A Closer Look
Targeted Therapies Offer Treatment Options for Advanced Kidney Cancer
For decades, oncologists had little reason to be optimistic about treating patients with advanced kidney cancer. But over the past 15 years, important discoveries have produced targeted therapies to treat cancer that has spread beyond the kidney (metastatic disease) and offer new directions for developing even more effective treatments.
"When we first started working on kidney cancer in the early 1980s, it was thought of as a single disease, and all kidney cancers were treated the same," said Dr. W. Marston Linehan, chief of the NCI's Urologic Oncology Branch.
Then, as now, surgery was the first treatment for renal cell carcinoma (RCC), the most common type of kidney cancer, which had not spread. Once the cancer had metastasized, however, patients generally had a poor prognosis and most did not survive more than a year.
"Kidney cancer was thought to be this disease that inexorably led to death," said Dr. George Philips, a researcher at Georgetown Lombardi Comprehensive Cancer Center.
Because traditional chemotherapy is not effective in kidney cancer, Dr. Philips continued, patients with advanced disease were treated with cytokines, either interleukin-2 or interferon alpha, both of which have considerable toxic side effects. Only 5 to 10 percent of patients treated with high-dose interleukin-2 experienced a complete and lasting response.
To try to improve conditions for these patients, Dr. Linehan and his colleagues from across the National Institutes of Health (NIH) began recruiting families that had multiple members with kidney cancer. "We wanted to identify what we thought was the gene for kidney cancer," said Dr. Linehan. "Our hope was, if we could understand the gene that causes kidney cancer, that [understanding] could possibly provide the foundation for developing a targeted therapeutic approach."
Ten years later, the researchers identified mutations in a gene called VHL in patients with von Hippel-Lindau syndrome, a hereditary cancer syndrome in which patients develop kidney tumors with a specific histology, or cellular organization, known as clear cell RCC. They subsequently determined that the VHL gene was also mutated or silenced in most non-hereditary clear cell RCCs, suggesting that VHL was the kidney cancer gene they were seeking.
This discovery led researchers to test therapies that target the VHL pathway, and today there are six drugs approved by the Food and Drug Administration to treat patients with advanced clear cell RCC: vascular endothelial growth factor (VEGF) receptor inhibitors (sorafenib, sunitinib, and pazopanib); a VEGF-binding antibody (bevacizumab); and inhibitors of the mTOR pathway (temsirolimus and everolimus), another VEGF regulator. Although many patients benefit significantly from these agents, few patients are cured.
Multiple Genes, Multiple Diseases
Nearly three-quarters of RCC tumors have clear cell histology. The rest, however, display a variety of other histologic patterns. To evaluate the genetic basis of these rarer cancers, Dr. Linehan and his colleagues studied families with non-clear cell RCC. From some of these families they identified a new form of kidney cancer, called hereditary papillary renal carcinoma (HPRC).
Families with HPRC did not have the clinical characteristics of von Hippel-Lindau syndrome, nor did they have VHL gene mutations. Instead, the researchers identified mutations in the proto-oncogene MET, and showed for the first time that a different gene could cause a different type of kidney cancer.
The team wondered if this was a fluke, or if other RCC histologic types were associated with mutations in additional genes. When they examined families with Birt-Hogg-Dubé, a syndrome characterized by multiple skin lesions, the researchers determined that these patients developed chromophobe and oncocytic RCCs. Unlike the clear cell and papillary tumors, these tumors had alterations in a new gene that the group named FLCN.
In addition, another research group found that patients with hereditary leiomyomatosis RCC, a very aggressive form of kidney cancer that Dr. Linehan's group had been studying since the late 1980s, have mutations in fumarate hydratase, an enzyme that plays an essential role in the metabolic process that cells use to generate energy from glucose. To date, investigators have identified 15 different genes that cause distinct types of kidney cancer.
"Today we know that kidney cancer is not a single disease," commented Dr. Linehan. "It's made up of a number of different types of cancer, each with a different histologic type, with a different clinical course, responding differently to therapy, and caused by [mutations in] different genes. But each of these genes is fundamentally involved in the same pathway: the cell's ability to sense oxygen, iron, nutrients, or energy. We have concluded that kidney cancer is fundamentally a metabolic disease."
The Search for More Effective Treatments
Since as many as 20 percent of newly diagnosed patients will have metastatic disease, researchers are far from where they want to be, even with the well-studied clear cell type of RCC, commented Dr. Michael Atkins, leader of the Kidney Cancer Program at the Dana-Farber/Harvard Cancer Center. "We want to produce durable responses in the majority of patients," he said.
To improve patient outcomes, current studies are examining which treatment a patient should receive first based on the characteristics of his or her tumor, the optimal doses and schedules for current treatments, and the best sequence to use for available therapies. Because these tumors are highly vascular, imaging techniques, such as functional magnetic resonance imaging (fMRI) or positron emission tomography (PET), may allow researchers to observe subtle treatment effects and modify treatment accordingly.
Other groups, Dr. Atkins continued, are developing more selective inhibitors of the VEGF receptor. These more selective agents may allow clinicians to combine therapies to produce synergistic tumor-fighting activity while sparing patients the side effects associated with less-selective agents. The limited success of cytokine therapy, which activates the immune system, has prompted researchers to investigate the use of novel, more potent immunotherapies.
Researchers are also trying to tease out the pathways tumors use to resist current therapies in order to develop new drugs that target these pathways. Likewise, discovery of the genes that regulate the non-clear cell RCC subtypes has provided numerous potential drug targets. For example, Dr. Linehan's group is conducting trials of agents targeting fumarate hydratase.
Investigators may need to change the design of clinical trials to study the less-common non-clear cell cancers and to evaluate overall survival differences for all RCC therapies more stringently. Additionally, programs such as The Cancer Genome Atlas continue to look for new genes and pathways that regulate RCC, with the aim of developing novel therapy targets.
"I think there has been enormous progress made in kidney cancer," said Dr. Linehan. "Do we need to do better? Of course! But I am very encouraged about the future."