Issue No. 2013
Transforming Prostate Cancer
Valerie Matthews Mehl
Date: January 3, 2013
Prostate cancer is an iconoclast among cancers. It is at odds with what experts know to be the optimal approach for most cancers: Find it early and treat it early. Prostate cancer is different. It may be one of the few cancers humans can live with. It is most often slow growing, and even late-stage cancers can many times be held in check for years. On the other hand, it is a cancer that kills many men. It is the second leading cause of cancer death for men. The challenge, then, is deciphering the “good” prostate cancer from the “bad.” As a result, it is a model for personalized cancer medicine as Johns Hopkins urologists and cancer scientists and clinicians lead the way, using the most advanced science and technology to redefine for the world who to screen, who to treat, and who to safely leave alone.
Where We Came From, Where We Are Going
The innovation that sets the Johns Hopkins prostate cancer program apart can be traced, in part, to the inventive thinking of Patrick Walsh and Donald Coffey. They set the standard—challenging clinicians and investigators to think beyond the status quo; beyond what is adequate to what is extraordinary. Walsh developed an anatomical, nerve-sparing approach to surgery that, for the first time, cut out and cured prostate cancer without causing devastating side effects for men. Patients the world over traveled to Johns Hopkins to have Walsh’s surgery, and urologists-in-training sought to come to Johns Hopkins to learn the pioneering technique. Today, remains the most common surgery performed at Johns Hopkins.
Forward thinking, Walsh compiled an extensive database of thousands of patients and followed them for 30 years. What he and others learned from these men became the laboratory fodder for the bespectacled inquisitor Donald Coffey who began exploring the basic biology of prostate cancer and provided some of the first insights to the subtle and unique variations of cancer DNA. Like Walsh, he shared what he learned. One of Johns Hopkins School of Medicine’s first triple professors was the consummate teacher, inspiring generations of researchers to not only look for answers but to ask questions that had never before been asked.
Those who studied under Walsh and Coffey became leaders in prostate cancer treatment and research at Johns Hopkins and around the world. Walsh, a clinician, and Coffey, a basic scientist embodied the bench-to-bedside collaborations that are the hallmark of Johns Hopkins medicine and provided strong roots for a prostate cancer program.
This is, in many ways, the golden age. Generations of clinicians and investigators provide incredible depth to the prostate cancer program much like grandparents do for a family. Today, under the leadership of Kimmel Cancer Center Director William Nelson, Brady Urological Institute Director Alan Partin, and Radiation Oncology and Molecular Radiation Sciences Director Theodore DeWeese, Johns Hopkins experts, from a wide range of disciplines, are on the forefront poised to transform how prostate cancer is detected, diagnosed, and treated.
First Do No Harm
The purpose of early detection is to catch a cancer early so that it can be removed or destroyed before it causes harm. It makes sense for most cancers. The problem with detecting prostate cancer early, however, is that the diagnostic procedures and treatments can sometimes, particularly in older men, cause more harm than the disease itself.
PSA (Prostate Specific Antigen), the test that makes the early detection of prostate cancer possible, is at the center of the dilemma. Recently, the United States Preventive Task Force recommended against routine PSA testing for early detection claiming the harms outweighed the benefits. Their announcement gained widespread attention, but the truth is, experts at Johns Hopkins had been evaluating the test and changing prostate cancer screening and treatment long before the U.S. Preventive Task Force weighed in.
“We’ve know for a long time that there is a lot of harm that can potentially come with PSA testing,” says, urologist H. Ballentine Carter who has studied and evaluated the test in large populations of men for more than 20 years. Carter and other Johns Hopkins prostate cancer experts say that PSA is not inherently a bad test as it has been characterized in recent headlines. The problem, they say, is not so much with the PSA test, but instead how the test is used.
Before the Prostate Specific Antigen test, or PSA as it is now commonly known, hit the market in the late 1980s, prostate cancer was essentially an untreatable disease. There was no method for finding the cancer, and men went to the doctor only after they began experiencing symptoms, such as trouble urinating or blood in their urine. By that time, the cancer was already well advanced, and it could not be cured. Surgery was used primarily to relieve symptoms, such as bladder obstructions caused by tumors, and it often left men incontinent and impotent. For a man with prostate cancer, it seemed that if the cancer did not claim his life, it certainly would claim his quality of life.
It is no surprise, then, that when a test was developed that could detect the cancer early, before there were any symptoms, it was going to be used. Imagine, Carter says, if such a test existed for pancreas or lung cancer. Overdetection or not, people would be standing in line to get the test.
With no science to guide when prostate cancer screening should begin and how often it should be done, however, the nation, overzealously embarked on a practice of overscreening, overdetecting, and overtreating the cancer with free screenings and “awareness” campaigns that helped fuel the trend.
The result was a dramatic increase in prostate cancer incidence, and most experts agreed that many of the cancers detected would have never caused any harm. Doctors were finding a lot of prostate cancers, but many of them, Johns Hopkins scientists found, would never be a problem. “Now,” Carter says, “we must move to a more measured approach.”
He and other Johns Hopkins prostate cancer experts are putting medical science back in the equation and using sound research to determine how best to screen for prostate cancer and how to tease out the prostate cancers that are likely to kill from those less aggressive forms that may not require treatment.
Personalized Cancer Screening
The numbers are staggering. Each year 20 million men get screened with PSA. Many of them undergo unnecessary biopsies, suffer complications such as infection and bleeding, and still others have surgery, radiation treatment, hormonal therapies, and drug treatments that have unpleasant side effects. Out of all of these men, less than one-third of 1 percent will die from the disease. “It’s clear that for many men, the benefits may be small and the harms significant,” says health policy expert and Maryland Cigarette Restitution Fund supported investigator Craig Pollack. The challenge is figuring out from among the masses, which men will benefit from screening and which ones will not.
Confusion abounds, says Pollack. Ask patients why they get screened, and they say it is because their doctor recommended it. Ask doctors why they recommend screening, and they say their patients expect it. While Pollack finds that most primary care providers he has surveyed recognize the issues surrounding routine PSA screening, they are unsure about how to explain it to their patients.
“There are clearly some misperceptions,” Pollack says, “and since the majority of screening occurs in the community, we need to provide them with a decision-making tool that can help them improve their practice.”
Such a tool, a novel computer-based system, which can be integrated with patients’ electronic medical records, was developed by Carter, Pollack, cancer prevention and control expert Elizabeth Platz, and other Johns Hopkins cancer and public health experts. It will be piloted in Johns Hopkins Community Physicians offices throughout Maryland. They hope it will help primary care providers discuss prostate cancer screening with their patients and direct PSA to men who will benefit and away from those who will not.
The decision-making tool takes into account age and personal medical history, along with previous PSA test results and serves as an interactive guide for physicians to use when talking to patients about prostate cancer screening. Pollack and his colleagues found that while most physicians said they took age and life expectancy into account when deciding to order PSA screening, many also said they had a hard time estimating life expectancy in their patients and welcomed help in this area.
Screening is not one size fits all, says Carter. While Pollack acknowledges that making the shift from a population approach, in which everyone is screened, to an individualized approach, directed to only those who good research tells us will benefit, can be challenging. Men who are not recommended for screening, particularly if they have been screened in the past, may be concerned, and doctors may worry they could miss a cancer. However, Pollack says there is conclusive evidence that annual screening is not necessary for everyone. “An individualized approach just makes sense,” he says. “Our goal is to demonstrate that a personalized approach results in better care and fewer complications at a lower cost, and that is good for everyone,” says Pollack. “
If a man aged 40 to 75 comes in for an appointment, rather than routinely offering screening, doctors will instead be prompted to discuss the potential benefits and risk of PSA with him. The tool includes talking points to help guide doctors to speak to their patients about the potential risks and benefits of PSA screening. Doctors will also be prompted to explain the potential harms and benefits of treatment.
“The goal is to reduce screening, and ultimately treatment, in people we know, with certainty, will not benefit, and increase it among people who will,” Carter says. Men have grown to expect PSA screening to be part of their annual physical. This tool helps address misperceptions about screening and facilitates discussions that will help doctors and patients make more informed decisions. Carter has conducted large population studies involving thousands of men, and the data overwhelmingly show that men over age 75 are more likely to die with prostate cancer than of it, particularly if they have other more pressing health problems. As a result, these men will not benefit from PSA, and Carter says doctors should explain that to them. Kimmel Cancer Center director and prostate cancer expert William Nelson frames it this way, “I tell men who are over 75 and considering routine screening, ‘You don’t need it. You’ve won. Prostate cancer is not going to be a problem for you.’”
If the doctor and patient determine screening would be beneficial, the tool also provides recommendations for when and how often to rescreen.
With all of the confusion, clinician Michael Carducci wants to be sure that men who have prostate cancer understand that the PSA controversy only involves screening. PSA, he says, remains a vital tool in monitoring men who have already been diagnosed and in determining if there is a medical problem in men who are experiencing symptoms. “If you are a guy who is up five times a night going to the bathroom, you have blood in your urine, or erectile dysfunction. This is no longer screening. This is diagnosis,” says Carducci. “It is important that men understand the difference.”
To Treat or Not to Treat
Some of the greatest potential of personalized medicine is in using our new knowledge about the biology of cancer to get the right treatments to the right patients. Sometimes the right treatment may be no treatment.
One important way to reduce harm to men is to individualize the management of prostate cancer. PSA alone is not responsible for the adverse affects men have suffered; it has been what doctors have done with PSA—mainly overtreating the disease. When a man is diagnosed with cancer, Carter says, it is important for him to know that invasive treatments are not the only option.
Treatments for prostate cancer can include the surgical removal of the prostate, radiation, hormonal therapies, and chemotherapy. Each of these has the potential to cause serious problems, such as erectile dysfunction, impotence, and urinary incontinence or bowel damage. For many men, treatment is clearly the best option, and our prostate cancer clinicians are among the best in the world. Johns Hopkins clinicians have pioneered surgical, radiation, and drug remedies for the disease, but they have also been on the forefront of a nontreatment approach. It is called active surveillance—active being the key word.
Carter, although one of the world’s leading prostate cancer surgeons, believes that putting the scalpel aside is sometimes the best tactic for men who are diagnosed with a low-grade form of the disease. The approach has been the focus of research in the Brady Urological Institute at Johns Hopkins since 1995. Data gleaned from several large studies unequivocally showed that many men with low-grade disease would never be harmed by their cancer but could be, and all too often are, harmed by treatment. “The majority of men diagnosed with prostate cancer each year are over 65 and have a low risk of dying of their disease if treatment is deferred,” says Carter. “Yet, more than 90 percent of these men, including 80 percent who are over age 75, are likely to choose some form of treatment. Active surveillance addresses excessive treatment of milder stages of prostate cancer, especially in seniors.”
About 40 percent of men are diagnosed with low-risk disease, and for a significant number of them, active surveillance offers a way to very carefully monitor their cancer and give them the option to delay treatment as long as it does not progress. Many of these men will never require treatment, but if they do, careful surveillance allows the growing cancer to be spotted and treated while it is still curable. A National Cancer Institute (NCI) model that uses computer simulation to determine patient outcomes evaluated all of Carter’s active surveillance data and compared it to data from men who would have qualified for active surveillance but chose surgery. In a worst-case scenario, the NCI model found that over a 15-year period, men who chose active surveillance stood to gain an average of seven additional years of not being treated, and at the most, risked losing three months of life.
Pennsylvania businessman Alex Cameron was one of the first participants in active surveillance. Cameron was in his late 50s in 1999 when he was diagnosed with prostate cancer and began exploring options including hormone therapy, brachytherapy, and surgery. In his research, he also learned of Carter’s active surveillance approach and scheduled an appointment. He admits that with a wife, three daughters, and eight grandchildren to live for, the idea of leaving the cancer alone was somewhat troubling to him and his loved ones. Cameron’s prostate cancer fit the parameters for active surveillance. He had a low Gleason score and his cancer was very slow growing. “Active surveillance sounded like a win-win good thing,” says Cameron. He says regular biopsies done under local anesthesia to monitor his cancer were a minor inconvenience in exchange for his ongoing and treatment-free health. He said he was also comforted by the knowledge that five of the world’s best prostate cancer pathologists were reviewing his biopsy samples. Today, at age 71, Cameron remains active and healthy and confident that he made the right decision. “For any guy in my situation,” he says, “active surveillance is the way to go.”
Cameron is among the more than 1,000 men who have participated in active surveillance since Johns Hopkins began offering it 16 years ago, and there are currently about 600 men enrolled. The average participant is 67 or older. This option, Carter says, is for men who are likely to live out their natural lives without being harmed by prostate cancer. In other words, prostate cancer is not going to kill them. The men have a PSA test and rectal exam every six months as well as an annual biopsy to carefully monitor their cancer. More recently, Carter has added MRI (magnetic resonance imaging) to surveillance. “We know that there is potential to underestimate the extent of disease in some men, and MRI helps us make sure we haven’t missed anything,” says Carter. “A recent study showed that when MRI found there was no cancer there, there was really no cancer there.”
For many years, Johns Hopkins was the only cancer center to offer active surveillance. This is, in part, because medical reimbursement is a fee-for-service system that favors procedures. Johns Hopkins urologists, arguably the best trained in the world, were the only ones willing to explore the possibility of a better option for some patients.
Endorsement of active surveillance by the Prostate Cancer Foundation and heightened concerns about overtreatment stemming from the U.S. Preventive Task Force’s recommendation, is now bringing this “no-treatment” treatment new consideration.
The Prostate Cancer Foundation is working to provide patients more assurance and has established the National Proactive Surveillance Network, a Web-based system (NPSN.net) that provides education about active surveillance and helps patients find participating doctors. Soon, patients and physicians will be able to securely access the system to enter, review, and track their own data. Men participating in active surveillance would be able to enter all of their PSA data and track their personal results to see where they fall in respect to other participants.
Still, Many men, upon learning they have prostate cancer, are uncomfortable leaving the cancer untreated. “They need stronger, quantifiable reassurance that their cancer won’t hurt them, and we don’t have the ability to give them that right now,” says prostate cancer researcher Srinivasan Yegnasubramanian. He believes if physicians were able to remove any doubt, it might change minds and significantly improve outcomes for men. He is working to create an accurate test that could be applied to blood or urine and provide clear biological evidence to distinguish aggressive prostate cancers from the slow-growing type, which could be left alone.
A Gleason score is an excellent barometer of aggressiveness, but it is only as good as the sample, he says. In men who have a prostatectomy, it is very telling because pathologists have the entire prostate to examine. When a tumor is sampled through a biopsy, though technology has greatly improved, it is still possible to miss critical areas of a tumor that could be the key to distinguishing harmless cancers from dangerous ones. Removing this uncertainty is at the core of Yegnasubramanian’s research.
His test is based on chemical alterations to specific regions of genes. They occur without mutating DNA but can have the same effect as mutations and silence the function of important tumor suppressor genes. These changes, known as epigenetic alterations, are a signature for cancer and when they are seen or begin to increase, they can alert doctors to a growing cancer. Moreover, they are very common in prostate cancer. “Epigenetic alterations can occur more frequently and consistently than mutations in prostate cancer,” says Yegnasubramanian.
Not only do these alterations serve as signatures for cancer, they are also potential therapeutic targets. Unlike mutations, in epigenetic alterations, affected genes are not missing. Instead, they are silenced by changes in the chemical environment, so researchers have the opportunity to use drugs to revert genes back to normal function. Epigenetic signatures could be used to distinguish indolent prostate cancers from aggressive ones, monitor cancers for progression and recurrence, and to determine whether treatments are working.
In recent years, the pace of these discoveries has greatly accelerated because of a new technology known as next generation sequencing. This powerful technology has the ability to rapidly and simultaneously sequence millions to billions of DNA molecules. As a result, cancer research that used to take decades can now be completed in weeks. Yegnasubramanian is the director of the Kimmel Cancer Center’s Next Generation Sequencing Center, located in the David H. Koch Cancer Research Building.
He and his team are using this technology, in conjunction with new techniques they have developed, to profile prostate cancers and identify a panel of epigenetic markers unique to prostate cancers with high Gleason scores and another to characterize cancers with low Gleason scores. Once they identify the specific markers that brand both aggressive cancers and slow growing ones, they can adapt the technology to find them in blood and urine.
“If there is a question we can ask where genomic information can help inform who should get a particular treatment and who should be monitored, I think we can go after it,” says Yegnasubramanian. “The prostate cancer program has one of the best teams on earth to define and tackle these questions.” Though many centers are thinking about these problems, Yegnasubramanian says Johns Hopkins is uniquely positioned because of its strength in translational medicine to make progress. “We have equal strength in the clinic and the laboratory,” he says. “This is a major asset that is rarely found in other centers doing genome research. Some have the research component but do not have the clinical strength we have here. Having both, allows us to make the critical connection between what we find in the laboratory and what will truly benefit patients.”
Yegnasubramanian also is collaborating with Kenneth Kinzler, one of the world’s leading cancer genetics experts, Stephen Baylin, a foremost epigenetics expert, and veteran prostate cancer investigators Michael Carducci and Mario Eisenberger to better understand how differences in the prostate cancer genome and epigenome have an impact on treatment outcomes. His research will help physicians make the right treatment decisions for each individual prostate cancer patient.
In prostate cancer that recurs and spreads after treatment, the first line of approach is hormone (androgen) suppression therapy—in essence cutting off the supply of hormones that are believed to be fueling the cancer. At this stage, most men will survive about four years. However, our investigators have found that there are extremes in patient survival that could provide important new clues about the disease. Some men progress rapidly and may die within the first year of their recurrence, but others appear to be cured by the hormone suppression therapy, living for years without any sign of cancer recurrence. Yegnasubramanian and team believe the reasons for these differences are hidden within the genome and epigenome of prostate cancer, and they are hoping to use the power of next generation sequencing to uncover the biological differences.
What is different about the cancer DNA of long-term survivors versus those men who have a very rapid progression? The answer would allow clinicians to direct more intensive therapies to men whose cancer DNA predestines them to be less responsive to standard treatments and give less therapy, or stop treatment altogether, in men whose cancer DNA points to long-term remission. What they learn about the extremes of treatment responses should also help all men with prostate cancer by shedding new light on other mechanisms that could be targeted in treatment. What the investigators uncover about the genetic and epigenetic basis of extremes of therapeutic response in prostate cancer will likely reveal similar information about other cancers.
Proving a Negative
There is the old adage, “You can’t prove a negative.” This dilemma is at the core of creating better screening and diagnostic tests for prostate cancer that limit the need for invasive procedures. How do we use scientific discoveries to prove the absence of cancer with the same certainty as we prove the existence of cancer?
Despite its problems, Brady Urological Institute Director Alan Partin and other prostate cancer experts say PSA is an invaluable tool in helping monitor men who have already been diagnosed and, even with its limitations, remains useful in the diagnosis of prostate cancer. With a little help, Partin says it could be even better.
Throughout his career, Partin collected blood, urine and serum samples from his patients and created the world’s largest prostate biorepository. It greatly advanced the understanding of prostate cancer and has been critical in his work to develop biomarker tests that could augment PSA. The tests, he says, could help diagnose prostate cancer without exposing men to repeated biopsies. PSA detects cancer but it also detects a lot of other things. “We need a test that when it’s negative, we know the patient is OK. When it’s positive, we want to be confident that it’s truly positive. We don’t want to continue doing four biopsies to find the one cancer we’re looking for,” says Partin, who is the David Hall McConnell Professor of Urology.
A positive PSA means only that a man could have prostate cancer. Currently, the only way to know for sure is to biopsy the cancer, a process in which a needle is guided by ultrasound, and more recently MRI and other imaging technologies, through the rectum into the tumor. While Johns Hopkins cancer researchers and engineers have led the way in developing new technologies that make prostate tumor biopsies [For Web exclusives and IPAD version, link to Song/Stoinavici story on robot-assisted biopsies from “Engineering Cures” issue.”] remarkably precise and safe, many men still undergo repeat biopsies to confirm or disprove a cancer. Each biopsy carries a risk of bleeding and infection. Partin believes a new urine test based on a genetic discovery by Brady Institute laboratory scientist William Isaacs may help dispel some of the uncertainty and alleviate the need for multiple biopsies.
Unlike PSA, this new gene-based urine test, called PCA3, only detects prostate cancer, but it too has its limitations. While PCA3 outshines PSA in terms of its specificity to prostate cancer, it is not as sensitive, so it has the potential to miss cancers. PSA, on the other hand, is very sensitive—quite good at picking up abnormalities in the prostate—including (but not limited to) cancer. Combined, the two tests compensate for the other’s shortcomings and, as a result, have the potential to very accurately detect cancer. If a man has an elevated PSA, but a biopsy did not reveal cancer, Partin says the PCA3 test could potentially serve as the final word. “If a PCA3 is negative, you can trust that the patient probably does not have prostate cancer. If it is positive, then he probably does,” Partin explains. “It adds another piece of information to help us better and more safely diagnose prostate cancer.”
Partin also is working on a test called AccuPSA to monitor prostate cancer patients following surgery for what is referred to as biochemical recurrence. The test uses new nanotechnology approaches to measure PSA values 1,000 times lower than a standard PSA test. A rising PSA without any visual tumors is considered a biochemical recurrence, and warns clinicians that prostate cancer cells may remain in the prostate and increases the likelihood that the cancer will ultimately return and spread.
Partin and team studied blood samples from 31 men who had undetectable PSA, using the standard test, for five years after prostatectomy. One-third of the men later began to have a rising PSA, and when Partin used AccuPSA on the blood samples, he found that the one-third of men with biochemical recurrence had a small but measurable rise in their PSA just three months after surgery. In the other men, 75 percent had AccuPSA levels lower than the men who recurred. The small study allowed Partin and team to determine a threshold for AccuPSA that could help them distinguish, within a few months after surgery, men whose cancer has been entirely eliminated with surgery from those who may have had some remaining cancers cells that could put them at risk for cancer recurrence in the immediate years after surgery.
Identifying which men will have cancers that are likely to be cured with standard treatments and those men who have cancers destined to return and spread is essential to the management of prostate cancer, says Partin.
Separating the “Good” from the “Bad”
The complexities of managing prostate cancer go beyond the PSA controversy.
Prostate cancer experts have gotten extremely adept at separating aggressive cancers from nonaggressive cancers. The Gleason score, first established in the 1950s and later refined by Johns Hopkins pathologist Jonathan Epstein, ranks the nature of the prostate cancer on a scale of six to ten. Gleason six represents a lower- risk cancer; seven through 10 means the cancer is more dangerous. In short, the lower the number is, the better. Evaluated in conjunction with PSA (Prostate Specific Antigen) tests, biopsy results, and the size of the tumor, our experts say it does a good job guiding treatment.
As one of Hopkins busy prostate cancer surgeons at Johns Hopkins, Edward Schaefer has observed first hand that while many of his patients are cured with surgery, some of them inexplicably have their cancers return. In his laboratory, he is working on ways to identify these patients and to develop new treatments to prevent the cancer’s return.
To decipher clues about the abnormal cell growth that leads to prostate cancer growth and spread, Schaeffer identified and focuses on a group of genes that regulates and controls normal prostate development. He postulated and subsequently showed that genes that control the movement and invasion of prostate cells during normal prostate development, become reactivated in prostate cancers. Schaeffer’s work has not yet revealed the triggers to turn these invasive genes back on, but he has found that the molecular process is linked to the most aggressive prostate cancers. This promising finding allows him to not only pinpoint those patients whose cancers are destined to return after surgery, but it also reveals a potential new target for treatment.
Schaeffer’s laboratory team, led by Paula Hurley, is particularly interested in a gene known as SPARCL1, which can accurately predict whether a seemingly localized tumor will return and spread within a few years after surgery. The normal prostate has high levels of SPARCL1 expression, which holds cells in check, preventing them from migrating and moving around. Low levels of SPARCL1 allow cells to move well, serving as a biological red flag that the cancer will return with a vengeance.
Currently, Gleason Score is used to identify more aggressive prostate cancers. For example 30 percent or more of patients with a Gleason Score of seven or higher are at highest risk of having their cancers return. Unfortunately, there is currently no way to differentiate the patients who are cured with surgery from those whose cancer will recur. Measuring SPARCL1 expression at the time of surgery seems to provide the answer. In addition, Schaeffer’s research indicates that SPARCL1 could also play a role in predicting tumor recurrence in a number of other tumors, including bladder, breast, colon, rectum, tongue, lung, skin, and ovarian cancers.
Schaeffer is now working to decipher the specific mechanism that controls the gene in hopes of developing a treatment that can reset SPARCL1 to normal and prevent cancers from returning.
The Case for Open and Closed
The da Vinci robotic surgical system has made minimally invasive surgery a household word and has become a favorite marketing tool of community hospitals around the country.
The da Vinci system boasts smaller incisions, less pain, shorter hospital stays, and shorter recovery time for patients. In certain instances, this is true. For prostatectomy, however, not everyone agrees. Prostate surgeons—like Alan Partin, H. Ballentine Carter, Edward Schaeffer, and the many other urologists who learned how to do prostatectomies by training under its pioneer Patrick Walsh, the undisputed paragon for how it should be done—do not need the assistance of da Vinci. On the other hand, robots can be quite helpful and sometimes make it possible for surgeons who do not have the skills to perform a Walsh-style open procedure to perform prostatectomies.
When it comes to prostate cancer, men may have a difficult time distinguishing good marketing from good medicine. Patients hear advertisements about one machine or another, and they think if their doctor does not use it, he is not practicing good medicine, warns John Wong, a Kimmel Cancer Center medical physicist who has invented several cancer-related devices. Many claims, he says, are made with no scientific evidence to back them up.
Partin agrees saying that Johns Hopkins always evaluates new approaches from an evidence-based scientific standpoint. “We were using the da Vinci robot long before it was famous,” says Partin. “But, we take marketing and profits out of the equation and look at what really works the best for patients.”
Investigators in the Johns Hopkins Center for Computer-Integrated Surgical Systems helped develop some of the technology used in the da Vinci system, which employs robotics, sensors, imaging devices, and guidance systems to interface and assist surgeons when operating. Brady Urologist and biomedical engineer Mohamad Allaf works with these scientists and is director of minimally invasive and urological robotic surgery. Johns Hopkins was one of the first medical institutions to integrate robotics into urologic surgery, and Allaf is considered one of the world’s leading experts. He travels around the globe demonstrating and training other surgeons in robotic prostatectomy, nephrectomy (kidney) and other urological operations. Like the other Brady surgeons, Allaf is as skilled at open procedures as he is at robotic approaches, but with the continuing demand from patients for minimally invasive procedures and his work innovating the next generation of robotics in medicine, it is his focus.
In terms of prostatectomy, Partin says it’s a draw. Studies show that open procedures and robotic procedures, when performed by trained surgeons, are equally good and there is really not much difference in pain or recovery.
Training is key. Patients need to understand that that the robot is not as important as who is operating the robot, says Schaeffer. Johns Hopkins urologists are probably the best in the world at both open procedures and robot-assisted surgery, he says. Patient demand supports this contention. Johns Hopkins urologists are the most sought after, performing hundreds more prostatectomies than any other hospital in the world. Their record is stellar, getting all of the visible cancer 90 percent of time while also preserving sexual and urinary function. Schaeffer says he finds that some men prefer the minimally- invasive prostate surgery approach, so unless the tumor is large and bulky or has other characteristics that demand an open procedure be performed, he usually leaves the choice up to the patient. This is where the skill of the Johns Hopkins urologists, experts at both types of surgery, makes a difference. They are not limited to one or the other, so they can select the approach that is best suited to each patient’s individual cancer.
Targeted Radiation Therapy
A new form of targeted radiation therapy, known as proton beam therapy, very precisely zeroes in on tumors, increasing the damage to cancer cells, while minimizing radiation exposure to healthy tissue and organs. Its precision and safety have rightfully made it the standard of care for pediatric tumors; tumors of the brain, spine and eye, and cancers of the lung, head and neck, and bone (sarcoma). The most common cancer currently treated with proton beam therapy, however, is prostate cancer. This widespread use has raised concern among prostate cancer experts because there is currently no evidence to prove that proton beam is safer or more effective than other forms of radiation therapy. Many cancer experts suspect that the large numbers of prostate cancer patients explain the trend. Proton beam equipment is expensive, and many facilities, particularly for-profit ones, may be recommending it to their prostate cancer patients to ensure a steady stream of revenue. The Kimmel Cancer Center is currently developing plans for a proton beam facility on its Washington, D.C., campus. These plans include the important basic science and clinical studies to help resolve with evidence-based research the scientific controversy surrounding the benefits of proton therapy in treating prostate cancer.
Helping Patients Make the Right Decision
Johns Hopkins prostate cancer experts have pioneered therapies, diagnostic tests, imaging techniques and basic science discoveries. However, what Schaeffer and his fellow Johns Hopkins urologists and oncologists take the most pride in is providing personalized treatment plans for each patient, whether it is surgery, radiation treatment, hormone therapy, active surveillance or a combination of these approaches.
Schaeffer, medical oncologist Charles Drake, and radiation oncologist Danny Song co-direct a clinic where patients from around the world come to have their prostate cancer scrutinized by leaders in the field. Some men have localized disease and are uncertain about what is the best treatment for them. Others have more aggressive cancers they have been told are not treatable. About-one quarter of the patients who come to the clinic have a change in the grade or stage of the cancer, once examined by the Johns Hopkins team, which include radiologists and pathologists, like Jonathan Epstein, the world’s most sought after prostate cancer pathology expert. Most of the time, patients get better news than what they were initially told. By the end of the day, the crack team will have laid out for them treatment options and plans.
“We offer a service based on our extensive experience that delivers the treatment best suited to each patient,” says Schaeffer. “People come to our clinic after being told they need surgery and are relieved to find out we can offer them an alternative to surgery. By the same token, we have men who come to our clinic because they have been told they cannot have surgery, and we cure them,” he says. He recalls one patient, in particular. He was 47 years old and had been told his cancer was incurable. He came to the prostate cancer clinic, where Schaefer and team worked out a plan that included surgery and radiation therapy. That patient continues to do well today.
Why can Johns Hopkins experts offer patients treatments that other hospitals cannot? “The technical experience is better here than anywhere else in the world,” says Schaeffer. “But just as important, we know how, when, and to whom to employ this expertise. This personalized approach is the essence of the Prostate Multi-D Clinic, and we do it better than just about anyone.
Science, Populations and Prostate Cancer
Cholesterol Drugs Good for Heart Disease and Prostate Cancer
Population studies at Johns Hopkins have shown that men on cholesterol-lowering drugs known as statins have a greatly decreased risk of developing advanced prostate cancer. Physician and scientist Phuoc Tran has gone back to the laboratory to figure out why. He suspects that these drugs block the activity of an important cancer-growth-promoting gene known as c-myc, and he proved in laboratory studies that high-dose statins, in fact, reduce c-myc activity. Now Tran, a radiation oncologist and expert on the c-myc oncogene, has initiated a clinical trial in collaboration with urologist Edward Schaeffer to verify in prostate cancer patients what he observed in the laboratory. If he confirms his findings, it could open the door to treatment strategies that could improve surgery or radiation therapy outcomes. Similarly, statin-based prevention approaches could lock prostate cancer in a nonthreatening stage and potentially stop it from occurring at all
Elizabeth Platz is a population scientist. She uses questionnaires, records, and biospecimens to observe men—what they do and what they do not do—and applies what she sees to prostate cancer. For example, her landmark study of nearly 5,600 men aged 55 and over, found those with normal or low serum cholesterol had a 60 percent lower risk of developing aggressive (high-grade) prostate cancer than men who had borderline and elevated levels. In an earlier study she observed that men who used cholesterol-lowering drugs known as statins had a decreased risk of developing aggressive prostate cancer.
There seemed to be a link—men with lower cholesterol and men who used cholesterol-lowering drugs, improved there prognosis, decreasing their risk of developing a more aggressive form of prostate cancer. To determine why she finds the things she finds, Platz, the Martin D. Abeloff Scholar in Cancer Prevention and Control, turns to her laboratory and clinical science colleagues to unearth answers, and vice versa.
Marion I. Knott Professor and Director of the Kimmel Cancer Center William Nelson and investigator Srinivasan Yegnasubramanian worked with researcher Jun Liu, who has constructed a repository of more than 3,000 FDA-approved medicines, in hopes of identifying some commonly used noncancer drugs that might work against prostate cancer. When they screened human prostate cancer cells against the drug library, two of the top 15 hits were statin drugs. One was digoxin, an older drug that, in the past, was commonly used to treat congestive heart failure.
Scientists are looking for new ways to contain the cost of drug discovery, an enterprise in which a billion dollars can be spent to bring one drug to market. The promise of most drugs, or lack thereof, is usually only realized after years of costly research. As director of a cancer center, Nelson understands cancer researchers have to do better. He envisioned a two-stage approach to see if what he, Yegnasubramanian, and Liu found in the laboratory studies of prostate cancer cells would be supported or refuted by what Platz observed in men. Platz and her epidemiology colleagues followed nearly 50,000 men and compared digoxin users to nondigoxin users and found men who took the drug had a 25 percent lower risk of developing prostate cancer than those who did not. Now, the team had laboratory evidence that digoxin halted prostate cancer cell growth and a population study that found a significantly decreased risk of prostate cancer among men who took the drug.
It was unlikely a fluke. Getting the same findings twice, once in the laboratory study and then in the population study, removed the likelihood that that the results they were finding occurred by chance. Prostate cancer experts at Johns Hopkins and around the world deemed Nelson and team’s laboratory/population approach quite clever. Combining the two types of research helped ensure that the investigators were not wasting time or limited resources pursuing a dead end. With good evidence that the heart drug truly has anticancer properties, the researchers are now working to figure out exactly how it works in prostate cancer.
Digoxin has a number of side effects, but Nelson says if they figure out how it works, they can develop or identify another drug that can safely treat or even prevent prostate cancer.
A Train Ride and Telomeres
Riding the train together on the way back from a prostate cancer meeting in 2004, researchers Alan Meeker, Angelo De Marzo, and Elizabeth Platz enthusiastically planned the next phase of their breakthrough prostate cancer study.
De Marzo is among the world’s best prostate cancer pathologists, but what he couldn’t figure out was why men with seemingly similar cancers under the microscope often had very different outcomes in the clinic.
What was different about their cancers, De Marzo, Meeker, and Platz wondered. If they could figure it out, perhaps they could develop treatments that would benefit all men. In this new age of molecular medicine, was there something else beyond currently used pathology indicators—stage, Gleason grade, and PSA—hidden within the cancer cell that could determine prognosis?
It was 2004, four years before Johns Hopkins researcher Carol Greider would win a Nobel Prize for her research on chromosome ends known as telomeres. Similar to the plastic coverings that shield the ends of shoelaces from damage, one can think of telomeres as the protective end caps of chromosomes. Building upon Greider’s growing body of work, Meeker and De Marzo received a Maryland Cigarette Restitution Fund grant to study telomere length and its potential link to cancer. As normal cells age and divide, some of the telomere DNA is lost and telomeres get shorter and shorter. Normal cells monitor the length of their telomeres and initiate cell death if they get too short. It was already well recognized that telomeres were shorter in cancer cells than normal cells. They wondered whether this monitoring system breaks down in cancer cells and whether assessing telomere length could be a marker for prostate cancer aggressiveness. In preliminary studies, the investigators examined precancerous prostate lesions and found much shorter telomeres.
This finding was the focus of their conversation as they sat huddled on the train outlining the next step in their research. Their excitement about studying telomere length to see if it could tell them something new about prostate cancer aggressiveness and prognosis did not go unnoticed by their fellow passengers in the “quiet car.” Unaware of their cancer discovery and unappreciative of the chatter, Meeker, De Marzo, and Platz were soon asked to find different seats on the train.
With funding from the Department of Defense, they began to study the ideas they discussed on the train ride. They examined telomere length in the chromosomes of human prostate cancer cells and nearby cells from the stromal or connective tissue surrounding the prostate that had been preserved in a special specimen bank at Johns Hopkins. Cell by individual cell, a research fellow painstakingly circled every relevant cell on digital images of tissue that was stained with a fluorescent dye to mark the telomeres. A computerized method quantified telomere length, the number of short telomeres, long telomeres, and mix of both. Meeker and De Marzo developed the approach to complete such a thorough and comprehensive examination. No research team had ever looked cell by cell, opting instead to study bulk tissue, primarily because it was a simpler and less labor-intensive process. Meeker recognized they could miss something doing it that way. In fact, what they found could only be deciphered by a method like the one Meeker and De Marzo developed. The research team was surprised to learn that it was not short telomeres in the cancer cells that seemed to matter but rather the variability in the length of telomeres from cancer cell to cancer cell that influenced the outcome of men with prostate cancer. The unconventional approach was dead on. “If we had done it the way everyone else does it, we would have never found this,” says Platz. “Some were shorter. Some were longer, but it was the variability from cell to cell that predicted lethal prostate cancer, and it could be found only by looking at each cell.”
Variable telomere length in prostate cancer cells and short telomere length in the nearby stromal cells translated to a much higher risk of dying from prostate cancer. Prostate cancer cells with less variability in telomere length and longer telomeres in the stromal cells marked a less aggressive form of prostate cancer. When they separated the samples based on these characteristics and referenced back to the actual patients from whom they were obtained, the investigators found that only one man in the lower-variability/longer telomeres group died from his cancer compared to 20 in the higher-variability/shorter telomeres group. “The marker gives us information and detects high-risk disease independent of other screening and staging tests,” says Platz.
With support from the Department of Defense, the National Cancer Institute Prostate Cancer SPORE grant, and the Johns Hopkins Prostate Advisory Council, the research team is now working to develop an automated approach to speed up the burdensome process of measuring telomere length in individual cells.
The team sees many potential applications for their discovery. “Maybe there are subsets of men in whom we can use telomere length to predict response to treatment and determine precisely what treatments will work for each patient,” Platz says. Examination of telomere length could also be used to help identify men whose cancer is likely to progress and would not be good candidates for active surveillance. Conversely, it could be used to provide more evidence of low-risk disease and give reassurance to men who are enrolled in active surveillance. “Treatment has side effects. We don’t want to give it to a man who does not need it or when we know it will not help,” says Platz. “Telomeres may be a marker we can use to individualize our prostate cancer therapy to maximize benefit and minimize risks and adverse affects for each patient.”
Wondering About the Wonder Fruit
The idea for Michael Carducci’s clinical research of the pomegranate fruit actually came from the Kimmel Cancer Center’s benefactor and namesake Sidney Kimmel. A pomegranate product manufacturer was widely touting a UCLA study that seemed to indicate that the fruit had prostate cancer-fighting properties. Kimmel wanted his cancer center to figure out if it was true, and Center Director William Nelson thought Carducci was just the person to sort it all out.
Carducci, the AEGON Professor in Prostate Cancer Research, decided not to limit his work to pomegranates. There are a range of natural products marketed for prostate health, and Carducci decided to follow Kimmel’s lead and conduct studies to look for real, scientific evidence that these natural ingredients had an effect on prostate cancer cells through clinical studies. He has recently completed studies of pomegranate and is now beginning to look at Vitamin D and soy protein as well as muscadine grapes skins.
The UCLA study found that pomegranate juice slowed PSA doubling time in men who had prostate cancer, an indication that pomegranates could be slowing the progression of the disease. Carducci wanted to see if he could replicate these results and also determine if the amount a person consumes makes a difference. For his studies he used POM Wonderful pomegranate extract capsules because the product is 100 percent pomegranate. Regarding the pomegranate industry, he cautions buyer beware, as the demand for the fruit is 15 times greater than production. Many products on the market contain a very small amount of pomegranate juice mixed with blueberry, grape, acai or other juices. Carducci says pomegranate is of interest to cancer researchers because it is the highest in antioxidants, chemicals known to have cancer-fighting properties.
Carducci and his team, which includes Emmanuel Antonarakis and Channing Paller, are still sorting through their findings. They confirmed the findings of the UCLA study, also finding that PSA doubling time slowed, an indication, but not proof, that it has an impact on the progression of the disease. Moreover, they resolved the issue “how much is enough” issue, and showed that low doses of the extract had the same effects as higher doses. “We have to verify that the affect we’re seeing is caused by the pomegranate and not just a natural process we’re picking up because we’re watching more closely,” says Carducci. “We think that slowing PSA is good thing, but we have to prove that it actually makes a difference in patient outcomes,” he says.
Another similar study in partnership with Howard University is exploring the benefits of muscadine grapes. The skin of these large, dark-purple grapes contains two antioxidants, resveratrol, which is common to grapes, and ellagic acid, the same antioxidant in pomegranates.
Carducci hopes that their studies will lead them to alternative therapies for men whose PSA begins to rise after surgery, an event called biochemical recurrence. One option for these men is hormonal therapy, but these therapies have annoying side affects such as weight gain and hot flashes and, even more of a concern, they may accelerate heart disease. “If there is a more natural approach that would allow these patients to avoid adverse affects, it would be very exciting,” says Carducci.
Tracing the Muddled Genealogy of Prostate Cancer
It took 20 years of work, but a research team led by prostate cancer laboratory scientist William Isaacs has uncovered the genetic driver for a hereditary form of prostate cancer that tends to strike younger men. It is the first major gene finding associated with inherited prostate cancer.
“It’s long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging and earlier studies have provided inconsistent results,” says Isaacs, the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology.
Isaacs’s work was inspired two decades ago by the pioneering work of Bert Vogelstein and team that uncovered genetic alterations linked to hereditary forms of colon cancer. These findings led to cancer being defined as a genetic disease and ultimately revealed the complex landscape of colon and other cancers among the general population. Unlike colon cancer, which provided inherited syndromes and early onset of disease as clues, in prostate cancer “there were no syndromes families where 25-year-olds were getting the disease, and we could study them,” says Isaacs.
It was frustrating for Isaacs because earlier studies seemed to indicate that prostate cancer had a strong hereditary susceptibility, higher than colon and breast. Where was it? Why couldn’t they find it?
It turns out that techniques that worked so well in defining the genetic culprits for colon and breast cancer did not work so well with prostate cancer. “It’s a disease that most men get,” says Isaacs. He points to volumes of books on his shelf that contain pedigrees of families where three or four families had prostate cancer. “It is the most common cancer in men. We are going to find families with multiple members who have the disease, even without a genetic component, just because it is so common.” Tweezing out which ones were genetically linked and which ones were not turned out to be a monumental task.
With other cancers, early age at diagnosis is a red flag for a hereditary link. In prostate cancer, the best determinant of early age of diagnosis relates directly to how early a person is screened. “If you have a 20 year old with a lump in her breast, you know it’s early onset,” says Isaacs. “With prostate cancer, you could have a guy diagnosed at 75 who may have had the tumor since he was 45 or younger.” It is well known that prostate cancer is a slow-growing cancer and autopsy studies done at Johns Hopkins have revealed early cancers in men in their twenties and thirties. “We wouldn’t know if a man had prostate cancer at 25 because no one screens for it at that age, and he probably wouldn’t have any symptoms that would cause him to see a doctor,” says Isaacs.
Enter PSA. Now men were being diagnosed in their 40s and 50s, and they wanted to come to Johns Hopkins to have Patrick Walsh take their prostates out because he was the only guy in the world that could do it without leaving them impotent and incontinent. Over a five-year period, prostatectomy went from a surgery rarely done to the most common surgery performed at Johns Hopkins. Walsh was asking his patients about family history, and some of them were telling him that their grandfather, father, brothers all had prostate cancer. Influenced by the late Barton Childs, a legendary Johns Hopkins pediatrician and geneticist that shaped the understanding of inherited disease, Walsh began cataloging prostate tumors to characterize a hereditary form of the cancer.
Bob Carter, a young medical student working with Isaacs and Bloomberg School of Public Health investigator Terri Beatty, asked Walsh if he could look at his first 600 patients, and using their wives as controls determined that if a man has prostate cancer or one of his brother’s has prostate cancer, the other brothers were at risk. This 1990 finding reignited the search for an inherited form of prostate cancer and the gene or genes behind it. Isaacs was intrigued.
The group put an ad in Parade Magazine seeking volunteers with a family history of prostate cancer. Within two weeks, they had 2,500 men who responded and were eager to help decipher the disease. Public announcements by General Norman Schwarzkopf, Senator Robert Dole, and financier Michael Milken about their own diagnoses with prostate cancer all conspired to bring attention and interest to the disease. “Research ticked up, but when the smoke cleared 15 years later, we still didn’t have anything particularly useful,” says Isaacs. “A few genes turned up, but their effects turned out to be small.”
Then, in the mid 2000s a new idea was being explored. Adopting the premise that humans are really all one big happy family extending from a small number of original founders, there should be a limited number of founder chromosomes in the population. Bert Vogelstein’s research revealed founder gene mutations associated with cancer in the Ashkenazi population. “The same thing occurs with everyone on the planet. It’s just harder to find,” says Isaacs. The HapMap Project, an international endeavor to describe the common patterns of human genetic variations, was beginning and their work had the potential to shed new light on the problem. It did. “In six years, we went from having no genetic risk factors for prostate cancer to as many as 70,” says Isaacs. “For the first time we could determine increased genetic risk, but the effect was small, increasing risk by 10 to 20 percent, so there really was no clinical implication,” says Isaacs.
At Johns Hopkins, with the mission of using science to improve patient care, the findings were disappointing for an additional reason. “It didn’t tell us what type of prostate cancer men were at risk for or if it should be treated,” says Isaacs. “Again, we were running into the same wall.”
“Here’s the dilemma. We know statistically that most prostate cancers are not going to progress to a point where quality of life is affected. Most men will be fine, so we say we are overdiagnosing and overtreating men,” says Isaacs. “But, prostate cancer is the second leading cause of cancer death in men. We’re not overdiagnosing and overtreating these men. To the contrary, I’d say these men are underdiagnosed and undertreated.”
So, in the United States, we have erred toward caution, Isaacs says, because we have not yet been able to unearth the genetic factors that will definitively separate the “good” cancers from the “bad.” In some countries in Europe, the opposite approach is taken and prostate cancer is rarely treated because of the financial burden it would place on its socialized medical system.
“Prostate cancer is tailor-made for personalized medicine, but we need to figure out what predicts aggressive disease,” says Isaacs.
In the meantime, Isaacs heads an international consortium for prostate cancer genetics funded by the National Cancer Institute. Investigators at the University of Michigan, one of the participant groups, were getting a reproducible hits in their researched that pointed them to a region on chromosome 17. An examination of this region in the prostate cancer families collected at Hopkins revealed the same but weaker signal. Some of the most interesting genes in this region were members of the HOX gene family. The earliest information on these genes evolved from fruit fly studies. Isaacs recalls a prominent journal that had displayed a photo of a fruit fly on its cover. The fly had legs coming out of its head where its antennae should be due to a HOX mutation. “The legs were perfectly normal, except they were growing in the wrong place,” says Isaacs. Kimmel Cancer Center breast cancer researcher and Barbara Rubenstein Professor of Oncology Saraswati Sukumar was an expert on HOX proteins and had associated them with breast cancer development and resistance to chemotherapy. “We knew from previous work that specific HOX genes were very important in normal prostate development in mice. What if it was somehow linked to the growth of prostate cells in humans,” he wondered. Isaacs was interested in a particular gene in the HOX family, HOXB13. In mice, this gene is turned on just at the time the prostate is developing.
Working with the University of Michigan group, Isaacs focused his research on families with alterations on chromosome 17. One of these families had nine members with prostate cancer, and he had DNA from seven of them. The University of Michigan team had three families where all of the members with prostate cancer had the same HOXB13 mutation. Isaacs had to make sure it wasn’t simply a result of the mutation being common in the population, so he started genotyping everyone he could find, regardless of family history, and including men without prostate cancer. He looked at 5,000 samples and found the mutation was extremely rare in the general population, but in the men who had it, it translated to a ten times greater risk of developing prostate cancer. Finally, they also had the significant link to early onset that Barton Childs had pointed to so many years earlier. The mutation was most prevalent among men diagnosed early, under age 55, and many of them had a father or brother who had prostate cancer. Now he had met both of Child’s requirements: early onset of disease and family history; and he had zeroed in on the cause. The mutation was rare in men diagnosed over age 65 with no family history.
It was a textbook case. On one hand, Isaacs was incredibly excited, on the other, he was not finding the indisputable link to aggressive disease he had hoped for, or, for that matter, one that conclusively pointed to an indolent form of the disease. “Right now, it doesn’t help us with that critical question of who to treat and who not to treat, but we feel like we’re on the right track,” says Isaacs.
The mutation was most prevalent in families of European descent. Isaacs found a different HOXB13 mutation in men of African descent, and another team of investigators found yet another mutation in Han Chinese men. “It appears there are different founder mutations for different ethnicities,” says Isaacs. It could be useful for families where a member had an aggressive prostate cancer associated with the mutation. “We could potentially test the other men in the family to see if they have mutation so that those who carried it it could be monitored more closely and at an earlier time,” says Isaacs.
He continues to delve deeper into the causes of prostate cancer in African-American men where incidence and death rates are double those of white men. “Treatment is effective, and so we have to figure out how to get to these men when it will work,” says Isaacs. There are some men, he suspects who could benefit from much earlier PSA screening, perhaps starting as young as 25 or 30. Prostate cancer clinician-scientist Michael Carducci agrees. “Research finds that it is the 50-year-old guy who is more likely now to present with metastatic disease than the guy who is 65 or 75,” says Carducci. “Maybe there should be an early check to find these guys. We’re trying to figure that out, so together, our research group is evaluating limited but early screening for men at highest risk.”
In the end, Isaacs says, “It’s a mixed bag. I’m very excited about this discovery, but I also realize that this is a tough cancer to figure out, and there is still much work to be done. The good news, Isaacs says, is that at Johns Hopkins, the experts have known this, so we’re ahead of the curve. The prognostic question—which cancers will progress and kill and which ones will not—is the single most important question in prostate cancer.”
Andy Kramer’s Vision
Andy Kramer was a patient of prostate cancer clinician Mario Eisenberger’s. For 12 years, Eisenberger was able to control Kramer’s prostate cancer with standard hormone therapies, and when they no longer worked, a number of experimental drugs. Throughout his treatment, Mr. Kramer was able to spend quality time with his family and remained active professionally as an internationally renowned labor attorney. “Andy was singularly able to focus on the positive aspects of life throughout his treatment at Johns Hopkins and expressed his gratefulness at being able to survive his aggressive tumor for more than a decade,” says Eisenberger, the R. Dale Hughes Professor of Oncology. He talked of “returning the favor” by creating fund to support and accelerate the discovery and implementation of effective new treatments for prostate cancer. Mr. Kramer died last year, but Jones Day, the law firm for which he was a partner and worked for nearly three decades, is making his vision a reality. The Washington-based law firm made a $1.5 million dollar endowment to fund Kimmel Cancer Center prostate cancer research.
The last few years have seen unprecedented strides in drug discovery for prostate cancer. Six new drugs have been approved, and Eisenberger is working with Michael Carducci, Sam Denmeade, and Emmanuel Antonarakis, and others to determine how to best integrate them into clinical practice. “We have to figure out who should get which drug or combination of drugs,” says Carducci.
Carducci says the drug discovery pipeline at the Kimmel Cancer Center has played a key role in advancing the treatment of prostate cancer. Drugs like Tasquinimod, an interesting new agent that appears to work both through the immune system and by cutting off the blood and nourishment that tumors need to grow and spread, are finding much success. Carducci and team have been involved with the laboratory development of the drug, and he heads the international team that is conducting the continuing studies required for FDA approval.
Eisenberger believes the generous gift from Jones Day will strengthen these advances by supporting work to identify molecular signatures that allow for personalized therapies and improve quality of life for men with prostate cancer. It will fund several projects, including a tissue bank, laboratory and clinical collaborations aimed at rapidly identifying new targeted immune and drug therapies, and the identification of new biomarkers for monitoring disease progression and treatment effectiveness. Eisenberger and team are exploring various novel approaches, including natural compounds that could prevent or keep prostate cancer in check, targeted hormone therapies, and immune approaches that sensitize prostate cancer cells to drug treatment.
The gift will also help support the work of laboratory scientists, including Srinivasan Yegnasubramanian who is working to identify biologic markers of response to treatment. “We want to understand why two men with metastatic prostate cancer and similar clinical features and tumor pathology can have drastically different responses to the same therapy,” says Eisenberger. They are studying tumor samples from 60 patients whose cancer spread to the bones and other sites and were then treated with androgen deprivation therapy, a type of therapy that suppresses androgen, a hormone that is known to fuel the growth and spread of prostate cancer. “If we can uncover molecular genetic clues that predict which cancers are predestined to be sensitive to treatment, we may be able to personalize treatments,” he says. “Conversely, we can use genetic biomarkers to identify men who will not respond to hormone therapy and design better treatments for this group.”
“Andy Kramer was an inquisitive and intelligent man,” recalls Eisenberger. “He was eager to learn about treatment advances in prostate cancer and wanted to make a contribution that would improve and prolong the lives of patients with prostate cancer. The Jones Day endowment honors Andy’s commitment and vision.
There is a compelling body of evidence that links inflammation to prostate cancer. It’s not acute inflammation, the kind that occurs briefly when tissue is injured, but chronic inflammation—an ongoing assault and stress to tissue that continues day after day without end. Population studies by Elizabeth Platz and team have found that men with chronic inflammation have a higher risk of developing aggressive forms of prostate cancer. William Nelson led a research team that found that environmental exposures, such as eating charbroiled meat, can cause inflammation inside the prostate gland and potentially influence the early stages of prostate cancer. Now, investigators are comparing normal prostate tissue and prostate cancers to better understand the extent of prostate inflammation and how it influences cancer development and progression. They will also identify the specific types of immune cells that are triggered by an inflamed prostate to improve and develop immune-based treatment approaches.
A Good Reason to Quit; A Good Reason Maintain Healthy Weight
Corinne, the Martin D. Abeloff Cancer Prevention and Control Scholar-in Training, was looking for straightforward lifestyle remedies that could decrease the risk of recurrence in men who had surgery for prostate cancer and whose cancer had not spread. She found that men who were smoking one year after surgery doubled their risk of their prostate cancer coming back. Former smokers and nonsmokers had no increased risk. Joshu says that smoking causes cell damage that triggers the growth of new cells to replace damaged cells. It’s possible that this process sets in motion genetic changes that facilitate the return of the prostate cancer.
Joshu also looked at weight change from five years before surgery to one year after. She found men who gained five or more pounds (10 to 11 pounds on average), between five years before and one year after surgery also doubled their risk of cancer recurrence when compared to men who maintained their weight. It didn’t matter if they were normal weight or overweight to begin with. It was the act of gaining weight that seemed problematic. Joshu is working with her basic science and clinical colleagues to figure out why. “If you’re gaining weight, you are in the process of active growing. Perhaps this growth-promoting environment allows evasive tumor cells to set up shop and cause a cancer recurrence down the road,” she says.
With support from the Abeloff Scholars program, the Maryland Cigarette Restitution Fund, and the Prostate Cancer Foundation, Joshu is investigating precisely how these lifestyle factors contribute to prostate cancer progression.
“On a day-to-day basis, our bodies are trying to fight the outside world,” explains prostate cancer expert Michael Carducci. “Internally things are getting turned on to combat these exposures. The more you can limit these forces by not smoking and maintaining a healthy weight and diet, the easier you make it on your body.”
Antiangiogenesis: It’s a long word to describe cancer treatments that work by cutting off the blood supply that tumors need for nourishment and growth. Clinician-scientist Hans Hammers is hoping to take what he’s learned from success using antiangiogenesis therapies for kidney cancer to better treat prostate cancer, where antiangiogenesis has not worked so well.
Traditional chemotherapy does not work at all in kidney cancer. The kidney, adept at flushing out toxins, gets rid of anticancer drugs before they can go to work. Antiangiogenesis discoveries totally changed the way kidney cancer is treated, Hammers says, and every antiangiogenesis agent they use targets a single pathway, known as VEGF
VEGF helps tumors develop the blood vessels they need to grow and spread. Targeting the pathway with treatment tears down vessels that have already formed, and blocks the development of new ones, and shrinks kidney cancers by half. Hammers believed he should be able to achieve the same response in prostate cancer, but theses cancers were inexplicably resistant to the treatment. Animal studies funded by the Maryland Cigarette Restitution Fund allowed him to trace the resistance to very primitive cells that march away from the tumor and begin growing elsewhere in the body, in a process known as EMT. Hammers examined stable, treatment-responsive kidney and prostate cancers. When he altered tumor cells to initiate EMT, the cells became resistant to antiangiogenesis treatment. “What we see in a high Gleason grade, which represents the most aggressive prostate cancer, is essentially EMT occurring,” says Hammers. “Gleason rating is a depiction of EMT.” Hammers is working to decipher the specific cellular mechanisms involved in EMT and identify targets for treatment. He believes targeting EMT could make antiangiogenesis treatments effective against prostate cancer and potentially many other cancers as well.
Death Carrot is a Molecular Grenade for Cancer
Thapsia garganica is a 3-foot tall weed that grows wild and abundantly in the Mediterranean. It is abundant because of its not so favorable reputation. Ancient Greek writings refer to it as the “plant of death” and Arabs named the weed the “death carrot” when they witnessed that camels who ate it quickly died. In the late 1970s, a Danish chemist isolated its toxin, calling it thapsigargin. Kimmel Cancer Center researcher John Isaacs began collaborating with the chemist in hopes of harnessing its killing power to treat prostate cancer. Thapsigargin, Isaacs found, indeed killed prostate cancer cells, but unfortunately it also killed heart cells and brain cells. “We gave it to mice, and they were dead within minutes,” he recalls.
Undeterred, Isaacs, one of the world’s leading experts in apoptosis (cell death through the natural cell life cycle) began putting his extensive understanding of how cells die to formulate a version of the toxin that would be lethal only to cancer cells. He recruited the help of fellow prostate cancer researcher and clinician Samuel Denmeade, and for more than a decade the two worked to chemically modify the toxic weed to specifically and safely target prostate cancer cells.
Thapsigargin kills by making cells think they need calcium when they do not, Denmeade explains. As a result, cells are flooded with unending amounts of calcium and die. The trick was to re-engineer the lethal toxin to deliver its killing power only to prostate cancer cells. For this, Denmeade and Isaacs created a compound that remains inactive until it comes in contact with cells that secrete a protein known as the prostate-specific membrane antigen (PSMA). This modification meant that the toxin would now selectively target the prostate and, unlike its predecessor, would leave heart cells, brain cells, and other normal cells alone. In laboratory studies that used human prostate tumors transplanted into mice, their engineered drug looked promising. A three-day course of the drug shrunk tumors in half and outperformed other standard cancer drugs.
With critical funding from David H. Koch, investigators Isaacs and Denmeade worked with Michael Carducci, Angelo De Marzo, and other Kimmel Cancer Center prostate cancer experts and colleagues to take their discovery to patients. Denmeade likened their chemically modified form of thapsigargin to a medicinal grenade. When the drug comes in contact with PSMA-secreting cells, it pulls the pin killing all prostate cancer cells in its vicinity.
Delivered by injection, the drug, now called G202, works by blocking the function of an essential protein that keeps calcium levels in cells at the correct level. In essence, it causes tumor cells to overdose on calcium and die. It also shuts down the blood vessels that feed prostate tumors.
Contrary to its namesake, the research team says PSMA is not only found in the prostate but also in blood vessels in brain, kidney, bladder, breast, colon, and lung cancers, so it has the potential to work against many different types of cancer. Laboratory findings in breast, kidney, and bladder cancers reported by the team in Science Translational Medicine support this theory.
To date, the Johns Hopkins team, and collaborators from the University of Wisconsin and the University of Texas-San Antonio, has treated 29 patients with advanced cancer in a clinical trial assessing the safety of the drug. New trials will evaluate the safety and the effectiveness of G202 in patients with prostate and liver cancers.
“What we like best about this drug,” says Isaacs, “is that it causes the cancer cell itself to bring about its own demise.”
Editor’s Note: This research was funded by the Department of Defense Prostate Cancer Research Program, the Prostate Cancer Foundation, David Koch, the Danish Cancer Society, the Danish Research Council, the Aarhus University Research Foundation, and the National Institute of Health’s National Cancer Institute SPORE(CA058236 and CA006973)
Theranostics and More
In a new approach dubbed “theranostics” because it combines the diagnostic properties of molecular imaging with cancer therapy, a multidisciplinary team of experts, including Radiation Oncology Director Ted DeWeese, and cancer imaging experts Martin Pomper and Zaver Bhujwalla, developed an idea that takes advantage of important molecular components of cancer and allows researchers and clinicians to see inside the cancer cell and view them as they are being treated. The team is developing ultra-tiny structures called nanoparticles filled with an anticancer drug that also sensitizes cancer cells to radiation and a radiopharmaceutical or cell-imaging agent. The nanoparticle is targeted to PMSA, a biomarker for prostate cancer, so that it zeroes in on and delivers its anticancer payload specifically to prostate tumors. The particle is labeled with a radioactive isotope, which can be imaged or used to treat cancer. It is given intravenously so that it can attack cells growing anywhere in the body.
In other work, DeWeese and prostate cancer researcher Shawn Lupold became the first to show that targeted small inhibitory RNA (siRNA) could be used for prostate cancer therapy. This breakthrough research focuses on siRNA, small molecules that have the ability to interfere with the expression of genes. DeWeese and Lupold used aptamers, a guidance system of sorts, to get the RNA molecule to its target inside of cancer cells where it shuts down cancer cells’ ability to repair the injury that radiation inflicts and, as a result, they die. The aptamers, which allow the repair-blocking inhibitory molecules to be targeted specifically to cancer cells, are unique to Johns Hopkins and considered the gold standard. Moreover, it is a platform technology that can be used not only for prostate cancer but any cancer type, simply by changing the aptamer.
Yet another nanotech approach DeWeese is exploring for prostate cancer treatment uses alpha particles, a type of radium isotope, that are naturally targeted to the bone where prostate cancer most often spreads. It captures the killing power of decaying radium, but in this form it has a short life of about ten days and only causes damage in the limited path it travels in the body. Radium has a chemical relationship to calcium, and so acts in the human body like calcium, naturally traveling to the bone. Investigators are studying a combined nanoparticle/alpha particle/radiation treatment. The nanoparticle, loaded with its radiation-sensitizing anticancer drug, is given simultaneously with the bone-metastasis-targeting alpha particle to exquisitely and precisely attack prostate cancer and its spread.
A first-of-its-kind prostate cancer combined therapy will make surgery an option for more men. Clinical studies, led by Charles Drake, a cancer immunology expert and co-director of the Prostate Cancer Multidisciplinary Clinic, will include a prostate cancer vaccine. GVAX, the immune system-boosting vaccine developed more than a decade ago by Kimmel Cancer Center investigators will be given after surgery in combination with the anticancer drug cyclophosphamide and a new prostate hormone therapy drug called MDV 3100. The treatment is for men who are diagnosed with high-grade prostate cancers that are likely to recur. In the past, these men were not candidates for surgery because of the likelihood that microscopic tumor cells, invisible to surgeons, had already broken away from the tumor and destined the cancer to return. Drake, who is collaborating with medical oncologist Emmanuel Antonarakis and urologists Alan Partin and Edward Schaeffer, is excited to have a potentially curative treatment to offer these men. They hope to find out what immune cells are already present at the time of prostatectomy and figure what army of immune cells they need to cause an attack against prostate cancer cells. They believe the vaccine/drug treatment could work to mop up the microscopic cancer cells missed at surgery.
Rehab after Prostate Cancer Treatment
The two big quality-of-life issues that men experience following prostate cancer surgery are urinary incontinence and erectile dysfunction. Urologic oncologist and prostate cancer surgeon Trinity Bivalacqua and nurse practitioner Kristen Burns are helping men through a new rehabilitation/survivorship clinic. Bivalacqua is skilled at both open and robotic prostatectomy that gives him both the unique perspective and the experience to help men recover from prostate cancer surgery. “If we’re going to work to cure everyone, we want be sure we also try to eliminate the adverse quality of life issues,” says Brady Urological Institute Director Alan Partin. Any prostate cancer patient who receives surgery or radiation therapy is a candidate for rehabilitation. Some men who experience problems may only need counseling while others could require a more invasive intervention to alleviate symptoms, but the team says they want patients to know that this service is part of the care we offer them. Initially, they will focus on Johns Hopkins prostate cancer patients only, but eventually they hope to expand the program to help patients across the country.
Prostate Cancer Legend
Urologist Patrick Walsh is perhaps the most famous and revered figure in the world of prostate cancer. For 30 years he served as director of the internationally renowned Brady Urological Institute at Johns Hopkins. He transformed prostate surgery by developing an anatomical approach to remove the cancerous prostate without causing life-changing side effects, taught the procedure to hundreds of urologists-in-training; and gathered information from patients that propelled prostate cancer research forward. In June 2011, he performed the procedure he pioneered for the last time. It was his 4,569th prostatectomy. He remains a familiar figure at “The Brady,” and through the Patrick C. Walsh Prostate Cancer Research Fund continues to advance the understanding and care of prostate cancer.
Titans of Prostate Cancer
Following the Johns Hopkins model, leaders in the Prostate Cancer Program never disconnected discovery from the patient. Keeping the two aligned, its investigators and clinicians have made more advances than any other place in the world.
Johns Hopkins Prostate Cancer Milestones:
- Performed the first prostatectomy in 1904 and later pioneered the anatomical nerve- sparing approach
- Developed some of the first therapeutic approaches and clinical models for prostate cancer, including the earliest form of brachytherapy, and were the first to culture human prostate cancer cells to study therapeutic targets
- Developed the first animal models to characterize the properties and types of prostate cancer; the models were sent all over the world to further research
- Discovered the first human gene mutation in prostate cancer
- Deciphered the mechanisms for prostate cancer metastasis
- Provided the first description of the basic cellular and molecular properties of prostate cancer
- Were the first to describe the importance of stem cells in prostate cancer
- Deciphered how prostate cancer growth is regulated
- Defined hereditary prostate cancer
- Performed the first DNA methylation studies in prostate cancer
- Developed an animal model of prostate inflammation and defined PIA (proliferative inflammatory atrophy), a new model for what causes prostate cancer
- Pioneered quantitative pathology to refine staging and prognostic markers
- Developed the Partin Tables, Pound Tables and Han Tables to predict localized cancers, relapse time, metastasis and survival
- Used PSA velocity to define lethal types of prostate cancer
- Developed and clinically tested the first prostate-specific adenovirus to treat recurrent and metastatic prostate cancer
- Performed the first protein analysis of normal prostate and prostate cancer
- Developed new biomarker tests for prostate cancer
- Led the work in robotics for prostate cancer treatment
- Pioneered tumor immunology studies and developed GVAX, the first therapeutic vaccine for prostate cancer
- Identified new drug targets, PSA-activated prodrugs, and other agent