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Kidney Cancer Program: Progress Against Kidney Tumors

Angiogenesis and targeted therapies in renal cell carcinoma: VHL inactivation leads to increased HIF activity, which increases levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). These factors activate VEGF and PDGF receptors to promote angiogenesis. Bevacizumab is a neutralizing antibody for VEGF. Sunitinib, sorafenib, pazopanib and axitinib [not shown] block activation of VEGF and PDGF receptors. Activity of mTOR kinase also influences HIF protein levels. Temsirolimus and everolimus block mTOR, inhibiting HIFα production and signaling downstream of VEGF. From Figure 3: Li L, Kaelin WG Jr., “New insights into the biology of renal cell carcinoma.” Hematol Oncol Clin North Am. 2011 August; 25(4): 667–686 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161447/figure/F3/.

Common mutations in kidney cancer turn on genes that signal oxygen deprivation, which promotes the growth of new blood vessels and alters cancer cell metabolism towards pathways that support more rapid growth, proliferation, and metastasis. A tumor’s dependence on new blood vessel growth, or angiogenesis, makes it exquisitely sensitive to anti-angiogenesis drugs such as Sutent (sunitinib) and Avastin (bevacizumab), which inhibit the vascular endothelial growth factor (VEGF). These drugs became available about seven years ago, and the excitement at cancer research meetings was palpable.

“We have had seven new drugs approved by the FDA in the last five years. No field of cancer has seen more new therapies than kidney cancer,” said David McDermott, MD (BIDMC), the leader of the Kidney Cancer Program at Dana Farber/Harvard Cancer Center (DF/HCC). Previously, the median survival for the common kind of kidney cancer, clear cell renal cell carcinoma, was 13 months. Today it is two to three times as long. “That is a meaningful improvement, but not nearly good enough. We need to improve remission rates and prevent or delay resistance.”

Researchers in the Kidney Cancer Program made pivotal discoveries and led the development of the drugs and the clinical trials culminating in these new treatments. The program is home to a SPORE (Specialized Program of Research Excellence) grant from the National Cancer Institute (NCI) to promote translational research.  Of the 62 active SPOREs located at academic centers across the US, this SPORE grant is the only effort that focuses solely on kidney cancer. Within DF/HCC, it promotes an extensive collaborative network with all the institutions.

“No matter where your work takes you, you can find someone at DF/HCC who is already an expert and will accelerate your research,” said William Kaelin, MD (DFCI). For example, in the 1990s he was studying a rare genetic disorder, Von Hippel-Lindau (VHL) syndrome, to learn why these patients develop kidney tumors. He and Othon Iliopoulos, MD (MGH), discovered that VHL mutations release the cell’s normal control of angiogenesis. Most non-hereditary renal cell carcinomas also have acquired VHL mutations that promote vascularization. “I could tap into the expertise here on angiogenesis,” said Kaelin, “and now I’m turning to our experts on cellular metabolism and epigenetics to investigate the underlying causes of kidney cancer.”

How Hypoxia Drives Kidney Cancer

McDermott credits Kaelin as the scientist most responsible for advancing the understanding of kidney cancer genetics and biology by explaining how cells sense and respond to changes in oxygen levels in their environment. This work also has a major impact on cell biology in general. In normal oxygen conditions, VHL suppresses the hypoxia inducible factor, HIF, flagging it for degradation. Under anaerobic conditions, such as at a wound or stroke lesion, VHL allows HIF to accumulate and switch on genes, including VEGF, that promote cell survival and produce new blood vessels and red blood cells. In kidney cancer, VHL mutations inappropriately activate HIF, which persistently signals for more vascularization and tumor growth.

Hyper-vascularization makes the cancer hard to kill by standard therapies but also makes it more susceptible than other cancers to angiogenesis inhibitors. This discovery was quickly translated to the clinic, and led to the FDA approval of five angiogenesis inhibitors. Subsequent research on kidney cancer has built upon these DF/HCC findings. Clinical studies are now combining new, more potent VEGF inhibitors with new inhibitors of mTOR and PI3K, which are both involved in oxygen- and nutrient- sensing pathways.

VHL loss, although critical to the development of kidney cancer, is not sufficient by itself to cause the cancer. Moreover, VEGF inhibition alone is not curative. The Kidney Cancer Program is investigating other genetic, epigenetic, and metabolic changes that underlie kidney cancer development and could be targeted by new therapies.

A Reversible Metabolic Shift

An immediate challenge in kidney cancer concerns determining what drives resistance to VEGF inhibition and how to foil it. What enables the tumor to survive the insult of the hypoxia that follows VEGF inhibition?  In the clinic, physicians observe that after resistant patients are switched from VEGF inhibition to another therapy, their tumors re-acquire sensitivity to the VEGF inhibitor as if they had never been exposed to it before. James Mier, MD (BIDMC), and others found that resistance does not result from cancer cells acquiring new mutations, as happens in lung and other cancers. In those cancers, patients with resistant tumors need a different drug targeting the new mutation and will not benefit from the first drug again. 

Instead, the kidney tumor makes reversible, metabolic adaptations to survive hypoxic conditions induced by the loss of the vascular supply. “That mirrors what clinicians see in the clinic when patients are taken off the inhibitor and they later regain sensitivity to it,” said Mier. “It’s possible, therefore, to cycle patients on and off the VEGF inhibitors.” Specifically, kidney tumors shift their cellular metabolism from the oxygen-intensive demands of metabolizing glucose via the Krebs cycle to glycolysis. Glycolysis uses less oxygen to burn glucose, and also produces more building blocks that growing and dividing cancer cells require – amino acids, lipids, and nucleotides.

Iliopoulos found that HIF activation (caused by inactivation of VHL and a hallmark of kidney cancer) also re-wires the cancer cell metabolism in order to generate building blocks by metabolizing the amino acid glutamine. The switch to glycolysis and glutamine metabolism provides the tumor a more efficient way to fuel its growth while also surviving hypoxia.

Because the cancer cell depends on these alternate metabolic pathways, inhibiting them provides an attractive therapeutic strategy to essentially starve the tumors to death. Iliopoulos, for example, is testing an investigational compound that inhibits glutaminase, a key enzyme in glutamine metabolism. “Our preclinical data indicate that we can significantly suppress growth of renal cell carcinomas in experimental animals by treating them with this enzyme inhibitor.”

Releasing the Suppressed p53

Kidney tumors also adapt to VEGF inhibitors by disabling the important tumor suppressor p53, the “guardian of genome.” P53 normally drives stressed and DNA-damaged cells towards cell cycle arrest and cell death, so by decreasing p53 levels the tumor cells escape this checkpoint. In addition, when the tumor becomes hypoxic, myeloid progenitor cells infiltrate the tumor and facilitate cell survival. Normally, these myeloid cells are recruited into poorly oxygenated tissues and aid the reacquisition of the blood supply. In kidney cancer, they enhance the tumor’s ability to survive the effects of VEGF treatment, and also to evade the immune system and to metastasize.

In preclinical work, Mier’s laboratory has developed a way to foil this dual survival strategy and prevent or delay resistance to VEGF inhibitors. They found that inhibiting an enzyme called HDM2, which tags p53 for deactivation, raises p53 activity levels and blocks the influx of myeloid cells into the tumor. HMD2 inhibitors thus both promote cell death – without actually causing DNA damage and cytotoxic side effects – and suppress a resistance strategy. “As a translational researcher, I’m very encouraged that so many HDM2 antagonists are in preclinical or phase I development,” said Mier. “I believe they will be a wonderful additive for other drugs by blocking a key compensatory pathway to resistance.” He hopes to begin clinical trials testing HMD2 inhibitors in the next year.

“We hope this work targeting the hypoxia response and metabolic reprogramming will help other solid tumors too,” said McDermott.

The CT scans show a large mass in the left upper quadrant of a 57-year-old patient with renal cell carcinoma who had developed disease progression after receiving the angiogenesis inhibitors sunitinib, temsirolimus, sorafenib, and pazopanib (left panel). The right panel shows partial regression after six cycles of treatment with the immunotherapy BMS-936558, which is ongoing two years later. This compound is a human antibody to the Programmed Death (PD)-1 ligand pathway, an immune checkpoint that suppresses activated T cells and promotes tolerance to cancer cells. Courtesy of Charles Drake MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Hitting HIF Upstream

Most existing targeted therapies inhibit oncogenes, the accelerators that drive cancer, but mutations also disable the brakes – tumor suppressors like VHL – and disabled brakes allow something else to accelerate, like HIF. “We want to inhibit what brakes normally inhibit,” said Iliopoulos. “But rather than trying to inhibit downstream molecules like VEGF, we want to hit HIF near the top of the pathway. Since HIF turns on many other genes, inhibiting individual byproducts will have a short-term effect. If we inhibit HIF directly, we inhibit the others in one fell swoop.”

In a chemical library screen at the ICCB (Institute of Chemical and Cellular Biology/HMS), Iliopoulos discovered a small molecule that inhibits the translation of HIF from RNA into the protein. In zebrafish with clinical features of VHL disease, the inhibitor reversed the disease phenotype. Now he is collaborating with medicinal chemists to improve the efficiency and pharmacokinetic behavior of the inhibitor in mice.

Likewise, Kaelin is applying RNA interference (RNAi) technology to turn off enzymes one at a time in VHL-defective tumors in hopes of identifying specific vulnerabilities that might be exploited to kill such cancers. (RNAi uses short RNA sequences that bind to messenger RNA and prevent protein synthesis.) He is also exploring whether RNAi can be used therapeutically to silence HIF in kidney cancers.  In preclinical studies, he is also using RNAi to accomplish the opposite, keeping HIF activated in anemia, heart disease, and stroke to stimulate the production of red blood cells. “It’s very gratifying that some of our work in cancer may touch other diseases as well,” said Kaelin, who has two cardiologists in his lab studying the role of HIF in cardiac diseases.

Other Therapeutic Approaches

Researchers in the DF/HCC Kidney Cancer Program are also exploring underlying causes of kidney cancer, and other approaches to therapy. They are major contributors of kidney samples to the NCI-funded Pan Cancer Genome Atlas (PCGA), which supports a tissue bank that researchers can use to make discoveries and test hypotheses. Kaelin, for example, is finding that many genes that cooperate with HIF in kidney cancer are involved in remodeling chromatin, the protein packaging around tightly wound spools, or histones, of DNA. Chromatin remodeling enzymes can open or close histones to transcription factors, thus regulating the gene expression. These epigenetic changes may directly result from changes in metabolism and oxygen levels in the tumor. Understanding how such epigenetic changes and metabolic enzymes contribute to cancer could lead to therapies that prevent those changes.

In other work, DF/HCC researchers are revisiting immunotherapy, which once meant revving up the body’s own immune cells to attack tumor cells – often causing intolerable side effects. Now, building upon basic discoveries by Gordon Freeman, PhD (DFCI), and Arlene Sharpe, MD/PhD (HMS), that cancer cells suppress activated T cells by binding to their Programmed Death (PD)-1 receptor, McDermott is using antibodies to prevent that suppression and release the normal immune response with fewer side effects. “We’ve known that kidney cancers, and also melanoma, are more responsive to immunotherapy,” said McDermott, who reported positive results in a multi-center phase 1 trial of a PD-1 antibody at the June, 2012, meeting of the American Society of Clinical Oncology. “Immunotherapy antibodies may benefit patients with more common tumors as well, and they may prove particularly effective in conjunction with other drugs that target the tumor itself.”

The Kidney Cancer Program is also tackling the challenge of early detection. Currently, most kidney cancers are first diagnosed at an advanced, hard to treat stage. To address this issue, a SPORE-funded project led by Joseph Bonventre, MD/PhD (BWH), is investigating the potential of the Kidney Injury Molecule 1 (KIM1) to detect kidney cancer earlier from blood samples.

Challenges Ahead

These examples illustrate how the DF/HCC Kidney SPORE has facilitated discoveries and translational research in the Kidney Cancer Program. “Our ability to understand the genetic changes in kidney cancer has grown substantially as a result,” said McDermott. “But we are still behind other fields in more personalized medicine based on the characteristics of an individual’s tumor that tells which tumors are more sensitive to a particular drug, or more susceptible to develop resistance or recurrence, or who needs more aggressive treatment.” Clear cell renal carcinoma, for example, is not classified by genetic subtypes, as non-small cell lung cancers are. Knowing the genetic subtypes could provide new drug-able targets for drug development and may have direct impact on therapeutic decisions.

Researchers in the Kidney Cancer Program remain enthusiastic that they can rapidly apply their improving understanding of kidney cancer to benefit patients. “Unlike twenty years ago,” said Kaelin, “translational work today is easier and more celebrated, and that’s a great thing” – and a hopeful development for patients in need of better, more durable therapies.

Support
Research detailed in this article was funded in part by NIH grants, including CA065164, CA101942, CA160458, CA068490, CA101942, and from the Howard Hughes Medical Institute.