Innovation provides solutions for treating and curing urologic conditions to improve and save lives. Northwestern Medicine Urology has long fostered a culture of research excellence found in only a handful of academic medical centers. While many academic and clinical departments of urology conduct research, we possess a unique and far-reaching research program featuring a depth and breadth of research initiatives that few institutions can match. From clinical trials to translational and basic science studies, our investigators tirelessly work to advance urologic care and better care.
Here are some highlights of the high impact research studies underway at Northwestern Medicine Urology:
Developing Cancer Blockers to Key Cancer Gene
Prostate cancer is the most common cancer and the second-leading cause of cancer death among men in the United States. To develop more effective therapies, the Sarki Abdulkadir Lab focuses on the molecular pathways that drive prostate cancer. Making landmark discoveries, the Abdulkadir team has identified genetic mutations that help jumpstart prostate cancer growth. These findings have led to the design of small molecules to block these cancer-causing proteins such as MYC. Because MYC proteins play a role in 70% of all human cancers, they have been an attractive target for cancer therapy. Yet several structural aspects of going after the protein, including potential harm to healthy tissues, have deemed it “undruggable” — until recently thanks to innovative genetic modeling studies.
In animal models, the team has made significant headway in identifying a series of MYC inhibitors that offer favorable pharmacokinetic profiles to help silence MYC expression and remodel the tumor-immune microenvironment. Currently, the team is developing several novel MYC inhibitor compounds.
Additionally, the Abdulkadir Lab has identified a gene — PRRX2 — that appears to be involved in the development of resistance to a commonly used prostate cancer treatment: androgen receptor pathway inhibitors (ARPIs). Many metastatic prostate cancers eventually become resistant to standard therapy and become AR-negative. Patients with upregulated PRRX2 tend to have worse survival compared to other patients, especially those who are AR-negative. While much is still unknown about this gene and its connection to androgen insensitivity, it offers potential to mitigate these pathways by inhibiting them downstream. This research offers hope in finding solutions for the growing numbers of patients that fail therapy because they become AR-negative.
Boosting the Effectiveness of Immunotherapy
While a game changer in cancer treatment today, immunotherapy has yet to work well for patients with advanced or late-stage prostate cancer. The Jennifer Wu Lab has focused on developing a unique immunotherapy antibody approach to target tumor-secreted elements called sMIC. An oncogenic stress-induced molecule, sMIC is not typically expressed in healthy cells. Advanced prostate cancer cells, however, can disable sMIC’s ability to call for help from immune cells like “natural cancer killer” T-cells. Free of immune cell detection, these cancer cells live another day and grow beyond the prostate to other parts of the body. The Wu team has developed a first-in-class monoclonal antibody to target sMIC and stop prostate cancer spread or metastasis.
In animal models, the investigators found this novel drug worked to “fuel up” immune system function and effectively stop the spread of tumor cells. These results also offer hope for improving the response of prostate cancer patients to current immunotherapies. The Wu team hopes to bring this innovative therapy to the clinical trials stage soon.
Understanding Epigenetic Regulators of Cancer
The Qi Cao Lab has uncovered a previously unidentified role of a protein involved in regulating cancer development and progression. Studying a well-known oncogene known as EZH2 found in solid tumors, the team identified the function of EZH2 at a translational level. The investigators used ribosome-profiling technology to analyze active ribosomes in human prostate cancer cell lines. They discovered that EZH2 regulates two crucial RNA modification and translation processes in the cancer cells: impairing one kind of methylation and reducing a specific form of translation initiation in the ribosome.
The findings suggest EZH2’s dual role in regulating transcription and translation in EZH2-high cancer cells to promote cancer progression by accelerating ribosome functions and contributing to cancer-related translational control. Targeting EZH2 by ridding it of its non-methyltransferase roles could be an effective therapeutic approach to treating solid tumors. This new approach would be encouraging, as current EZH2-targeting strategies primarily focus on inhibiting the lysine methyltransferase activity of EZH2, which previous work has found does not completely prevent solid tumor progression.
Using Big Data to Enhance Precision Medicine
Starting with genomics — an organism’s complete set of genetic instructions — a variety of “omics” data has opened the door to understanding diseases at the molecular level in ways that were once unimaginable. Evaluating disease at this minute level of detail offers great potential for revolutionizing the diagnosis and targeted treatment of a wide array of human disorders. The Rendong Yang Lab uses innovative genomic, bioinformatic and statistical methods to identify the genetic mechanisms and biologic underpinnings of diseases such as prostate cancer.
Developing algorithms for next-generation sequencing technologies and leveraging multi-omics data results, the Yang team is working to better understand the complex genetic mutations that drive the development and growth of both primary and metastatic prostate cancer. Identifying of specific subtypes of prostate cancer and their distinct pattern of genetic variations offers an invaluable blueprint for more reliably predicting patient outcomes and prescribing personalized treatment.
Linking Immune Dysfunction to Chronic Pelvic Pain
Chronic prostatitis (male pelvic pain) affects some 8% of men. From difficulty urinating to pain in areas below the belly button and between the hips, this condition often has no known cause and can lead to poor quality of life. Diagnosis of chronic pelvic pain syndrome (CPPS) often relies on a process of elimination and treatments that only focus on symptom relief. In lab studies, the Praveen Thumbikat Lab has shown that immune cells known as “mast” — the same cells involved in allergic reactions — play a role in pain and urinary tract issues. In a clinical pilot, the Thumbikat team found that two drugs used for allergy relief reduced symptoms of CPPS within a few weeks for participants. They also identified a potential marker — mast cell tryptase — to help diagnose of CPPS in patients with high levels of the enzyme. As leaders in translating this work to the clinical arena, Northwestern Medicine investigators hope to build on these promising findings in a larger clinical trial.
The Thumbikat team also is investigating the role of bacteria in benign prostate pain using a unique E. coli strain isolated from a patient that appears to be involved in immune activity in the prostate. This novel work has led to several promising paths of inquiry, from enhancing pain relief for urologic conditions to treating prostate cancer with immunotherapy.
In addition to CPPS, urologic chronic pelvic pain syndrome includes interstitial cystitis/bladder pain syndrome (IC/BPS). This condition mostly afflicts women but, like CPPS, it lacks clinically useful biomarkers and effective therapies. The David Klumpp Lab focuses on host-microbe interactions that modulate bladder inflammation and pelvic pain. The team’s work includes characterizing changes in gut microbiota associated with IC/BPS and changes identified in clinical studies and then modeled in mice mimicking IC/BPS. The researchers have observed that fecal transplant can relieve the chronic pelvic pain in the IC/BPS mouse model. It also appears to reduce rodent correlates of anxiety and depression, a frequent co-morbidity in patients with chronic pelvic pain.
Most recently, the team has found that specific brain immune cells known to influence pain and cognitive function — microglia — undergo activation in IC/BPS mice and appear to transduce signals from altered gut microbiota. This discovery points to the potential of developing novel IC/BPS therapies. In parallel studies, the team has identified specific strains of E. coli commonly associated with benign colonization of the bladder of older adult patients that possess potent analgesic activity. The investigators hope these strains of E. coli can be developed to treat IC/BPS and other chronic pain conditions.
Starving Kidney and Other Urologic Cancers to Death
The C. Shad Thaxton Lab has developed a first-of-its-kind drug therapy — a cholesterol-mimicking particle that targets cancer cells dependent on cholesterol uptake. The synthetic lipoprotein nanoparticle fools cancer cells into thinking it is a delicious cholesterol snack. In reality, the new therapy binds to the cancer cells and upsets their overall cholesterol balance. The cells then try to compensate by making more cholesterol, which ends up turning off essential pathways they need to stay alive.
In the meantime, the drug has no ill effect on normal cells with a different cholesterol metabolism. The Thaxton team initially looked at lymphoma cells, but the new experimental agent holds promise for use in urologic cancers, such as kidney cancer and prostate cancer. Patients with advanced disease in these urologic organs currently have little to zero options when standard therapies fail to work. This exciting new treatment offers new hope. The synthetic lipoprotein nanoparticle is now in the pre-clinical drug phase, with Northwestern Medicine investigators working to drive the novel therapy through to clinical trials.
Overcoming Health Disparities in Urologic Cancers
In the United States, Black men and men of African ancestry have double the risk of dying from prostate cancer than white men. Enhancing the health outcomes for this minority group and others is a major area of research for the Adam Murphy Lab. In one of the largest clinical trials of its kind, the investigators have been recruiting men from three public Chicago hospitals to optimize active surveillance for men with low-risk prostate cancer. This “wait-and-see” approach is considered the current gold standard of care. But for many high-risk patients from vulnerable communities, lack of insurance, mistrust of the medical field and difficulty navigating the healthcare system makes complying with follow-up biopsies and scheduling health check-ups difficult, if not impossible. Not adhering to active surveillance, though, could be particularly deadly for those men who may have more aggressive disease. In this study, the Murphy team has added genomic markers and prostate MR imaging to better screen patients for prostate cancer and ensure that active surveillance is their best treatment option.
No single reason accounts for the disparity in outcomes for Black men and men of African ancestry compared to their white counterparts. Taking a multifactorial approach, Edward Schaeffer, MD, PhD, is studying the multiple avenues that meld biological and socioeconomic discoveries to better understand the disproportionate impact of prostate cancer on this particular racial group. Investigating molecular drivers, the Schaeffer team has observed specific gene mutations associated with more aggressive disease progression and anatomic differences in tumors in men of African ancestry. They have also looked at social determinants of care and found that — with similar access to care and standardized treatment — Black men with localized prostate cancer fare as well, if not better, than white men.
Other groundbreaking work in the Schaeffer group has revealed that Black men with aggressive prostate cancers respond better to immunotherapy than white men due to an abundance of plasma B cells. On average, the team found more of these specialized immune cells in tumors from Black men, and in all men with elevated plasma cell levels — advancing knowledge that ultimately benefits all patients with advanced metastatic prostate cancer.
Although men are four times more likely to develop bladder cancer (urothelial carcinoma), women often develop more aggressive disease. Additionally, because blood in the urine is frequently the first symptom of bladder cancer, women who have periods may associate blood in their urine with menstruation and delay seeking medical advice. Scientists are beginning to understand the importance of differences between male and female bladders. The Joshua Meeks Lab uniquely works on tackling gender differences in bladder cancer — both at a basic translational science level and at a personal level. Northwestern Medicine offers one of the nation’s few bladder support groups specifically for women, providing a safe and inviting space for these patients to share their cancer journeys. The all-female group attracts participants from Texas to Washington, DC to Alaska.
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