Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
An international research team led by MedUni Vienna may have found a new cancer treatment strategy – by activating a pathway which normally promotes cancer. Unexpectedly, this turned out to not only slow tumour growth, but also stimulates the immune system to combat tumour cells. The results of the study have just been published in Molecular Cancer.
The scientific team focused its investigations on the GP130 signalling pathway, which researchers expect to have a major potential in the fight against cancer. The signalling pathway, which is mediated by the protein GP130, plays a central role in cell communication and influences the activity of the transcription factor STAT3, which in turn is associated with the development and spread of tumours. Accordingly, blocking the GP130 signalling pathway is currently seen as a great hope in cancer medicine. Yet the current study proves the opposite: tumour growth can be slowed down not by inhibiting but by activating the GP130 signalling pathway in prostate cells.
New hope, especially for aggressive tumours
To achieve these new findings, the researchers investigated genetically modified mice in which GP130 was specifically activated in the prostate. “This allowed us to directly observe the reduction in tumour growth in the cell,” reports Lukas Kenner (Clinical Department of Pathology, MedUni Vienna), who led the study together with Stefan Rose-John (Biochemical Institute, University of Kiel). The results were further backed up by analyses of tissue samples from prostate cancer patients. This showed that high GP130 values correlate with a better survival rate. At the same time, extensive molecular analyses were carried out, including gene expression profiling.
“Our research provides exciting new evidence that the activation of GP130 in prostate cells not only slows tumour growth, but also stimulates the immune system to actively fight the cancer cells,” says Lukas Kenner, summarising the significance of the results, which will now be confirmed in further studies. The research work opens up a promising new therapeutic option, particularly for aggressive prostate cancer, which is still difficult to treat.
US county-level data point to specific pesticides that may increase prostate cancer incidence and death.
Photo by Arjun Mj on Unsplash
Researchers have identified 22 pesticides consistently associated with the incidence of prostate cancer in the United States, with four of the pesticides also linked with prostate cancer mortality. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.
To assess county-level associations of 295 pesticides with prostate cancer across counties in the United States, investigators conducted an environment-wide association study, using a lag period between exposure and prostate cancer incidence of 10–18 years to account for the slow-growing nature of most prostate cancers. The years 1997–2001 were assessed for pesticide use and 2011–2015 for prostate cancer outcomes. Similarly, 2002–2006 were analysed for pesticide use and 2016–2020 for outcomes.
Among the 22 pesticides showing consistent direct associations with prostate cancer incidence across both time-based analyses were three that had previously been linked to prostate cancer, including 2,4-D, one of the most frequently used pesticides in the United States. The 19 candidate pesticides not previously linked to prostate cancer included 10 herbicides, several fungicides and insecticides, and a soil fumigant.
Four pesticides that were linked to prostate cancer incidence were also associated with prostate cancer mortality: three herbicides (trifluralin, cloransulam-methyl, and diflufenzopyr) and one insecticide (thiamethoxam). Only trifluralin is classed by the Environmental Protection Agency as a “possible human carcinogen,” whereas the other three are considered “not likely to be carcinogenic” or have evidence of “non-carcinogenicity.”
“This research demonstrates the importance of studying environmental exposures, such as pesticide use, to potentially explain some of the geographic variation we observe in prostate cancer incidence and deaths across the United States,” said lead author Simon John Christoph Soerensen, MD, of Stanford University School of Medicine. “By building on these findings, we can advance our efforts to pinpoint risk factors for prostate cancer and work towards reducing the number of men affected by this disease.”
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
In a peer-reviewed study believed to be the first of its kind published, a research team led by Johns Hopkins Medicine provides scientific evidence that a healthy diet may reduce the chance of low risk prostate cancer progressing to a more aggressive state in men undergoing active surveillance – a clinical option in which men with lower risk cancer are carefully monitored for progression in lieu of treatments that could have undesired side effects or complications.
The findings are reported in the journal JAMA Oncology.
“Many men diagnosed with low grade prostate cancer are interested in changes they can make to reduce the risk of their tumour becoming more aggressive, and the role of diet and nutrition is one of the most commonly asked questions,” says study co-senior author Bruce Trock, PhD, a professor of urology, epidemiology and oncology at the Johns Hopkins University School of Medicine, and director of the Brady Urological Institute’s epidemiology division. “These men are motivated to make changes that may improve their prognosis, which is why we began collecting data on their diets, lifestyles and exposures 20 years ago. Hopefully, these latest findings will enable us to develop some concrete steps they can take to reduce the risk of cancer progression.”
When a patient is found after a biopsy to have developed prostate cancer, the sampled cells are assigned to a grade group based on comparison normal prostate tissue. Grade groups range from 1 to 5, with grade group 1 indicating indolent cancer cells that don’t look very different than normal tissue and do not metastasise. At the other end of the scale, grade group 5 indicates cancer cells that are quite abnormal in appearance, and can grow and metastasise if untreated
During active surveillance, biopsies are performed at regular intervals to see if prostate cancer should be move it to a higher grade group. Called grade reclassification, this often leads to a recommendation for treatment. It also is a common way for researchers to evaluate the effectiveness of therapies and lifestyle modifications.
“While there have been previous research studies looking at diet and its relationship to prostate cancer, we believe that ours is the first to provide statistically significant evidence that a healthy diet is associated with a reduction in risk of prostate cancer progressing to a higher grade group, as shown by a reduction in the percentage of men on active surveillance experiencing grade reclassifications over time,” says study co-senior author Christian Pavlovich, MD, a professor in urologic oncology at the Johns Hopkins University School of Medicine and director of the Brady Urological Institute’s prostate cancer active surveillance program.
In the newly published study, the researchers prospectively evaluated the histories of 886 men (median age at diagnosis: 66) diagnosed with grade group 1 prostate cancer from January 2005 to February 2017, all of whom were in the Johns Hopkins Medicine active surveillance program and whom, at the time of enrolment, completed a validated food frequency survey regarding their usual dietary patterns. Of the participants, 55 were Black (6.2%), 803 (90.6%) were white and 28 (3.2%) identified as other races and ethnicities.
Based on their responses to the questionnaire, a Healthy Eating Index (HEI) score was calculated for each patient. The HEI ranges from 0 to 100.
“The HEI is a validated measure of overall diet quality, quantifying how well an individual’s dietary pattern adheres to the recommendations of the U.S. Department of Agriculture’s Dietary Guidelines for Americans,” says study lead author Zhuo Tony Su, MD. “We looked at each patient’s HEI score – as calculated from their dietary information recorded at enrolment in our active surveillance programme – and assessed whether men with a higher quality diet were less likely to experience grade reclassification in the years afterward.”
Su says the researchers also evaluated the patients using an energy-adjusted HEI (E-HEI) score that takes into account a person’s daily caloric intake.
Along with those two metrics, Su says, the researchers calculated scores for each study participant using the Dietary Inflammatory Index (DII) and the energy-adjusted DII (E-DII).
“The DII and E-DII scores assess the inflammatory or anti-inflammatory potential of any diet, so higher scores indicate a diet that may cause more inflammation, which in turn, may contribute to the development and progression of prostate cancer,” says Su. “We evaluated whether higher inflammatory potential was associated with increased risk of grade reclassification.”
By a follow-up assessment at 6.5 years after diagnosis, 187 men (21%) had been reclassified as grade group 2 or greater, of whom 55 (6%) had extreme grade reclassification to grade group 3 or greater.
“When our team looked at the HEI and E-HEI scores in relation to the grade reclassification rates, we found a statistically significant inverse association between adherence to a high quality diet – as indicated by high HEI and E-HEI scores – and the risk of grade reclassification during active surveillance,” says Trock. “In other words, the higher the HEI and E-HEI scores, the more reduced the risk that a low grade prostate cancer had progressed to a higher grade disease that mandated curative treatment.”
Pavlovich says for patients adhering to a high quality diet, every increase of 12.5 points in the HEI score was associated with an approximately 15% reduction in reclassification to grade group 2 or greater, and a 30% reduction in reclassification to grade group 3 or greater.
The researchers say their findings also indicate that lower inflammation potential is among several possible risk lowering mechanisms as a result of a higher quality diet. However, they did not find an association between grade reclassification and baseline DII/E-DII scores.
“This lack of association with DII/E-DII may indicate that inflammation plays a role in driving the progression from a healthy prostate to one with cancer,” says Trock. “Whereas, in men who already have prostate cancer, the more subtle biological change from a lower to higher grade may reflect other mechanisms potentially influenced by diet.”
The researchers report several limitations in their study, including diet data based on patient self-reporting, results subject to potential nonresponse bias (bias occurring when respondents and nonrespondents differ in ways that impact the research, making the sample population less representative of the whole population) and not accounting for dietary changes over time. Additionally, they say the study population, consisting predominantly of white men with grade group 1 disease at diagnosis, may not be generalisable to all patients.
“Our findings-to-date should be helpful for the counselling of men who choose to pursue active surveillance and are motivated to modify their behaviours, including quality of diet,” says Pavlovich. “However, to truly validate the association between higher quality diet and reduced risk of prostate cancer progression, future studies with more diverse populations are needed.”
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
A blood test, performed when metastatic prostate cancer is first diagnosed, can predict which patients are likely to respond to treatment and survive the longest. It can help providers decide which patients should receive standard treatment versus who might stand to benefit from riskier, more aggressive new drug trials. The research, which forms part of a Phase III clinical trial, was just published in JAMA Network Open.
Once prostate cancer has metastasised and is no longer curable, systemic treatments are used to prolong survival as much as possible. Biomarkers that predict how patients will respond could allow for better personalisation of treatments, but they are few and far between.
A new study found that measuring circulating tumour cells (CTCs), rare cancer cells shed from tumours into the blood, is a reliable way to predict later treatment response and survival prospects. CTCs have been studied in prostate cancer before, but only in its later stages.
“No one, until now, has looked at whether CTC counts can be used right at the beginning, when a man first presents with metastatic prostate cancer, to tell us whether he’s going to live a long or short time, or whether or not he will progress with therapies,” said Amir Goldkorn, MD, lead author of the study and associate director of translational sciences at the USC Norris Comprehensive Cancer Center at the Keck School of Medicine of USC.
The research leveraged CellSearch (Menarini, Inc.), an FDA-cleared liquid biopsy technology at the Norris Comprehensive Cancer Center, to detect and measure CTCs in blood samples. Patients with more CTCs had shorter median survival lengths and a greater risk of death during the study period. Those with more CTCs also had less “progression-free survival,” which refers to the length of time when a patient’s disease is controlled by treatment without getting worse.
“You couldn’t tell these men apart when they walked through the door,” said Goldkorn, who is also a professor of medicine at the Keck School of Medicine. “All of their other variables and prognostic factors were seemingly the same, and yet they had very, very different outcomes over time.”
The researchers say that the CellSearch blood test, which is already widely available from commercial providers, can help quickly identify patients who are unlikely to respond to standard treatment options. Those men could benefit from a more intensive approach to therapy, including clinical trials of new drugs that may have more side effects but could improve survival in these high-risk patients.
Counting CTCs
The research was part of a phase 3 clinical trial of the NCI-funded SWOG Cancer Research Network, a group of more than 1300 institutions around the country that collaborate to study various cancers. Baseline blood samples from 503 patients with metastatic prostate cancer, who were participating in a new drug trial, were sent to the Keck School of Medicine team for analysis.
To analyze the blood samples, the researchers used the CellSearch platform at the Norris Comprehensive Cancer Center’s Liquid Biopsy Research Core, a facility that Goldkorn founded and directs. CellSearch uses immunomagnetic beads, antibodies attached to small magnetic particles, which bind to CTCs in the blood and pull them out to be detected and counted by specialised equipment.
Patients with five or more CTCs in their blood sample had the worst outcomes. Compared to patients with zero CTCs, they were 3.22 times as likely to die during the study period and 2.46 times as likely to have their cancer progress. They were only 0.26 times as likely to achieve a complete prostate-specific antigen (PSA) response, meaning they responded poorly to treatment.
Men with five or more CTCs had a median survival length of 27.9 months following the blood test, compared to 56.2 months for men with one to four CTCs and at least 78 months for men with zero CTCs. (Many patients in the latter group survived past the date of publication, so the median survival length could not yet be calculated.)
The bottom line: more CTCs meant that patients survived for less time, progressed much more quickly and were unlikely to respond to standard treatments.
Candidates for clinical trials
The new study shows that measuring CTC counts at the start of therapy can predict long-term survival rates, even in men who go on to receive many treatments for metastatic prostate cancer over a years-long period. That means the test can help identify men early on for trials of new and potentially more aggressive therapies.
“We want to enrich these clinical trials with men who need all that extra help – who really would benefit from three drugs versus just two, or from being on a new chemotherapy drug, even though it may have more side effects,” Goldkorn said.
Goldkorn and his team are now testing a new blood test that measures not just CTC counts, but also the molecular composition of CTCs and tumour DNA circulating in the blood, as well as other factors. Their goal is to create biomarkers with even more predictive power, which may ultimately help match patients with specific treatment options.
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
A multi-institutional clinical trial led by Weill Cornell Medicine and NewYork-Presbyterian investigators showed that a newer technique for collecting prostate biopsy samples reduced the risk of infection compared with traditional biopsy approaches and removed the need for prophylactic antibiotics. The results of the study appear in JAMA Oncology.
The technique, called transperineal prostate biopsy, collects prostate tissue via a needle through the skin of the perineum, the area between the rectum and the scrotum. The procedure, which uses local anesthesia to numb the area, allows physicians to bypass the traditional and more infection-prone route of collecting prostate biopsy tissue with a needle through the rectum.
The PReclude infection EVEnts with No prophylaxis Transperineal (PREVENT) trial, funded by the National Cancer Institute, part of the National Institutes of Health, was conducted at multiple sites, including NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian Queens and NewYork-Presbyterian Brooklyn Methodist Hospital. The study found no infections among 382 men randomised to undergo the transperineal procedure compared with six infections affecting 1.6% of the 370 men randomised to undergo the traditional transrectal biopsy procedure. The lower infection rate is particularly remarkable because the men in the transrectal biopsy group received a targeted course of antibiotics designed to help reduce their infection risk, and the men in the transperineal group received no antibiotics.
“Transperineal biopsy should be the new standard of care for prostate biopsy,” said Dr Jim Hu, Professor of Urologic Oncology at Weill Cornell Medicine. “It was as effective as the traditional transrectal biopsy approach at detecting cancer, but without the risk of infection or the need for antibiotics.”
Prostate biopsies are an essential tool for detecting prostate cancer, and about 3 million people worldwide undergo the procedure each year. Dr Hu noted that physicians collect about 90% of these biopsies in the United States via a transrectal procedure. Yet studies have found that 5% to 7% of patients develop infections after biopsy, and 1% to 3% require hospitalisation for these complications, he said. To help prevent infections, physicians typically prescribe a prophylactic course of antibiotics before the procedure.
Dr. Hu noted that the investigators used a personalised approach to prophylactic antibiotics in the patients undergoing the transrectal biopsy procedure. Rather than giving the men a broad-spectrum antibiotic or multiple antibiotics, they matched the antibiotics to cultures obtained from the patient’s rectum during prostate exams before the procedure. This targeted antibiotic approach reduced the infection rate in those undergoing the traditional transrectal procedure substantially compared with the national infection rate for the procedure. Yet, they achieved a statistically significant reduction in infections in the transperineal group by eliminating infections altogether.
“Transperineal prostate biopsy makes a common diagnostic procedure safer for men,” said Dr Hu, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “It also eliminates the use of antibiotics, helping to reduce the emergence of antibiotic-resistant infections, a growing public health concern.”
Despite the promise of the new procedure, Dr. Hu acknowledged a few hurdles to making it more widely available to men in the United States. He explained that few physicians in the country have been trained in the perineal procedure. Additionally, he noted that US insurers pay the same amount for either procedure but the transperineal biopsy costs more and takes longer to perform, creating a financial disincentive for physicians to make the switch.
However, there is reason to think the status quo will change, Dr Hu said, noting the switch to transperineal prostate biopsies in Norway after a man died after a routine transrectal prostate biopsy. The change virtually eliminated biopsy-related infections and deaths in that country with the nationwide switch to transperineal biopsy, he said.
“There is a strong case to make the switch,” he said. “It will take time. But as more patients request the new procedure, we think it will become more widely available.”
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
Men with metastatic castration-resistant prostate cancer should be treated primarily with second-generation hormone drugs, which offer better treatment response and longer life expectancy than chemotherapy. But the effect depends on which mutations the patient’s tumour carries. This is shown by results from the ProBio study, led by researchers at Karolinska Institutet in Sweden. The findings are published in Nature Medicine.
Every year, around 2500 men in Sweden are diagnosed with metastatic prostate cancer. Initially, all are treated with testosterone blockade to prevent testosterone from activating the androgen receptor, the gene that mainly fuels the growth of cancer cells. Over time, the cancer cells develop resistance and become so-called castration-resistant. This requires the use of new drugs – usually chemotherapy or second-generation hormone drugs (abiraterone/enzalutamide) that inhibit the androgen receptor. These are called Androgen Receptor Pathway inhibitors, or ARPi. Although these drugs have been available for over a decade, there is no direct comparison from a randomised trial until now.
Personalised treatment
“For the first time, we have compared these treatments with each other and also analysed the DNA of the cancer cells to find out which drug that works best for different individuals,” says Johan Lindberg, senior researcher at the Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet.
The bloodstream contains so-called cell-free DNA from cells that have died, something that happens all the time in healthy individuals and is perfectly normal. In patients with cancer, a fraction of the cell-free DNA originates from the cancer cells and is called circulating tumour DNA (ctDNA). By analysing ctDNA, it is possible to see what changes, or mutations, are present in a person’s tumour. The ProBio study aims to use knowledge of the tumour’s genetic signature to provide the best treatment. The idea is to be able to identify patients whose tumours are particularly sensitive or resistant to certain treatments through ongoing analyses.
“It creates a self-learning system to continuously improve treatment for men with metastatic prostate cancer,” says Martin Eklund, Professor of Epidemiology at the same department. “We are also gathering knowledge about which regions of the genome are important in prostate cancer.”
Longer life expectancy
The current sub-study included 193 patients with metastatic castration-resistant prostate cancer. They were randomly chosen to receive either chemotherapy or ARPi, which was compared to a control group where the doctor decided on the best treatment. The ARPi group responded the longest to treatment (a median of 11.1 months compared with 6.9 for chemotherapy and 7.4 for the control group). Survival for the ARPi group was also significantly longer – a median of 38.7 months compared with 21.7 months and 21.8 months respectively.
The effectiveness of ARPi varied depending on the patient’s genetic profile. For example, there was no significant difference between the treatments in the short term in patients whose tumours had mutations in the p53 gene, which occurs in around 45% of men with metastatic prostate cancer. However, data from the study suggest that also this group may have better survival if they receive ARPi rather than chemotherapy.
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
The US Food and Drug Administration (FDA) has granted Fast Track designation for SYNC-T SV-102 therapy for the treatment of patients with metastatic castrate-resistant prostate cancer (mCRPC). SV-102 is part of Syncromune Inc.’s SYNC-T platform, an in situ personalised therapy that uses a combination multi-target approach to cancer treatment, aiming to improve outcomes and quality of life for patients.
The Fast Track designation was granted based on the potential of SYNC-T SV-102 therapy to address the significant unmet need in treating patients with mCRPC. This advanced form of prostate cancer affects over 40 000 men in the US alone and is associated with a very poor prognosis. The Fast Track process is designed to facilitate the development and expedite the review of therapies that treat serious conditions and fulfil an unmet medical need, with the goal of getting important new treatments to patients sooner. Fast Track designation provides Syncromune with several key benefits, including more frequent FDA interactions, eligibility for accelerated approval, and priority review.
“The Fast-Track designation for SYNC-T SV-102 therapy signifies another step forward in bringing our potentially groundbreaking therapy to patients who need it most,” said Eamonn Hobbs, Chief Executive Officer and co-founder of Syncromune. “This accomplishment builds upon the foundation of positive Phase 1 clinical data and recent IND clearance.”
Syncromune’s lead candidate, SYNC-T SV-102, is a platform therapy that combines an in situ vaccine via partial oncolysis of a tumour followed by intratumoural infusion of the SV-102 fixed-dose multi-target biologic drug into the lysed tumour. This combination is designed to provide both immune stimulation and block immune suppression to activate and proliferate T cells to elicit a systemic anti-tumour response. Interim data from a Phase 1 study of SV-102 in males with mCRPC demonstrated an overall response rate of 85% with a favourable safety profile and tolerability. The Fast-Track designation comes on the heels of clearance of the company’s investigational new drug (IND) application, with studies expected to begin in the US this year.
Charles Link, M.D., Executive Chairman of Syncromune added, “We believe that Fast-Track designation for SYNC-T SV-102 will significantly aid our development goals for this therapy for men with difficult to treat prostate cancer. We look forward to initiating trials at multiple US sites later this year to expand our efforts to develop the SYNC-T SV-102 Therapy.”
The Stockholm3 blood test, developed by researchers at Karolinska Institutet, is equally effective at detecting prostate cancer in different ethnic groups, according to a new paper published in The Journal of Clinical Oncology. The test produces significantly better results than the current PSA standard.
Stockholm3, a prostate cancer test developed in Sweden, runs a combination of protein and genetic markers from a blood sample through an algorithm to find the probability of a patient having clinically significant cancer.
Studies in more than 90 000 men have shown that Stockholm3 produces significantly better results than the current PSA standard. The test improves prostate cancer diagnosis by reducing unnecessary MRI and biopsies and by identifying significant cancers in men with low or normal PSA values.
Ethnically diverse group
However, previous studies have been conducted primarily in Scandinavia on a mainly White population with uncertain generalisability to the rest of the world. A Swedish-American research group has now examined how well it works in an ethnically mixed group of men in the USA and Canada.
The study included over 2000 men at 17 different clinics, 16% of whom were Asian, 24% African-American, 14% Latin American and 46% White American. All participants had a referral for a prostate biopsy on the basis of an elevated PSA score, abnormal rectal examination, MRI scan or other suspicious clinical finding.
Before the biopsy was performed, a blood test was taken along with clinical data pertinent to the Stockholm3 test, which was conducted blinded to the biopsy results.
Halving the number of unnecessary biopsies
The analysis shows that clinically relevant prostate cancer cases were found in a total of 29% of the men, somewhat more in African Americans and slightly fewer in Asians.
It also shows that the Stockholm3 test could almost halve the number of unnecessary biopsies (45 per cent fewer: 673 as opposed to 1226) while being no less effective at detecting all clinically relevant cases. The results were similar across the different ethnic groups.
“The study demonstrates that the Stockholm3 test is just as effective on an ethnically mixed group as it is on a White, Swedish population,” says the study’s lead author Hari T. Vigneswaran, doctor and PhD student at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
According to him, the research answers several important questions and will lead to a more widespread use of the method:
“Colleagues in other countries are very interested in these data, which show that Stockholm3 works for a non-Swedish population and among minorities.”
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
Researchers have developed a new urine-based test that addresses a major problem in prostate cancer: how to separate the slow-growing form of the disease unlikely to cause harm from more aggressive cancer that needs immediate treatment.
The test, called MyProstateScore2.0, or MPS2, looks at 18 different genes linked to high-grade prostate cancer. In multiple tests using urine and tissue samples from men with prostate cancer, it successfully identified cancers classified as Gleason 3+4=7 or Grade Group 2 (GG2), or higher. These cancers are more likely to grow and spread compared to Gleason 6 or Grade Group 1 prostate cancers, which are unlikely to spread or cause other impact. More than one-third of prostate cancer diagnoses are this low-grade form. Gleason and Grade Group are both used to classify how aggressive prostate cancer is.
Results from the University of Michigan Rogel Cancer Center-led study are published in JAMA Oncology.
“Our standard test is lacking in terms of its ability to clearly pick out those who have significant cancer. Twenty years ago, we were looking for any kind of cancer. Now we realise that slow-growing cancer doesn’t need to be treated. All of a sudden, the game changed. We went from having to find any cancer to finding only significant cancer,” said co-senior study author John T. Wei, M.D., David A. Bloom Professor of Urology at Michigan Medicine.
Prostate-specific antigen, or PSA, remains the linchpin of prostate cancer detection. MPS2 improves upon a urine-based test developed by the same U-M team nearly a decade ago, following a landmark discovery of two genes that fuse to cause prostate cancer. The original MPS test, which is used today, looked at PSA, the gene fusion TMPRSS2::ERG, and another marker called PCA3.
“There was still an unmet need with the MyProstateScore test and other commercial tests currently available. They were detecting prostate cancer, but in general they were not doing as good a job in detecting high-grade or clinically significant prostate cancer. The impetus for this new test is to address this unmet need,” said co-senior author Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology. Chinnaiyan’s lab discovered the T2::ERG gene fusion and developed the initial MPS test.
“If you’re negative on this test, it’s almost certain that you don’t have aggressive prostate cancer,” said Chinnaiyan, S. P. Hicks Endowed Professor of Pathology and professor of urology at Michigan Medicine.
Moreover, MPS2 was more effective at helping patients avoid unnecessary biopsies. While 11% of unnecessary biopsies were avoided with PSA testing alone, MPS2 testing would avoid up to 41% of unnecessary biopsies.
“Four of 10 men who would have a negative biopsy will have a low risk MPS2 result and can confidently skip a biopsy. If a man has had a biopsy before, the test works even better,” Wei explained.
For example, a patient may get a prostate biopsy due to an elevated PSA, but no cancer is detected. The patient is followed over time and if his PSA inches up, he would typically need another biopsy.
“In those men who have had a biopsy before and are being considered for another biopsy, MPS2 will identify half of those whose repeat biopsy would be negative. Those are practical applications for patients out there. Nobody wants to say sign me up for another biopsy. We are always looking for alternatives and this is it,” Wei said.
Ccancer-associated fibroplasts surrounding a prostate tumour. Credit: Moscat and Diaz Meco lab.
Extracted from the core of sandalwood trees (santalum album tree), sandalwood oil has been used for many centuries by several cultures throughout the world for perfume, soaps, incense and candles. With its earthy sweet scent, this essential oil also is used in the food industry and topically in various cosmetic preparations.
Importantly, this natural oil is known for its health benefits and medicinal applications from antibacterial to anticancer because of its phytochemical constituents. In addition to containing esters, free acids, aldehydes, ketones and santenone, sandalwood oil primarily (> 90%) constitutes santalol, equal amounts of two compounds, alpha and beta-santalol.
Now, researchers from Florida Atlantic University’s Schmidt College of Medicine and collaborators are the first to demonstrate in vivo the chemo-preventive properties of alpha-santalol against prostate cancer development using a transgenic mouse model.
Results of the study, published in the journal Phytomedicine Plus, showed that administration of alpha-santalol decreased the incidence of prostate tumours by decreasing cell proliferation and inducing apoptosis, without causing weight loss or any noticeable side effects.
Apoptosis (programmed cell death) is a method the body uses to get rid of unneeded or abnormal cells such as cancer cells. Findings revealed that the area occupied by normal tissue in alpha-santalol-treated mice was 53% compared to 12% in control mice.
This suggests that administering alpha-santalol protected the normal tissue and delayed progression from prostatic intraepithelial neoplasia, a precancerous condition, to poorly differentiated carcinoma, a high-grade form of cancer where cancer cells and tissue look very abnormal.
These results are significant because mortality in prostate cancer patients is mainly attributable to advanced stages of the disease.
In prior studies, the researchers demonstrated the efficacy of alpha-santalol in suppressing growth and inducing apoptotic cell death in cultured human prostate cancer cells.
Based on these observations, they selected a genetically engineered mouse model that resembles many features similar to human prostate cancer, eliciting different lesion grades and cancer progression.
“Although our cellular studies provided important mechanistic insights, relevant in vivo models are vital for developing novel chemo-preventive agents for clinical use and to determine if alpha-santalol offers protection against prostate cancer development,” said senior author Ajay Bommareddy, PhD, associate professor of pharmacology in the Department of Biomedical Science, FAU Schmidt College of Medicine.
“Prior to this new study, alpha-santalol’s in vivo efficacy against prostate cancer development had not yet been established.”
Additional findings of the current study showed alpha-santalol reduced the incidence of visible prostate tumors compared to control-treated mice.
Only 11% in the treated group developed prostate tumours whereas more than half in the control group developed the tumours.
The differences in urogenital and prostate weights were statistically significantly different in alpha-santalol-treated mice compared with controls.
The average wet weight of urogenital tract in alpha-santalol treated mice was about 74.28% lower compared with control mice.
Similarly, the average wet weight of the prostate gland was lower by 52.9% compared with control mice.
Current treatment methods for prostate cancer include androgen ablation, chemotherapy, radiotherapy and radical prostatectomy, but are ineffective against advanced prostate cancers.
Early detection and local therapy have resulted in improved outcomes but has been challenging with the management of advanced stages.
“Identifying agents that have the ability to selectively target cancerous cells and delay onset and progression of prostate cancer is greatly needed,” said Bommareddy.
“Additional studies are essential to systemically explore the feasibility of alpha-santalol as a promising chemo-preventive and anti-tumour agent against human prostate cancer development and to elucidate the mechanisms surrounding the role of pro-apoptotic and antiapoptotic proteins.”
