Wistar scientists develop novel immunotherapy technology for prostate cancer

A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific protein. This is the first application of the new technology, called DNA-encoded monoclonal antibody (DMAb), for cancer immunotherapy. The study was published online in Cancer Immunology, Immunotherapy.

Prostate cancer is the second most common cancer in men worldwide. Traditional treatments are invasive and can impair the quality of life of patients, underscoring the need for alternative therapeutic strategies, including immunotherapy. One of the immunotherapeutic approaches that has been explored thus far relies on the use of monoclonal antibodies that specifically target a protein present on the surface of prostate cancer cells called prostate specific membrane antigen (PSMA) to elicit an anti-tumor immune response and control the cancer. Although promising, this strategy is limited by the production cost required to make these therapeutic antibodies. Additionally, multiple infusions are often required to achieve efficacy.

Wistar researchers devised a novel DNA-based approach in which an engineered DNA plasmid is constructed and used to deliver the instructions to make the desired anti-PSMA antibody so that the therapy can be generated in the patient’s body in a sustained manner. This research has important implications for the use of DNA-encoded monoclonal antibody technology as a platform for delivering the next generation of immunotherapies for cancer and many human diseases.

“This is an important demonstration of the possibilities opened up for immunotherapy by DMAb technology to direct in vivo production of antibodies of major relevance to human cancer,” said David B. Weiner, Ph.D., executive vice president of The Wistar Institute, director of The Wistar Institute Vaccine & Immunotherapy Center, W.W. Smith Charitable Trust Professor in Cancer Research, and senior author of the study. “There is a great need for such new approaches for prostate disease as well as many other cancers. As recent data suggest, PSMA is an important cancer antigen expressed on many human prostate, bladder, renal as well as ovarian cancers, so additional study of the possible benefits of this therapy are important.”

The new technology was tested in mice for the ability to generate antibodies in their blood stream that would target human PSMA as well as target PSMA-positive tumors. Results showed that antibodies were able to bind to the cancer cells and recruited specific immune cells called natural killer cells, resulting in shrinkage of the tumor, significantly improving survival.

“Our data provide proof of concept that DMAb engineered DNA plasmids can be successfully used to target important cancers,” said Kar Muthumani, M.Sc., Ph.D., assistant professor in the Translational Tumor Immunology Program at Wistar, member of the Vaccine & Immunotherapy Center and lead author of the study. “The unique features of our synthetic DNA-based system make it a promising novel approach for cancer therapy, alone or in combination with other treatments.”

Prostate Cancer Cells Become ‘Shapeshifters’ to Spread to Distant Organs

Johns Hopkins Kimmel Cancer Center scientists report they have discovered a biochemical process that gives prostate cancer cells the almost unnatural ability to change their shape, squeeze into other organs and take root in other parts of the body. The scientists say their cell culture and mouse studies of the process, which involves a cancer-related protein called AIM1, suggest potential ways to intercept or reverse the ability of cancers to metastasize, or spread.

Results of the research are described in the July 26 issue of Nature Communications.

For the study, the Johns Hopkins scientists mined publically available research data on the genetics and chemistry of hundreds of primary and metastatic cancers included in five studies of men with prostate cancer. They found that a gene called AIM1 (aka “absent in melanoma 1”), which makes proteins also called AIM1, is deleted in approximately 20 – 30 percent of prostate cancers confined to the gland and about 40 percent of metastatic prostate cancers. In addition, the scientists found, on average, two- to fourfold less amounts of AIM1 expression in metastatic prostate cancers compared with normal prostate cells or those from men with prostate cancers confined to the prostate, suggesting that reduction of AIM1 proteins is somehow linked to tumor spread.

Aside from its link to the development of melanoma, a deadly skin cancer, scientists knew little about the function of AIM1.

“Our experiments show that loss of AIM1 proteins gives prostate cancer cells the ability to change shape, migrate and invade. These abilities could allow prostate cancer cells to spread to different tissues in an animal and presumably a person,” says Michael Haffner, M.D., Ph.D., a pathology resident and former postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center who is involved in the research. “It’s not the whole story of what is going on in the spread of prostate cancer, but it appears to be a significant part of it in some cases.”

Looking more closely at the AIM1 gene and its protein levels in prostate cancer tissues, the Johns Hopkins scientists found that many times, even when the gene isn’t completely deleted and its protein production is reduced, its location in the prostate cancer cell is highly abnormal compared with normal prostate cells. This occurs even in primary prostate cancer cells, which have invaded the local structures to form invasive cancer within the prostate gland, say the scientists.

The research team used dyes to track the location of AIM1 proteins in human cells grown in the lab and followed where they appear in normal and cancerous prostate tissues. In normal prostate cells, AIM1 was located along the outside border of each cell and paired up with a protein called beta-actin that helps form the cell’s cytoskeleton, or scaffolding. However, in prostate cancer cells, the protein spread away from the outer border of the cells and no longer paired up with beta-actin.

The scientists found this pattern among a set of human prostate tissue samples including 81 normal prostates, 87 localized prostate cancers and 52 prostate cancers that had spread to the lymph nodes.

“It appears that when AIM1 protein levels drop, or when it’s abnormally spread throughout the cell instead of confined to the outer border, the prostate cancer cells’ scaffolding becomes more malleable and capable of invading other tissues,” says Vasan Yegnasubramanian, M.D., Ph.D., associate professor at the Kimmel Cancer Center and a member of the research team. With AIM1, the scaffold, Yegnasubramanian says, keeps normal cells in a rigid, orderly structure. Without AIM1, cells become more malleable, shapeshifting nomads that can migrate to other parts of the body, he says.

To track how these shapeshifting cancer cells move, the Johns Hopkins scientists, with Steven An, Ph.D., an expert in cellular mechanics and an associate professor at the Johns Hopkins Bloomberg School of Public Health, took a close-up look at AIM1-lacking prostate cancer cells, using sophisticated and quantitative single-cell analyses designed to probe the material and physical properties of the living cell and its cytoskeleton.

They found that cells lacking AIM1 remodeled their scaffolding more than twice as much as cells that had normal levels of AIM1, and that they exert three- to fourfold more force on their surroundings than cells with normal levels of the protein. Such cellular properties are reminiscent of cells with high potential to invade and migrate, An notes.

In addition, the scientists found that AIM1-lacking prostate cells were capable of migrating to unoccupied spaces on a culture dish or invading through connective tissue-like materials at rates fourfold higher than cells with normal levels of AIM1.

Next, the scientific team implanted human prostate cancer cells engineered without AIM1 in five mice and found that the cells spread to other tissues at levels 10 to 100 times more than cells with normal levels of AIM1 that were implanted in five similar mice. However, the AIM1-lacking cells were not able to establish full colonies and tumors at those other tissues, suggesting that AIM1 depletion is not the whole story in the spread and growth of metastatic prostate cancer.

“AIM1 may help prostate cancer cells disseminate throughout the body, but something else may be helping them form full-blown metastatic tumors when they get there,” says Yegnasubramanian.

The Johns Hopkins scientists plan to further study what happens to the AIM1 protein to cause its abnormal location in prostate cancers and identify other proteins and genes that work with AIM1 to cause metastasis. Such studies could help scientists find new drug targets aimed at preventing or reversing prostate metastasis.

Estetrol (E4) Shows Promise as a Safe, Effective Drug for Use in Advanced Prostate Cancer

The natural fetal estrogen estetrol, also called E4, is being tested as a new drug that may help treat advanced prostate cancer, according to an ongoing industry-sponsored study from the Netherlands. The final results will be presented in a poster on Saturday, April 1, at ENDO 2017, the annual scientific meeting of the Endocrine Society, in Orlando, Fla.

“E4 for the treatment of prostate cancer would offer a new and affordable option compared to current standard and new therapies. An important advantage of E4 is expected to be the avoidance of the hypoestrogenic side effects that occur with other types of testosterone-suppressing hormone therapy, including hot flushes and sweating, arthralgia, mood, sleep and cognition disturbances, and bone loss and fractures,” said Ellen Dutman, M.Sc., clinical research associate at Pantarhei Oncology BV in Zeist, the Netherlands, the company that is developing the drug.

“Furthermore, E4 treatment may not be as expensive as recently developed new prostate cancer therapies,” Dutman added.

“E4, a steroid produced by the human fetal liver during pregnancy only, is a potential candidate for the treatment of advanced prostate cancer, both as a single entity and for combination treatment with hormone therapy,” she said.

The hormone testosterone stimulates tumor growth and therefore maximal suppression of testosterone levels is the cornerstone of the endocrine treatment of prostate cancer. To test whether oral E4 lowers testosterone levels, Dutman and her colleagues conducted a double-blind, randomized, placebo-controlled study in 45 healthy male volunteers between 40 and 70 years of age at one medical center.

For each group of 15 men, 10 received the E4 and 5 received placebo for 28 days. The 10 men in the first group received one daily dose of 20 mg E4. And after that dose was found to be safe, the 10 men in the second group received 40 mg E4. That dose was found to be safe as well, and a third group of 10 men received a dose of 60 mg E4.

The results of the groups show promise. With 20 mg E4, 40 mg E4, and 60 mg E4 respectively, both total and free testosterone decreased: total testosterone absolute change: -3.74 nmol/L, -11.0 nmol/L, and -13.88 nmol/L respectively; and free testosterone absolute change: -0.059 nmol/L, -0.095 nmol/L, -and – 0.163 nmol/L respectively. Follicle-stimulating hormone (FSH) and estradiol (E2) levels also declined, while luteinizing hormone (LH) levels remained steady and sex hormone-binding globulin (SHBG) levels increased.

All three doses were well tolerated. Body weight and safety parameters did not change but libido decreased and nipple tenderness was reported.

“We expect that in the future, patients with advanced prostate cancer will have the opportunity to choose to be treated with E4, especially in combination with their current therapy,” Dutman said. “The addition of E4 will further improve the efficacy of their current therapy and have a positive impact on the quality of life of the patients.”

Estetrol is also being developed by Pantarhei Oncology for the treatment of advanced breast cancer. Mithra Pharmaceuticals in Belgium is developing E4 for contraception and menopausal hormone therapy in women.

First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

Prostate Cancer Clinical Trial Shows Treating with Precision Radiotherapy Reduces Course of Treatment by 50%

An Ontario-led international clinical trial with 1,206 men with localized prostate cancer shows that compressing radiation treatments into four weeks from eight delivers similar outcomes.

The findings, published online today in the Journal of Clinical Oncology, provide a new standard of care worldwide, which the participating centres have already adopted, says co-principal investigator Charles Catton, radiation oncologist, Princess Margaret Cancer Centre, University Health Network. Dr. Catton is also a Professor, Department of Radiation Oncology, University of Toronto.

“We conducted a randomized clinical trial looking at a way of improving radiation therapy for men with intermediate-risk prostate cancer. Using modern radiation therapy techniques that are very precise, we determined there was no noticeable difference between eight- and four-week treatment regimens in terms of cancer control or side effects of treatment,” says Dr. Catton. The trial participants were followed for six years.

“In fact, for some men, the shorter regimen meant slightly fewer side effects (particularly regarding bowel function) and therefore improved quality of life. The compressed course of treatment is of great benefit to patients and also to the system in terms of being able to treat more patients in less time,” he says. In Canada, 20,000 men are diagnosed with prostate cancer every year; many of whom have intermediate-risk disease that has not spread.

The trial was conducted with co-principal investigator Himu Lukka, radiation oncologist, Juravinski Cancer Centre, and Professor, Department of Oncology, McMaster University, and coordinated by the Ontario Clinical Oncology Group, Hamilton, Ontario. Twenty-seven cancer centres in Canada, Australia and France participated in the study, which began in 2005.

Dr. Catton says the trial further improved patient care by standardizing quality delivery of precision radiation techniques among participating institutions.

The research was funded by the Canadian Institutes for Health Research and The Princess Margaret Cancer Foundation.

Study Finds Single, Escalated Dose of Brachytherapy Radiation May Be a Safe and Effective Treatment for Localized Prostate Cancer

Option for high-dose-rate brachytherapy marries efficacy of implant-based therapy and convenience of a single treatment

Results from a new prospective clinical trial indicate that high-dose-rate (HDR) brachytherapy administered in a single, 19 Gray (Gy) treatment may be a safe and effective alternative to longer courses of HDR treatment for men with localized prostate cancer. The study is available online in the International Journal of Radiation Oncology ● Biology ● Physics, the flagship journal of the American Society for Radiation Oncology (ASTRO).

With brachytherapy, also known as internal radiation therapy (RT), implants are surgically inserted in or near cancerous tissue to deliver a curative radiation dose directly to the tumor while limiting exposure for surrounding healthy tissue. Reducing this exposure is of particular concern for treating tumors in the prostate, which is surrounded by multiple critical structures. In contrast to low-dose-rate (LDR) brachytherapy, where radioactive seed implants are placed permanently in the body and gradually deposit low levels of radiation over a period of months, HDR treatments deposit the dose in one treatment, after which the radioactive implant is removed from the patient.

Typically, HDR brachytherapy is administered in four to as many as nine treatment sessions, which generally requires multiple invasive procedures to insert the implants. While the number of sessions can be streamlined by increasing the dose given in each session, data on the safety and tolerability of highly escalated brachytherapy doses are still relatively new and therefore limited. In this study, researchers found that patients who received a single fraction of 19 Gy HDR brachytherapy experienced similar clinical outcomes as with LDR brachytherapy, but with the convenience of a single visit.

“It is becoming apparent that patients may be treated definitively for their prostate cancer in as little as a single day with a minimally invasive outpatient procedure,” said lead study author Daniel J. Krauss, MD, a radiation oncologist at Oakland University’s William Beaumont School of Medicine in Royal Oak, Michigan. “We found that patients generally can resume normal activities the following day with typical side effects.”

The study, which appeared in the Red Journal’s January 2017 issue, presented the results of a nonrandomized, prospective clinical trial of 58 patients with low- or intermediate-risk (non-metastatic) prostate cancer, with a median follow-up period of 2.9 years. All patients received a single, 19 Gy fraction of HDR brachytherapy. The median patient age was 63 years (range 43-73), and 91 percent of the patients presented with stage T1 disease.

At an average of nearly three years following treatment, cancer control rates were favorable and the toxicity profile was highly favorable. Three patients experienced recurrence or progression, yielding an estimated three-year cumulative biochemical control rate of 93 percent. Within the six months following HDR therapy, seven patients (12.1%) experienced grade 2 urinary side effects, most commonly frequency/urgency (6.9%). No patients experienced short-term grade 3+ urinary toxicity or grade 2+ gastrointestinal (GI) toxicity. Rates were similarly modest for long-term side effects. Six patients (10.3%) experienced chronic grade 2 urinary toxicity and one patient (1.7%) experienced grade 3 chronic GI toxicity that subsequently resolved. No patients experienced long-term grade 3+ urinary toxicity or grade 4 GI toxicity.

“This study illustrates that a potentially curative dose of radiation may be delivered safely to the prostate entirely in a single administration,” said Dr. Krauss. “Giving the entire dose in a single treatment theoretically could have had a greater negative impact on the normal tissues in close proximity to the prostate—meaning the bladder, urethra and rectum—but this was not found to be the case. Toxicity rates were extremely low, with essentially no major complications encountered in this initial group of 58 patients.”

While findings highlight the potential tolerability of a single fraction of HDR brachytherapy for localized prostate cancer, the article also emphasizes the need for additional follow-up to compare long-term cancer control rates with conventional treatment approaches, which generally administer larger cumulative doses than the 19 Gy dose used in this trial.

“As the follow-up interval lengthens, 19 Gy dosing in a single fraction may or may not be sufficient to result in cure rates comparable to historical standards. One thing that this study has made clear, however, is that the extremely low toxicity and complication rates leave room to escalate the single fraction dose in subsequent trials,” said Dr. Krauss. “While additional study and longer follow-up are necessary to confirm the optimal dose for single-fraction HDR brachytherapy, we are optimistic that the single-treatment approach can eventually become a standard practice for prostate cancer treatment.”

Patient Prostate Tissue Used to Create Unique Model of Prostate Cancer Biology

For the first time, researchers have been able to grow, in a lab, both normal and primary cancerous prostate cells from a patient, and then implant a million of the cancer cells into a mouse to track how the tumor progresses. The achievement, say researchers at Georgetown University Medical Center who led the research, represents a critical advance in the effort to understand the origin and drivers of this puzzling cancer — the most common in men. The study was published online today in Oncotarget.

“This is a new and much-needed platform for prostate cancer research. By matching normal and cancer cells from a patient, we can now study the differences — what molecules are key to tumor development and growth, and, ultimately, match treatments that might disable this cancer,” says the study’s senior investigator, associate professor of pathology, Xuefeng Liu, MD, a member of the Center for Cell Reprogramming (CCR) at Georgetown University Medical Center.

The breakthrough was possible because the research team used conditional reprogramming (CR), a laboratory technique, developed and described by Liu, Richard Schlegel, MD, PhD, director of the CCR, and their colleagues at Georgetown in 2011, that makes it possible to continuously grow cells in a laboratory indefinitely. The method uses special “feeder” cells and a chemical inhibitor.

“This is the only system that can grow healthy and cancer cells as if they were just extracted from a patient, and expand them — a million new cells can be grown in a week — as long as needed,” he says.

The CR method is being developed for a number of uses, such as living biobanks, personalized and regenerative medicine, and this study, using donated tissue from a 57 year-old man who underwent a radical prostatectomy, demonstrates the first steps needed towards those goals in prostate cancer. Previous studies have proven the utility of CR in a variety of tissue types, including breast, lung, and colon cancer. Liu says many labs around the world are now using this technique, which is called “conditional reprogramming.”

“Prostate cancer is highly heterogenetic — it is different person to person, can be slow growing or rapidly aggressive, or both over time. We really don’t understand the basic biology of prostate cancer and that makes it very difficult to find targeted therapies,” Liu says. “The use of matched patient-derived cells provides a unique model for studies of early prostate cancer.”

In this proof-of-principle study, the researchers showed, using DNA sequencing and karyotyping technologies, that the patient’s unique cell characteristics were maintained in both normal and tumor CR laboratory cells. This means nothing genetically changed due to the CR laboratory technique, the researchers say. Investigators also demonstrated the malignant properties of tumor cells compared to the matched normal cells. These are all hallmarks of tumor development, Liu says.

“Now we can compare what is different between the patient’s normal and cancerous cells, and what changes when the cancer cells are allowed to morph into an advancing tumor,” he says. “We will then use this technique to explore prostate tissues from other cancer patients. Comparisons between what happens within an individual patient’s tissue, and then between patients, will give us priceless information about how we can best diagnose this baffling disease and treat it appropriately.”

Fusion Targeted Prostate Biopsy Proves More Accurate In Diagnosis Of Prostate Cancer

New research confirms that an innovative procedure combining MRI and ultrasound to create a 3D image of the prostate can more accurately locate suspicious areas and help diagnose whether it’s prostate cancer.

Using specialized equipment needed, physicians at UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer Center began using the fusion biopsy procedure about three years ago for its ability to blend live ultrasound images with captured MRI images. The fused image creates the 3D model, and flags anomalies that could be areas of concern. That helps guide urologists to get tissue samples called biopsies to determine whether cancer is present.

UT Southwestern’s early adoption of the cutting-edge technology allowed researchers to report on the superior diagnostic performance of this novel approach compared to traditional methods for diagnosing prostate cancer. Furthermore, these researchers have partnered with colleagues in Brazil to conduct follow up studies that now show the technique consistently improved detection of clinically significant prostate cancer under a wide variety of conditions, even when radiologists were using different equipment and protocols.

“In the past, we diagnosed prostate cancer by random biopsies of the prostate in men with elevated PSA values. With fusion biopsy, we actually find more cancer, we can differentiate between dangerous tumors and less aggressive tumors, and in some cases we perform fewer biopsies,” said Dr. Daniel Costa, Assistant Professor of Radiology and with the Advanced Imaging Research Center (AIRC) at UT Southwestern.

Prostate cancer is the second most common cancer diagnosed in men, after skin cancer. Prostate cancer risk increases with age, with most cases occurring after age 60. According to the National Cancer Institute (NCI), about 180,890 men will be diagnosed this year, and about 14 percent of men will be diagnosed sometime during their lifetime.

The procedure, technically known as MRI-TRUS (magnetic resonance imaging/transrectal ultrasound) fusion targeted prostate biopsy, requires special imaging capabilities and high level training for both radiologists and urologists, so its use has not become widespread.

It works like this: after the urologist identifies a patient at risk for prostate cancer, radiologists use a state-of-the-art MRI examination to identify potentially suspicious areas. If present, the MRI images are then sent to a device that blends those with an ultrasound used by urologists to take a biopsy or sample of the tissue in question to determine whether it has cancer.

“In many instances, MRI-TRUS biopsies performed at UT Southwestern have allowed us to diagnose and treat aggressive prostate cancer in patients whose prior biopsies failed to find the cancer,” said Dr. Ivan Pedrosa, Chief of the Division of Magnetic Resonance Imaging, Associate Professor of Radiology and with the Advanced Imaging Research Center, who holds the Jack Reynolds, M.D. Chair in Radiology.  “Because of its improved precision, patients and physicians are better informed to choose the most appropriate treatment. This helps to avoid surgery in patients with less aggressive disease, and ensures that patients with more aggressive cancers are identified earlier.”

The fusion biopsy technique has been used for nearly 1,000 patients at UT Southwestern.

 “Patients diagnosed at a later stage of disease, or with a more aggressive cancer, have lower rates of survival, making it vital that we quickly identify those who are at the highest risk,” said Dr. Claus Roehrborn, Chair and Professor of Urology, who holds the E. E. Fogelson and Greer Garson Fogelson Distinguished Chair in Urology and the S.T. Harris Family Chair in Medical Science, in Honor of John D. McConnell, M.D. “The close collaboration between radiology and urology, and the ability to exchange the images and information across a common network, enhances the productivity of this collaboration and the outcomes for our patients.”

Prostate cancer forms in tissues of the prostate, a gland in the male reproductive system found below the bladder and in front of the rectum. The prostate surrounds the urethra, the tube through which urine flows. A healthy prostate is about the size of a walnut. If the prostate grows too large, it squeezes the urethra. This may cause difficulty in urinating, burning or pain during urination, more frequent urges to urinate at night, loss of bladder control, and blood in the urine. These symptoms may also have a different cause, so men with prostate symptoms should speak with their physician, Dr. Roehrborn said.

Novel Mri Technique Distinguishes Healthy Prostate Tissue From Cancer Using Zinc

A novel MRI method that detects low levels of zinc ion can help distinguish healthy prostate tissue from cancer, UT Southwestern Medical Center radiologists have determined.

Typical MRIs don’t reliably distinguish between zinc levels in healthy, malignant, and benign hyperplastic prostate tissue, so discovery of the technique could eventually prove useful as a biomarker to track the progression of prostate cancer, according to researchers with the Advanced Imaging Research Center, part of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center.

“This research provides the basis for differentiating healthy prostate from prostate cancer by use of a novel Zn(II) ion sensing molecule and MRI,” said senior author Dr. A. Dean Sherry, Director of the Advanced Imaging Research Center and Professor of Radiology at UT Southwestern.

The findings appear in the Proceedings of the National Academy of Sciences.

“The potential for translating this method to human clinical imaging is very good, and will be useful for diagnostic purposes.  The method may prove useful for monitoring therapies used to treat prostate cancer,” said Dr. Sherry, who is also Professor of Chemistry at UT Dallas, where he holds the Cecil and Ida Green Distinguished Chair in Systems Biology.

The majority of prostate cancers are classified as adenocarcinomas and originate in epithelial cells. The UTSW researchers initially determined that glucose stimulates release of the zinc ions from inside epithelial cells, which they could then track on MRIs. The prostate cancer tissue secreted lower levels of zinc ions, offering an opportunity to distinguish between malignant and healthy tissue. When they tested the technique on mouse models, they were able to successfully detect small malignant lesions as early as 11 weeks, making the non-invasive imaging procedure a potentially useful method for detecting the disease and its progression.

“Prostate cancer often has no early symptoms, so identifying potential new diagnostic methods that might catch the cancer at an earlier stage or allow us to track how it is progressing is an important opportunity,” said co-author Dr. Neil Rofsky, Chairman of Radiology, Director of Translational Research for the Advanced Imaging Research Center, and holder of the Effie and Wofford Cain Distinguished Chair in Diagnostic Imaging.

Prostate cancer is the most common cancer in men in the United States, after skin cancer, and is the second leading cause of death from cancer in men, according to the National Cancer Institute. Prostate cancer occurs more often in African-American men, who are more likely to die from the disease.

Researchers with the Advanced Imaging Research Center are world leaders in developing new MRI tracers, which are non-radioactive, and techniques to reveal the aberrant machinery of cancer, diabetes, obesity, Alzheimer’s disease, schizophrenia, depression, and diseases of the heart, lung, and liver. As part of UT Southwestern’s Peter O’Donnell Jr. Brain Institute, the scientists are also mapping the brain in unprecedented detail, offering researchers new understanding of the normal brain and abnormal brain as found in subjects with autism and attention deficit hyperactivity disorder (ADHD).

Magnetic resonance imaging (MRI), which uses only harmless magnetic fields and radio waves, is one of the most benign technologies in medicine for studying and diagnosing medical disorders, enabling researchers to view diseases that afflict millions of people, without the need for surgery, X-rays, or radioactive tracers.

Compound Shows Promise as Next-Generation Prostate Cancer Therapy

In the search for new ways to attack recurrent prostate cancer, researchers at Duke Health report that a novel compound appears to have a unique way of blocking testosterone from fueling the tumors in mice.

The potential foundation for a next-generation therapy, called tetraaryl cyclobutane, or CB, is being studied as an option for prostate tumors that have grown resistant to current anti-androgen drugs, notably enzalutamide.

“Prostate cancer is the most prevalent form of cancer in men, and the principal driver of tumor growth is the androgen receptor,” said John D. Norris, Ph.D., associate research professor in the Department of Pharmacology & Cancer Biology at Duke and senior author of a study published online Aug. 8 in the journal Nature Chemical Biology.

“Suppression of androgen receptor function by anti-endocrine therapies is initially effective, but most tumors develop resistance, resulting in a more aggressive cancer,” Norris said. “Our research has been focused on finding a new approach to suppressing androgen receptor activity, because even in situations where tumors are resistant to current therapies, the androgen receptor remains a viable target.”

Norris and colleagues focused on a group of CB compounds developed in collaboration with scientists at the University of Illinois at Urbana-Champaign. The compounds act as competitive inhibitors of androgen receptors, but are structurally different from current anti-androgens such as enzalutamide.

One of the CB compounds, in particular, inhibits mutant forms of the androgen receptors that promote resistance to enzalutamide. It functions by preventing the androgen receptor from entering the nucleus of the cell where it can promote tumor growth.

“It’s encouraging that this compound has a different mechanism of action when compared to current therapies, which gives it a good chance of having efficacy in resistant disease,” Norris said. “We have shown in animal models that the compound has activity against prostate tumors where enzalutamide fails.”

Norris said additional studies are underway in additional animal models and in tests with other forms of cancer, including breast cancer.