January 01, 2017
We’re beginning our second decade! Since 2005, the Patrick C. Walsh Prostate Cancer Research Fund has awarded millions of dollars to Johns Hopkins scientists in every discipline with good ideas worth pursuing that can help us understand more about prostate cancer — and help us save lives with better ways to treat and prevent it. Applications are reviewed by a Scientific Advisory
Board composed of noted Hopkins scientists and lay members. These awards would not be possible without the tremendous and amazing generosity of our patients and friends. Here’s some of the exciting work this year’s award winners are doing, which wouldn’t be possible without your help.
Is This Cancer Safe for Active Surveillance?
The ideal candidate for active surveillance is “a man with low-risk disease whose likelihood of progression is low without treatment,” says Misop Han, M.D., the David Hall McConnell Professor in Urology. Still, in case the cancer is more aggressive than it seems, “we follow these men closely, and we recommend treatment if the disease progresses.” Despite its “demonstrated long-term overall safety and effectiveness,” there remains a “what-if” quality to active surveillance. “Active surveillance is not as widely used as it could be, because we have limited ability to accurately assess risk and detect cancer progression. There is a critical need to find accurate biomarkers that can discriminate indolent from potentially lethal prostate cancer.”
One of the most promising biomarkers is one that actually vanishes in aggressive prostate cancer: a tumor suppressor gene called PTEN. From studies led by Hopkins pathologists looking at biopsy tissue and removed prostate specimens after radical prostatectomy, we know that “PTEN is the most commonly inactivated tumor suppressor in prostate cancer,” Han notes. “This PTEN deletion is associated with aggressive clinico-pathologic features and worse prognosis.” Another common genetic change in prostate cancer is rearrangement of a gene called ERG. Together, these two findings make a powerful case for aggressive cancer — the kind of cancer that should not be treated with active surveillance. With pathologist Tamara Lotan, M.D., and support from the Patrick C. Walsh Prostate Cancer Research Fund, Han proposes “to improve the risk stratification of patients in active surveillance by validating PTEN loss/ERG rearrangement as a biomarker to stratify risk, and make sure that men on active surveillance are at very low risk.”
Changing the Metabolism of Prostate Cancer
Some of the things that feed cancer are the same old things that feed us: fat, sugar, and protein.
Some of the things that feed cancer are the same old things that feed us: fat, sugar, and protein. Many cancers are glucose-dependent; sugar cranks up the metabolism and helps the cancer grow. An enzyme that makes RNA, called RNA polymerase, or Pol I, also helps feed cancer by driving up its protein production. Pol I is driven by the same factors that drive cancer, and by the loss of genes that are supposed to suppress cancer. In exciting work, cancer molecular biologist Marikki Laiho, M.D., Ph.D., and colleagues have shown in mice that targeting the Pol I enzyme can slow the rate of growth in prostate cancer.
So that’s sugar and protein. What about fat? With support from the Patrick C. Walsh Prostate Cancer Research Fund, Laiho, with Nathaniel Brennen, Ph.D., Brian Simons, D.V.M., Ph.D., and Samuel Denmeade, M.D., are going after that, too. “Remarkably, prostate cholesterol content and synthesis equals that of the liver,” says Laiho. “In this project we will test a linkage between Pol I and the metabolism of lipids,” cholesterol and fat, “and implement combined therapies for synergistic targeting of prostate cancer cells.”
They will be looking for what Laiho calls the “crosstalk” between prostate cancer and the stroma, the tissue in between the cells. They hope that by blocking Pol I and blocking fat metabolism, as well, the dual-pronged effort will be more powerful than either approach by itself. “These studies outline a conceptually new approach that exploits the metabolic dependencies of prostate cancer, and may slow down cancer growth, or delay it altogether.”
Is Active Surveillance Right For You? What Do Your Genes Say?
In recent research, William Isaacs, Ph.D., and colleagues have shown that some genes nobody expected to be involved with prostate cancer — such as the hereditary breast cancer genes BRCA1 and 2 — may in fact, be lethal. These are faulty “mismatch repair” genes, and they can be inherited from your mother and father, and by your sons and daughters. These genes may be the reason why some men who otherwise appear to be perfect candidates for active surveillance go on to develop high-grade cancer.
These faulty genes may be the reason why some men who otherwise appear to be perfect candidates for active surveillance go on to develop high-grade cancer.
“Most men with prostate cancer have small, almost normal appearing cancers which are confined to the prostate,” says Isaacs. “Most of these cancers are destined to remain non-life threatening even without treatment,” and for these men, active surveillance is a safe alternative to surgery or radiation therapy. However, “some men suspected of having only low-risk disease will later be found to have high-grade cancers. These men may even lose their curability window because they delay treatment.” Is there any way to identify these men? Isaacs believes these DNA repair genes — genes that are known, and that can be identified in a simple blood test — may be the key. “Recently, we found that inherited mutations in DNA repair genes can significantly increase a man’s risk of developing lethal prostate cancer.” With urologist H. Ballentine Carter, M.D., and support from the Patrick C. Walsh Prostate Cancer Research Fund, Isaacs will look at the DNA of men who appear to be excellent candidates for active surveillance, and see if they carry any of these faulty genes. “We believe this information can be developed into a powerful tool to help determine which men can safely undergo active surveillance, and which men need to have their cancer treated immediately.”
Changing the Genes in Prostate Cancer
Just as our currency is the dollar, the body’s currency is protein. Every cell we have does whatever it does using proteins. The DNA, our genetic code, contains the instructions for how to print up more currency, or make a protein. Step one of protein-making is transcription: the cell makes a copy, or a transcript, of the DNA. This copy is called RNA. Then, the RNA gets converted, or translated, into a chain of amino acids, and voilà — a protein is born. Thus, RNA translates genes into working proteins. Back to our dollar image: just as the government embeds special images into paper money so it can’t be counterfeited, the body adds something, too. “A key regulatory element, the polyA tail, is added to the end of every protein-coding RNA,” says scientist Shawn Lupold, Ph.D. “This tail consists of hundreds of Adenosine nucleotides and serves to increase RNA stability.” Think of a kite with a long string of flags hanging beneath it; these Adenosine flags are the building blocks of DNA. “PolyA tails can be introduced at different sites within each gene transcript, and the location of the polyA tail affects gene expression. Moreover, its location often differs between normal and cancerous cells.”
Could these genetic kite tails possibly affect the genes of prostate cancer? In work supported by the Patrick C. Walsh Prostate Cancer Research Fund, Lupold and co-investigator Srinivasan Yegnasubramanian, M.D., Ph.D. propose to “apply specialized RNA sequencing techniques to map the altered location of polyA tails in all genes expressed by prostate cancer,” Lupold says. “We hope we will uncover new cancer pathways and biomarkers. Secondly, we propose to modify the machinery that regulates where these polyA tails are located, to study its influence on prostate cancer and aggressiveness.
These results may uncover new therapeutic targets for the management of aggressive prostate cancer.”
Lupold Named Distinguished Professor
Shawn Lupold, Ph.D., has been named the Catherine Iola and J. Smith Michael Distinguished Professor in Urology. This professorship was established by Mr. J. Smith Michael, a former president and board chairman of the First National Bank of Aberdeen and patient of the Brady Institute, and his wife, Catherine Iola Michael. The Chair was originally held by the Brady’s legendary scientist Don Coffey, who is now an Emeritus Professor.
Lupold, associate professor of Urology and Oncology, is Co-Director of the Sidney Kimmel Comprehensive Cancer Center’s Prostate Cancer Program. His research focuses on prostate cancer biology with the goal of exploiting prostate tissue-specificity to develop new diagnostic, prognostic and therapeutic agents.
Better than PSA: Proteomics?
As useful as PSA is, it doesn’t us all we need to know. “Unfortunately, PSA remains an imperfect marker for detecting cancer,” says urologist Michael Johnson, M.D., “and men with a ‘normal’ PSA may still harbor disease. Prostate biopsy only samples about 1 percent of the prostate. As a result, aggressive cancer can be missed.” Although PSA measurements taken over time can document the growth of prostate cancer, there is a more specific tickertape out there: proteomics.
Proteomics involves taking a very complex sample of proteins in the blood, or even in a few cells, and shining a powerful laser at it. The laser energy hits the proteins, smashes them and chucks them — think of extremely tiny Jackson Pollock paint splatters — at a detector. Each protein makes a unique signature, or fingerprint for each of its fragments. These protein splotches also serve as snapshots that mark stages in a disease: For example, in a heart attack, certain proteins made by the heart suddenly appear in the blood. Each snapshot tells a constantly changing story of disease.
Proteomics involves taking a very complex sample of proteins in the blood, or even in a few cells, and shining a powerful laser at it. The laser energy hits the proteins, smashes them and chucks them — think of extremely tiny Jackson Pollock paint splatters – at a detector.
If Johnson can learn to decipher the proteomics of the normal prostate and prostate cancer at its various stages, by measuring all of the proteins in the blood, he may come up with entirely new snapshots for doctors to use. In work supported by the Patrick C. Walsh Prostate Cancer Research Fund, Johnson will be comparing proteomic analyses on the blood of men who have undergone prostatectomy with the blood of men who have no prostate cancer; he will also be analyzing the proteins that show up in slow-growing prostate cancer and aggressive disease.
“My goal is to discover new, highly accurate markers for early diagnosis of disease that could potentially be lethal,” he says.
Developing the Brady Genomics Portal
“The Brady Urological Institute, in conjunction with the Department of Pathology, has an unrivaled biorepository of prostate cancer,” says pathologist Alex Baras, M.D., Ph.D. But this amazing library of prostate cancer samples and data could be even better, he believes. Baras, with pathologist Tamara Lotan, M.D., and urologist Ashley Ross, M.D., Ph.D., plans “to leverage this unique resource to develop the Brady Genomics Portal,” taking the understanding of prostate cancer to a new level with new molecular and genetic characterizations of prostate cancer.
In work funded by the Patrick C. Walsh Prostate Cancer Research Fund, the investigators will examine the Natural History Cohort, “a data set that includes 356 men with intermediate- or high-risk prostate cancer,” Baras explains. The team will augment tissue samples from these tumors, which have had DNA and RNA extracted, with genomic studies characterizing gene mutations and copy number alterations. The team will integrate clinical and pathologic findings with the latest molecular information; their comprehensive results will be made available to Brady researchers and updated regularly. “We hope this will prove to be an invaluable and renewable resource for the Brady for years to come.”
Finding Those “One in a Billion” Cells
“Analyzing these cells presents the potential of a ‘liquid biopsy’ – studying cancer cells without having to extract them during a prostate biopsy.” In prostate cancer, circulating tumor cells (CTCs) are cancer cells that have escaped the prostate and entered the bloodstream. The problem is, these elusive cells are few and far between — proverbial needles in the haystack, says Dan Stoianovici, Ph.D., Director of the Urology Robotics Program.
And yet, finding them would be so helpful: “Analyzing these cells presents the potential of a ‘liquid biopsy’ — studying cancer cells without having to extract them during a prostate biopsy,” Stoianovici says. “It would also open a wide range of possibilities for personalized medicine. However, isolating these rare cells is very difficult due to their extremely small concentrations, as low as one in a billion of blood cells.”
If anyone can figure out how to do this, it’s Stoianovici, a brilliant scientist and Professor of Urology, Mechanical Engineering, Neurosurgery, and Oncology. With support from the Patrick C. Walsh Prostate Cancer Research Fund and with co-investigator Michael Gorin, M.D., he plans to design and build a novel device to isolate these cells from blood samples. It will feature “a controlled magnetic CTC scanning process, and will directly transfer the CTC onto a standard microscope slide, eliminating the current need to discard part of the blood prior to the extraction.”
AR Mutations as a Predictor of Therapeutic Response
If hormonal therapy — blocking testosterone, also called “androgen deprivation therapy” — stops working in a man with metastatic prostate cancer, the next step is to go after the androgen receptor (AR). If testosterone is the key, then the androgen receptor is the lock it fits; sometimes, disabling the lock gives an extra benefit for these men. There’s a problem, however: “Some men become resistant to AR-targeting drugs,” says scientist Paula Hurley, Ph.D. It may be that these drugs don’t work because the androgen receptor defies the attempt to block it and keeps on functioning, “possibly through amplification or mutation of the AR gene.” In our last issue, Discovery reported on a test for a variant AR gene, called AR-V7, developed by Jun Luo and Emmanuel Antonarakis. For men who have this variant, the drugs enzalutamide and abiraterone do not work well.
If testosterone is the key, then the androgen receptor is the lock it fits; sometimes, disabling the lock gives an extra benefit.
“These types of AR gene alterations are almost exclusively seen in patients treated with therapies blocking androgen-AR activity,” Hurley notes. “However, there is still a lot we don’t understand about these AR mutations. Confounding variables have hindered our ability to determine fully their predictive capability and biologic role. For example, the prevalence of each individual AR mutation remains low. But AR mutations often overlap, making it difficult to determine their individual contribution to resistance.”
We need a better understanding what these different mutations do, and how they interact, says Hurley. With support from the Patrick C. Walsh Prostate Cancer Research Fund, she will explore how these AR mutations affect a man’s response to anti-cancer drugs, with the hope of finding ways around these roadblocks — so the medicines can work better in the men who need them most.
Infection and Prostate Cancer
What bacteria are supposed to be in the urine?
There are lot of “microbiomes” around your body. These are little microclimates, with their own unique residents. For example, the bacteria that thrive in your gut are not the same bacteria that live on your hands. “Trillions of bacteria live in and on our bodies and they are ‘good;’ they help maintain our health, not hinder it,” says pathologist Karen Sfanos, Ph.D. “But, the healthy microbiome can be altered by things like diet or exposures to toxins and carcinogens.” In the prostate, she continues, “an altered microbiome can lead to infections and chronic inflammation, a condition that is linked to many types of disease, including cancer. Scientists have discovered recently that urine, long thought to be sterile, in fact is not. There are bacteria in there all the time, not just in the presence of an infection.
“This recent discovery made us wonder whether infections that may cause chronic inflammation in the prostate could be caused by alterations to the normal urinary microbiome.” The first step in answering this question is to figure out what’s normal. What bacteria are supposed to be in the urine? “We have begun to profile the urinary microbiome in men with prostate cancer and in men without prostate cancer,” says Sfanos. In work supported by the Patrick C. Walsh Prostate Cancer Research Fund, with co-investigator Angelo De Marzo, M.D., Ph.D., Sfanos will “conduct the first study that will visualize and localize bacterial species of interest. What we ultimately hope to achieve is to determine what a high-risk urinary microbiome is in terms of developing prostate cancer. If men can be tested for this high-risk urinary microbiome, it may be that they could be treated with specific antibiotics or anti-inflammatory drugs as a means to prevent prostate cancer development or progression.”
Restoring the Immune System’s Memory
In effect, prostate cancer throws dust in the eyes of T-cells, specialized white blood cells whose job is to kill cells it recognizes as the enemy. Then it gives them a case of amnesia.
The immune system is extremely powerful — which is why one of prostate cancer’s first strategic attacks is to disable it. In effect, prostate cancer throws dust in the eyes of T-cells, specialized white blood cells whose job is to kill cells it recognizes as the enemy. Then it gives them a case of amnesia. But the amnesia may be reversible, says W. Nathaniel Brennen, Ph.D., assistant professor of oncologist. It turns out that the immune system has its own version of a backup hard drive — “special T-cells that live in the bone marrow known as memory T-cells.” With support from the Patrick C. Walsh Prostate Cancer Research Fund, Brennen and oncologist Ivan Borrello, M.D., will go after these memory cells and use them to remind the T-cells involved in fighting prostate cancer that there are enemies close at hand that need to be destroyed.
“The good news is that the body stores memory of what the prostate cancer looks like on these special T-cells, which normally are maintained in a resting state,” says Brennen. In this investigation, he will “isolate these memory T-cells from the bone marrow, grow them outside the body, activate them using special techniques, and characterize their anti-tumor immune responses.” Though this has never been shown to work against prostate cancer, “extremely promising” results in other tumor types have been observed by Borrello. “The ultimate goal is to re-infuse these tumor-specific memory T-cells back into the patient to hunt and kill cancer cells spread throughout the body,” Brennen adds, “essentially, generating a personalized cancer immunotherapy platform.”