC). Patients with HLRCC often develop benign tumors called leiomyomas in the skin and the uterus, as well as a very aggressive type of papillary kidney cancer that spreads (metastasizes) quickly even when the primary tumors are small.
Inherited mutations in a gene called FH have been associated with HLRCC. This gene produces a protein called fumarate hydratase (FH). FH protein deficiency resulting from mutation of the FH gene can lead to the inappropriate activation of molecular pathways that involve another protein called hypoxia-inducible factor α (HIFα). These pathways are activated normally when the supply of oxygen available to cells is inadequate, a condition known as hypoxia. Under normal conditions, cells use oxygen to generate most of the energy they need to survive, but, when oxygen is scarce, they may resort to an alternative way to produce energy, such as an oxygen-free metabolic process called glycolysis. HIFα increases the activity of enzymes involved in glycolysis as part of the cellular response to hypoxia. Researchers at NCI and elsewhere have demonstrated that HLRCC tumors rely almost exclusively on glycolysis for energy. This discovery may provide a means for targeting the metabolism of HLRCC.
NCI researchers want to know if inhibiting components of the HIFα pathway will help shrink malignant kidney tumors in patients with HLRCC. The drug erlotinib (Tarceva) suppresses tumor growth pathways that become overactive due to excess HIFα, and it may also interfere with the uptake of glucose and glycolysis by blocking proteins important to these processes. In addition, the biological agent bevacizumab (Avastin) targets a protein called VEGF that cancer cells use to spur the growth of new blood vessels (tumor angiogenesis). Tumors need an adequate blood supply to get the glucose and other nutrients they need for continued growth. Therefore, the researchers hope that targeting both the tumor blood supply and glycolysis will lead to the starvation of these tumors and result in tumor shrinkage or prolonged inhibition of tumor growth.
In this trial, patients with HLRCC or sporadic papillary renal cancer that has spread beyond the kidneys will be treated with erlotinib and bevacizumab. Patients will take erlotinib pills daily and receive bevacizumab intravenously once every 2 weeks. After 8 weeks of treatment (two 28-day treatment cycles) and every 8 weeks thereafter while they are in the study, the patients will be assessed at the NIH Clinical Center for response to treatment.
“Papillary kidney cancers are very difficult to treat and usually don’t respond to therapies used for other kidney cancers,” said Dr. Srinivasan. “We have seen in both the lab and the clinic that tumors associated with HLRCC are addicted to glucose and completely dependent on glycolysis for growth, so with this study we are targeting that metabolic basis for the cancer. And we are taking that approach and applying it to patients with noninherited [sporadic] papillary kidney cancer to see if they will respond to this novel therapy, as we hope patients with HLRCC will.”