Research

Marker Driven Selection of patients for prostate biopsy and management:

Principal investigator:  Sanoj Punnen, M.D.

The purpose of this research study is to determine if the interpretation of multiparametric MRI (mpMRI) with an algorithm called habitat risk score (HRS) in combination with a panel of blood and urine biomarkers is more effective at detecting prostate cancer than standard of care interpretation of mpMRI with the Prostate Imaging Reporting and Data System (PIRADS).

---

NSAID Use after Robotic Partial Nephrectomy (No-PAIN): a randomized, controlled trial.

Principal investigator: Mark L. Gonzalgo, M.D., Ph.D.

The purpose of this study is to see how effective non-steroidal anti-inflammatory drugs (NSAIDs) are at controlling pain without side effects in participants after robotic-assisted partial nephrectomy.

Phase 2 Randomized Trial: Human Amnion Membrane Allograft and Early Return of Erectile Function after Radical Prostatectomy (HAMMER).

Principal investigator:  Sanoj Punnen, M.D.

The purpose of this research study is to evaluate if placing a dehydrated human amnion chorion membrane (dHACM) over the nerves after removal of the prostate during surgery (radical prostatectomy) will allow an earlier recovery of erectile function and urinary control after surgery.

---

New treatment option for Erectile Dysfunction

Men between 30 to 70 years old with mild erectile dysfunction who have tried Viagra / Cialis or who have not tried these medications, were asked to participate in the study.

Click here to watch the TV coverage from ABC Local 10 Miami news about the trial. (2017)

For more information: Safety and Efficacy of Low Intensity Shockwave for the Treatment of Erectile Dysfunction.

---

Treatment option for Low Testosterone with Intranasal Testosterone NATESTO® (4.5% nasal testosterone) Nasal Gel

Men between 18 and 55 years of age, with documented onset of low testosterone (<350 ng/dL), were asked to participate in the study.

For more information: Natesto Effects on Testosterone, Luteinizing Hormone, Follicle Stimulating Hormone and Semen Parameters

American Cancer Society Awards Five Year Grant to Sylvester Urologic Surgeon

Ranjith Ramasamy, M.D., assistant professor in the Desai Sethi Urology Institute, was awarded a Clinician Scientist Development Grant in the amount of $729,000 for his research study, Nitric Oxide Based Immunotherapy for Castration Resistant Prostate Cancer (CPRC), which was published last year in the journal, Proceedings of the National Academy of Sciences.

---

CTSI Names Four New KL2 Scholars and Awards Pilot Grants to 10 UM Faculty

The Miami Clinical & Translational Science Institute’s (CTSI) Pilot Awards support research that is translational, innovative, and interdisciplinary. These awards of $40,000 each allow investigators to generate preliminary data for a federal grant submission. Ranjith Ramasamy, M.D., assistant professor of urology, will look at the therapeutic role of nitric oxide in regulating the tumor microenvironment of castrate-resistant prostate cancer.

---

Sylvester Researchers Show Nitric Oxide Suppresses Drug-Resistant Prostate Cancer

Dr. Ranjith Ramasamy, M.D and Dr. Himanshu Arora, Ph.D., researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown in animal models that S-nitrosoglutathione (GSNO), a compound that increases nitric oxide (NO) levels, suppresses castration-resistant prostate cancer and has a major impact on tumor microenvironments. The discovery could lead to new therapies for prostate cancer patients with few options. The study was published in the journal Proceedings of the National Academy of Sciences.

---

Dr. Ranjith Ramasamy Reports on First Clinical Trials Using Shockwave Therapy to Treat ED

Ranjith Ramasamy, M.D., assistant professor of urology and director of reproductive urology at the University of Miami Miller School of Medicine, spoke recently before members of the American Urological Association at its annual convention in San Francisco. His presentation was a summary of randomized clinical trials he conducted on the effects of shockwave therapy for treating erectile dysfunction (ED), a chronic condition that affects 30 million men in the U.S.

---

Dr. Ranjith Ramasamy, Research Award Winner, Presents at Boston Conference

Ranjith Ramasamy, M.D., assistant professor of urology and director of male reproductive medicine and surgery at the University of Miami Miller School of Medicine, gave a presentation at the recent American Urological Association (AUA) annual meeting in Boston. Ramasamy, who specializes in the treatment of disorders of male infertility and sexual dysfunction, discussed the research he is conducting under a two-year grant as a recipient of an AUA Research Scholar Award. The award program funds mentored training for outstanding young investigators to encourage urologic research and foster their career success.

The Arora Lab

Our group focuses on understanding the molecular endocrinology of Prostate Cancer which involves studying the molecular signatures and interactions that play a critical role in the progression of prostate cancer from androgen-dependent to the androgen-independent castration-resistant stage.

To achieve this goal, we use 2 major approaches:

1. We use cutting-edge Molecular biology and genomic and transcriptomic analysis to identify novel alterations in human cancers. We study these using genetically engineered mouse models and next-generation in vitro models.
2. We advance Machine learning models to study genomic signatures in patients in different stages of PCa.

Our long-term goal is to develop and use technological advances to bridge the gap between the clinical and basic science world and translate this information to the care of prostate cancer patients.

Research Projects

Androgen producing Stem Cells

We are researching a new treatment for testosterone deficiency that avoids the infertility side effects of traditional testosterone therapy. My team is experimenting with transplanting Leydig stem cells (LSCs) under the skin, along with Sertoli and myoid cells, to see if we can stimulate testosterone production. We're also trying to understand if this method can be controlled by the body's hormonal system. We've been working with cells from mice and human tissue, discovering that LSCs need to be with other cell types to work. Our early results are promising, showing that this combination can produce testosterone in a way that might preserve the body's natural hormonal regulation. This could be a breakthrough in treating testosterone deficiency more safely.

Paracrine Factors from Testicular Microenvironment regulates Androgen production.

While it's known that one in five men over 40 may suffer from testosterone deficiency (TD), the exact causes are still unclear. Our research delves into how Leydig stem cells (LSCs) develop into adult Leydig cells that produce testosterone, driven by luteinizing hormone pulses from the pituitary. We've discovered that the testicular microenvironment, including Sertoli and myoid cells, is crucial for this process, operating under the desert hedgehog signaling pathway. Our team is investigating the influence of this environment on LSCs by studying cells from men's testis biopsies. We've found that leptin, a hormone secreted by this microenvironment, promotes LSC development and boosts testosterone at low levels but has the opposite effect in high concentrations. This leptin-driven mechanism, which activates the desert hedgehog pathway, is a one-way street; altering the pathway doesn't impact leptin levels. These insights are significant, revealing leptin's role in LSC differentiation and testosterone production, which could have profound implications for treating TD.

Nitroso-redox Imbalance can Negative Impact Androgen Production

The reason behind the drop in testosterone with age is still a mystery. We hypothesize that an increase in nitroso-redox imbalance as we age might influence testosterone production. In our studies, we measure markers of this imbalance in a special breed of mice engineered to show higher levels of this stress, comparing them with normal mice. We're assessing how this imbalance affects hormones like luteinizing hormone (LH) and testosterone (T) across different ages of normal mice. Our ongoing results reveal that this stress marker is elevated in the blood of the engineered mice compared to normal ones and increases with age in normal mice, yet it doesn’t build up in their testes. Despite varying age, testosterone levels remain constant, but we observe higher LH levels in middle-aged and older mice, pointing to a type of hypogonadism that occurs without a drop in testosterone. This could potentially lead to a breakthrough in diagnosing and treating age-related changes in testosterone levels.

Overcoming nitroso-redox imbalance by Nitric oxide treatment can target Prostate Cancer growth by reducing tumor microenvironment

Prostate cancer is the second leading cause of cancer-related deaths in men, and for those whose cancer recurs post-local therapy, the battle often progresses to castration-resistant prostate cancer (CRPC) despite hormone therapy. Most research has centered on the cancer cells' androgen receptor variants; however, the tumor microenvironment (TME), which includes a mix of cells like immune cells and macrophages, is pivotal in the disease's progression. These tumor-associated macrophages (TAMs) are drawn to the tumors by various signals and are thought to significantly aid the cancer's advance. In this context, we focus on nitric oxide (NO), a molecule with diverse roles, including in the cardiovascular and immune systems, and its relevance to tumor suppression. NO donors have shown promise in various cancer studies, and my research aims to bring that potential to CRPC treatment. We are currently testing the hypothesis that increasing NO can suppress CRPC by influencing the TME. Our findings indicate that S-nitrosoglutathione (GSNO), an NO donor, reduces the tumor load in CRPC mouse models by targeting cell interactions within the TME. GSNO seems to inhibit the presence of M2 macrophages, known for their tumor-promoting properties, and decrease the expression of pERK, a marker indicating TAM activity. Additionally, GSNO appears to suppress IL-34, a cytokine implicated in TAM differentiation. This ongoing study affirms the critical role of NO in modulating the TME to inhibit CRPC tumors. These observations could be groundbreaking, offering a novel, NO-based therapeutic pathway for CRPC that targets the tumor's environment rather than the cancer cells directly.

Nitric oxide S-nitrosylates CSF1R to augment the action of CSF1R inhibition against castration resistant prostate cancer

Prostate cancer's resistance to hormone therapy partly stems from its capacity to adapt through mechanisms within the tumor microenvironment (TME) that promote immune escape. This environment is composed of various cell types, including macrophages, which exist in two forms: one that fights tumors and another that supports them. These macrophages are influenced by colony-stimulating factor 1 (CSF1), which binds to its receptor (CSF1R) to control their behavior. Blocking CSF1R was thought to be a promising strategy to impede tumor growth, but it has shown limited success due to a feedback mechanism where the blockade inadvertently recruits more tumor-supporting macrophages and cytokines that aid immune suppression. Here, we turn the spotlight on Nitric oxide synthase (NOS), particularly the endothelial NOS (eNOS), which is usually linked with the production of Nitric Oxide (NO). In cancer, a phenomenon known as NOS uncoupling leads to reduced NO and increased oxidative stress, which in turn support pro-tumorigenic cytokines. This challenge is not adequately addressed by blocking CSF1R alone. In our ongoing research, we find that in high-grade human prostate cancer samples, eNOS is associated with active CSF1-CSF1R signaling but remains uncoupled, failing to produce enough NO for effective S-nitrosylation at critical sites of CSF1R needed to inhibit tumor-promoting cytokines. We test if external NO treatment can counteract the effects of eNOS uncoupling. The results are affirmative: NO treatment, specifically using S-nitrosoglutathione (GSNO), not only achieves S-nitrosylation of CSF1R but also reduces oxidation in tumors, lessens tumor burden, and suppresses cytokines ineffectively targeted by CSF1R blockade alone. Furthermore, when we combine NO treatment with CSF1R inhibitors in murine models of CRPC, this approach significantly surpasses the efficacy of either treatment in isolation. This combined treatment modulates the immune cell composition within the TME, enhancing pro-inflammatory macrophages and cytotoxic T cells, while reducing anti-inflammatory macrophages and myeloid-derived suppressor cells. Our study suggests that combining NO therapy with CSF1R inhibition could recalibrate the TME, offering a potent new treatment avenue for prostate cancer that might improve outcomes for patients with limited current therapeutic options.

Studying Prostate Cancer Progression using Advance Machine Learning Modeling

A large number of deaths from any cancer type, including PCa, occur due to challenges with timely diagnoses and prognoses of the disease, which also increases the overall risk and cost of the treatment. In PCa, diagnosis starts with prostate-specific antigen (PSA) level detection, which is above the normal range, the patient is subjected to genomic testing such as - 4K scores, PCA3, or PHI test. Once/if the results of these genomic tests return positive, magnetic resonant imaging (MRI) is used to identify potential areas of PCa. The biopsies are extracted by the clinicians, further inspected by the board-certified pathologist, and are then sent for genomic testing to confirm the severity of the disease. Typically, a single worst area is selected for the test, leaving a large area from consideration. In case of false positive/negative outcomes, patients are subjected to the same steps making it financially cumbersome for the patients and increasing the time/accuracy of treatment. We are working to develop the machine learning pipelines that will allow us to 1) investigate the entire areas of the biopsies at a granular level before assigning a score and 2) predict the course of tumor progression/regression. For this, the pipelines utilize a multi-tiered approach which includes a) generating a digital map of the tissue architecture, b) overlaying this with the patient’s genomics, c) assigning sub-scores to the entire image, and computing the grade of cancer by generalizing the scores. We have submitted a provisional patent with some of the preliminary data from this application, with support from the University of Miami. We aim to refine this technology to 1) establish the efficiency of the developed AI model in a clinical setting (using data from patients enrolled in active surveillance trials, 2) map disease using advanced CNN tools, 3) create a user-friendly interface to enhance clinical use of the AI model. Successful completion of this study will yield a paradigm-shifting technology that will aid in clinical decision-making, improve patient outcomes through early detection and accurate prognostic assessment of PCa, and could potentially extend to other cancer settings.

The Sharifi Lab

Our group studies fundamental metabolic processes that govern prostate cancer progression. Our discoveries have revealed that cancer engages what are usually normal physiologic processes or their variants and redirects them for the purposes of tumor progression and treatment resistance. Overall, we have found that the biotransformation of steroids in peripheral tissues (e.g., prostate cancer) from inactive to active steroids (e.g., DHT), and vice versa, regulate not only broad transcriptional programs, but also and more importantly multiple clear clinical phenotypes in humans.

Research Projects

A short circuit from gonadal circulation to the prostate and sneaky testosterone

We have recently discovered that a subset of men with prostate cancer have very high periprostatic concentrations of testosterone (Alyamani, et al. J Clin Invest. 2023). This periprostatic venous testosterone probably comes from the enriched testosterone that is made in the testes. This prostatic testosterone exposure is not detectable by the usual measurements in blood. Men who have what we term sneaky testosterone physiology appear to have worse clinical outcomes after surgery. We are currently working on the implications of this variation in local testosterone physiology as well as how this alternative physiology is detectable through non-invasive means.

Genetic mutations and variations in androgen synthesis machinery

We investigate how genetic anomalies enable cancer cells to evade ADT and produce their own hormones for fuel. Our team discovered that a variation in the HSD3B1 gene—called HSD3B1(1245C)—encodes an enzyme that is effectively hyperactive and plays an important role in this process (Chang, et al. Cell 2013). We have also shown that this variant alters response to treatment and could be used as a predictive biomarker when designing treatment regimens (Hearn, et al. Lancet Oncol 2016; Hearn, et al. JAMA Oncol 2018; Almassi, et al. JAMA Oncol 2018; Hearn, et al. JAMA Oncol 2020). Our laboratory is working to transition this discovery into the clinic by developing a blood test to detect the variant, and also collaborating on clinical trials to test alternative treatments for prostate cancer patients who have the inherited variant.

How genetics affect treatment response.

Our team is interested in optimizing treatment regimens for all patient populations. Our team found that patients with the HSD3B1(1245C) variant metabolize abiraterone (a commonly prescribed prostate cancer drug) differently than men without the variant. They produce higher levels of a metabolite that shares a similar molecular structure with androgens, thereby “tricking” androgen receptors into turning on pro-cancer pathways. Our lab is working to confirm these results and identify an effective alternative drug for these patients (Li, et al. Nature 2015; Li, et al. Nature 2016; Alyamani, et al. J Clin Invest 2018).

Aberrations in glucocorticoid metabolism.

We have found that prostate cancer develops aberrations in glucocorticoid metabolism that enables the development of resistance to potent AR antagonist, including enzalutamide.  For example, the normal metabolic pathway that inactivates cortisol is lost, generating elevated tumor concentrations of cortisol that are required for drug resistance (Li, et al. eLife 2017).  We recently identified hexose-6-phosphate dehydrogenase blockade as a strategy that can reverse aberrant metabolism and reverse drug resistance (Li, et al. Science Translational Medicine 2021). Unexpectedly, AR antagonists also perturb glucocorticoid inactivation systemically.  This leads to a systemic increase and exposure to bioactive glucocorticoids in patients treated with enzalutamide and apalutamide and may be the basis for certain adverse effects that occur with these drugs (Alyamani, et al. Annals Oncol 2020).

Interface between glucocorticoids and androgens.

Glucocorticoids have had a long-standing role in the treatment of inflammatory disease processes, including severe asthma.  However, patients often have disease that is resistant to the anti-inflammatory effects of glucocorticoids.  An underappreciated observation of treatment with systemic glucocorticoids is that adrenal androgens are suppressed.  We have recently found that HSD3B1 genetics is associated with clinical response to glucocorticoids in severe asthma. This is probably due to suppression of adrenal androgens which are metabolized by the enzyme encoded by HSD3B1 to more powerful androgens and are processed in individual patients according to their HSD3B1 genotype (Zein, et al. PNAS 2020).

Residents and Fellows are encouraged to consider the laboratory for further research development in the areas of Andrology and Urologic Oncology. 

More information about our residency and fellowship programs may be found on our Education & Training Page.

Applicants interested in undergraduate and graduate research opportunities in any DSUI laboratories are encouraged to reach out via e-mail at DSUIscience@miami.edu.

The Desai Sethi Urology Institute Clinical & Translational Research Support (CTRS) team consists of a full time Sr. Clinical Research Manager, clinical research coordinators, a research associate, and a biostatistician. The team assists DSUI investigators by standardizing screening and enrollment of patients, collection of samples and data collection/analysis for specific interventional, non-interventional, and translational research studies. DSUI-CTRS also provides training resources and standard operating procedures that are compliant with institutional and federal regulations to ensure that the highest quality and ethical requirements are achieved.