Urologic cancers: Dispatches from research's front lines
March 28, 2014 | by ckitchens
Urologic cancers, including prostate cancer, kidney cancer and bladder cancer, are diagnosed in more than 381,000 Americans each year, and almost 60,000 people die from the diseases. City of Hope's physicians and scientists are determined to reduce those numbers.
Our groundbreaking research holds the promise of better treatments and cures for the millions of people worldwide battling these difficult cancers. The Division of Urology and Urologic Oncology, led by Timothy Wilson, M.D., Pauline & Martin Collins Family Chair in Urology and director of the Prostate Cancer Program, report the following developments in the treatment of urologic cancers.
Overcoming drug resistance in metastatic prostate cancer
When prostate cancer metastasizes, it is signaled to grow by a protein called the androgen receptor, which is activated by testosterone. Many men initially respond to hormone treatments that inhibit testosterone, but prostate cancer cells adapt and develop resistance to these therapies, and the cancer almost always returns.
Jeremy Jones, Ph.D., assistant professor of Molecular Pharmacology, found that pyrvinium, a drug used for decades to treat pinworm infections, could treat metastatic prostate cancer without targeting testosterone. Pyrvinium works by inhibiting the DNA binding domain – a different part of the androgen receptor that's activated when testosterone is blocked – and could be effective when all other therapies have failed. Jones is testing pyrvinium derivatives in cell cultures and mice, and his goal is to reach phase I clinical trial in the next two years.
Jones is also working with Cy Stein, M.D., Ph.D., Arthur & Rosalie Kaplan Chair of Medical Oncology, to combine the action of two drugs, enzalutamide and abiraterone, to treat prostate cancer that is resistant to hormone therapy. They have designed a compound called COH11023 that inhibits the production of testosterone, prevents testosterone from binding to the androgen receptor and breaks down the androgen receptor to rid the cancer cells of the protein.
COH11023 may prevent or delay cancer resistance, and Jones and Stein are developing a compound for testing in mouse models and eventually in human clinical trials.
Monitoring prostate cancer with circulating tumor cells
Jones and Sumanta Pal, M.D., assistant professor of medical oncology and co-director of the Kidney Cancer Program, have completed a study of circulating tumor cells (CTCs) in 35 men with high- risk prostate cancer that has not spread. CTCs are cancer cells that have detached from a primary tumor and traveled through the bloodstream, where they can form tumors in other parts of the body.
While it was hypothesized that very few CTCs would be detected in patients whose prostate cancer is confined to the pelvis, a new test developed by Jones found CTCs in nearly half of these patients. To better understand the mechanisms that enable CTCs to spread, Jones is characterizing each of these cells according to their DNA.
Jones and Pal plan to use this information to help identify which prostate cancer tumors are more likely to spread, so patients can be treated appropriately.
A new test to identify aggressive prostate cancer
The challenge in diagnosing prostate cancer is to differentiate which men have aggressive tumors and need immediate treatment from those men who have slow-growing disease that can be monitored with active surveillance. Steven Smith, Ph.D., professor of molecular science, has developed the secretion capacity test using expressed prostatic secretion (EPS) to help determine whether a patient has an aggressive cancer that has grown outside the prostate gland.
Testing samples of prostate fluid obtained from 528 men prior to prostatectomy, Smith found that patients whose prostate secreted lower amounts of fluid had aggressive cancer because the tumors had overtaken the gland and impaired its function. Smith concluded that the volume of fluid can be used as a biomarker to identify men with high-risk prostate cancer who should not be placed on active surveillance.
This research won the Best Abstract Award from the annual American Urology Association meeting in 2013, and has been published in the Journal of Urology.
Smith will collaborate with Wilson and Jonathan Yamzon, M.D., clinical professor of urology and urologic oncology, to administer the EPS test to a group of patients in active surveillance to identify any men who actually have high-risk prostate cancer and confirm that it is safe for the other patients to remain in active surveillance.
Distinguishing between prostate cancer and benign prostatic hyperplasia
Smith, Elizabeth Singer, Ph.D., assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation, and their colleagues are also developing a promising method to characterize molecular markers that distinguish prostate cancer from a noncancerous condition called benign prostatic hyperplasia (BPH), commonly known as an enlarged prostate gland.
They demonstrated that a synthetic protein DNA complex called a nanodevice, constructed using City of Hope’s patented nanotechnology and composed of proteins and fluorescent dye, can locate and attach to proteins in the cells adjacent to prostate cancer tumors. The researchers attached nanodevices to tissue samples of prostate cancer and BPH and, using a fluorescent microscope, discovered the regions around the cancerous tissues glowed and the BPH samples did not.
These results not only demonstrate the nanodevice can provide critical information that enables physicians to accurately diagnose patients, but suggest that the normal cells surrounding tumors can be used to help make a diagnosis. Smith and Singer also believe that these cells, known as reactive stromal cells, may be an effective target for prostate cancer treatment because they appear to promote the growth of cancer by causing mutations in the growing edge of a tumor.
Identifying the genetic blueprints of sarcomatoid kidney cancer
Pal and Jones also have been analyzing the DNA of sarcomatoid kidney cancer, a rare, fast-growing tumor that is difficult to treat.
Using next-generation DNA sequencing technology to obtain the most advanced genetic information of a patient’s tumor, Pal and Jones are investigating a specific protein that may distinguish sarcomatoid kidney cancer from typical kidney cancer. With this information, they will begin to develop drugs and identify an agent that targets the specific genetic mutation that drives this difficult form of kidney cancer.
Reactivating the immune system to fight metastatic kidney cancer
Although the immune system plays a critical role in recognizing and killing cancer cells, tumors can elude the body’s defenses and survive. To develop therapies that may help the immune system attack cancer, Pal has begun to study compounds that target a molecule called PD-1, which stifles the immune system’s response against cancer.
Drugs that inhibit PD-1 can restore the ability of the immune system to seek and destroy cancer cells. Pal is leading a clinical trial to study a drug combination for effectiveness in blocking PD-1 in patients with advanced kidney cancer.
Advancing therapies for kidney cancer
Pal is leading clinical trials to study the effectiveness of pazopanib, a targeted therapy that inhibits several proteins that trigger kidney cancer cells to grow and spread.
He completed a phase III study which showed that 43 percent of patients with metastatic kidney cancer who did not respond to pazopanib twice before during the course of their treatments actually responded when given the drug a third time. This is the highest response rate that researchers have seen to any drug used to treat metastatic kidney cancer after two prior therapies have failed.
Now, Pal and his team are conducting a phase III trial in collaboration with Southwest Oncology Group to determine whether pazopanib will reduce the risk of metastatic kidney cancer recurring in patients whose tumors were surgically removed and who have no evidence of cancer. Pal’s team has accrued more patients to this trial than any other cancer center in the nation, and the results could lead to major changes in treating kidney cancer.
Removing kidney tumors with fluorescent imaging
For patients with early-stage renal cell cancer, the standard of care is a partial nephrectomy to remove the cancer and spare normal kidney tissue. This procedure is very challenging because a surgeon cannot precisely visualize the margins between cancer cells and healthy tissues.
City of Hope developed an innovative technique to illuminate the tumor for more precise treatments. We were the first on the west coast to combine the state-of-the-art da Vinci Robotic Surgical System, near infrared (NIR) imaging technology and a special fluorescent dye called indocyanine green. This improves the surgeon’s ability to see the kidney and distinguish the blood vessels feeding the kidney from those vessels supplying the tumor. Then surgeons can remove cancerous tissue with greater accuracy while preserving as much healthy kidney as possible — and most important — enable patients to retain their kidney function after surgery.
Clayton Lau, M.D., director of the Urology & Urologic Oncology Fellowship and assistant clinical professor in the Division of Surgical Oncology, is completing a clinical trial to determine the optimal dose of indocyanine green dye to sufficiently illuminate kidney tumors. This new technology has tremendous potential for improving kidney cancer surgery, and the trial is expected to be completed in April 2014.
Premetastatic niche: Discovering how bladder cancer spreads
Pal and Jones have been studying the area outside a tumor site known as the premetastatic niche to uncover how bladder cancer cells spread.
In a study of tissue samples from 60 patients, they found that high levels of white blood cells called neutrophils in tissue near the tumors can indicate the development of a premetastatic niche. They also found that those patients with high levels of neutrophils had poor survival rates.
On the basis of this compelling data, Pal has obtained a grant from the Southwest Oncology Group to study tissue samples from over 600 patients with bladder cancer. The data will help confirm which patients have a high risk of developing metastatic bladder cancer so physicians can prescribe the best and most appropriate treatments for these patients.
Fluorescent visualization of cancerous lymph nodes during prostatectomy
Prostate cancer typically spreads through vessels in the pelvis known as lymphatic channels, which transport bacteria, impurities and cancer cells away from the prostate to lymph nodes.
To eliminate potential stray cancer cells, many of the lymph nodes in a patient’s pelvis are routinely removed during prostate cancer surgery. However, surgeons cannot identify which nodes actually contain prostate cancer, and more than 98 percent of current lymph nodes removed do not harbor any cancer cells. This can lead to longer surgery, longer hospital stays and complications after surgery.
Bertram Yuh, M.D., assistant clinical professor of urology and urologic oncology, is studying how indocyanine green dye and near-infrared imaging can also be used to highlight the specific lymphatic channels to target during surgery. He is preparing a pilot study with 20 patients to evaluate how this new technique helps surgeons to detect and remove cancerous lymph nodes, thus improving the outcomes for patients and reducing unnecessary lymph node removal and complications.
Targeting bladder cancer tumors with tiny gold particles
One of the greatest challenges in cancer treatment is killing cancer cells without harming normal cells, particularly when a tumor has spread to multiple locations.
Jacob Berlin, Ph.D., assistant professor of molecular medicine, and Karen Aboody, M.D., associate professor of neurosciences and neurosurgery, have developed a promising method which uses tiny, nontoxic gold particles called nanorods. These particles are enclosed in neural stem cells which take them to tumor sites. When near infrared light is directed to the tumor area, the gold particles heat up and destroy surrounding cancer cells with intense heat, while sparing damage to healthy tissues.
Pioneering research by Aboody has shown that neural stem cells naturally home to invasive tumors, making them ideal vehicles to carry the gold nanorods to cancer sites throughout a patient’s body. Aboody and Berlin have determined that neural stem cells will migrate to bladder cancer cells.
They now plan to load the neural stem cells with the gold nanorods in a mouse model of bladder cancer to learn how this method could eventually be investigated in clinical trials.
Training the next generation of urologic oncologists
Through the fellowship program, the Division of Urology and Urologic Oncology educates the next generation of urologic oncology specialists.
Directed by Lau, the program enables young physicians to engage in groundbreaking research and provide clinical care to patients. This rigorous program provides the fellows the advanced knowledge and specialized training which prepares them for a career in treating patients with urologic cancers.
In 2013, four physicians completed the fellowship program and are practicing in private and hospital settings across the country.
Urinary tract reconstruction
Some patients with bladder cancer require a radical cystectomy to remove their entire bladder, and surgeons create a new bladder using tissues from the intestines to enable these patients to store and pass urine through their bodies. Kevin Chan, M.D., assistant clinical professor in the Division of Urology and Urologic Oncology, Yuh, and their colleagues have published data on the benefits of the Indiana Pouch Reservoir and Orthotopic Neobladder urinary reconstruction surgical techniques.
In a study that evaluated patients who had a radical cystectomy with an Indiana pouch, Chan found that 97 percent of these patients had perfect urinary control at 20 months after surgery. This data was published in the journal Urology. Another type of urinary reconstruction is the orthotopic neobladder, which is very close to a “normal” bladder and allows patients to urinate through the urethra so they can resume their usual activities after surgery. These findings were published in European Urology in an article authored by Yuh.
In addition to patients who have undergone a radical cystectomy, men with prostate cancer who have had a prostatectomy may also require urinary tract reconstruction.
Chan studied the effectiveness of the transobturator sling in 37 men who became incontinent after a prostatectomy. This procedure allows men to regain their urinary control and improve their quality of life. Published in the journal Urology, this study demonstrated that men who have not had prior radiation treatment to their pelvis are the only appropriate candidates for this treatment.
Seeing the invisible
After several years of research and development, Andrew Raubitschek, M.D., professor and chief of radioimmunotherapy and co-leader of the Cancer Immunotherapeutics Program, has realized a new tumor mapping technique called intraoperative optical imaging (IOOI) that visualizes tumors to subcellular resolution in real time.
By attaching the highly-advanced Cellvizio conformal microscope and special lasers to the state-of-the-art da Vinci surgical robot, IOOI allows surgeons to see individual cancer cells that have been tagged with a fluorescent probe. The goal of the procedure is to provide patients the best outcome by removing all the cancerous tissues and microscopic deposits of cancer cells in the lymph nodes which drain the prostate.
Wilson will begin to perform radical prostatectomies using IOOI in 2014.
Getting results for patients with urologic cancers
Through these efforts and others, our scientists and physicians are accelerating scientific discoveries that are leading to improved detection techniques, more effective therapies and advanced surgical procedures that will benefit patients at City of Hope, across the nation and around the world. In 2013:
- Our physicians and surgeons in the Division of Urology and Urologic Oncology saw 3,601 patients for prostate, kidney and bladder cancers.
- Of those, 1,168 of these patients were new to City of Hope.
- A total of 714 men are now seen in the Prostate Cancer Survivorship Clinic.
- City of Hope surgeons have performed 6,525 robotic prostatectomies since pioneering this minimally-invasive procedure in 2003.
Learn more about our Urology and Urologic Cancers Program.