The Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital is committed to driving transformative new insights and successes in urologic cancer research, education and discovery. To achieve this mission, the institute provides support for projects with promising potential to advance knowledge and foster new, innovative research in the field of urologic oncology.
We have selected seven key projects to receive funding for the 2019 award year:
PI: Sarki Abdulkadir, MD, PhD, Professor of Urology, Feinberg School of Medicine
PI: Gary Schiltz, PhD, Research Professor, Center for Molecular Innovation and Drug Discovery and Pharmacology, Feinberg School of Medicine
MYC is a well-known cancer promoting protein and a much sought-after therapeutic target for cancer. However, the protein lacks specific pockets that can fit small molecules or enzymatic activity that can be inhibited, so it was widely regarded an “undruggable” target. Previous attempts at developing small molecule MYC inhibitors ended with compounds that show promising activity in the cell culture dish but no activity in living organisms. To overcome this barrier, the Abdulkadir laboratory designed an innovative approach for identifying small molecule MYC inhibitors that are active in vivo. They reasoned that sampling a large chemical universe (35 million compounds) by computer modeling to identify hits that are then put into a rapid screening system in animals will enhance the chance of identifying MYC inhibitors with drug-like properties. This approach was successful in identifying two series of small molecule MYC inhibitors with drug-like qualities that demonstrated anti-tumor effects in models of prostate cancer and leukemia. Interestingly, these inhibitors sensitized prostate cancers to immunotherapy with checkpoint inhibitors. It is notable that prostate cancer is generally not sensitive to immunotherapy and prostate cancer patients have not benefited from the recent advances in immunotherapy. Therefore the possibility of using these new MYC inhibitors to make prostate cancers respond to immunotherapy is exciting.
The major goal of this proposal is to conduct the necessary studies required to start testing this MYC inhibitor in humans. These studies will include lead optimization and the formal required studies for how compound is handled by the body as well its safety profile. Successful targeting of MYC could have far-reaching implications for cancer therapy in prostate cancer and beyond, as MYC is involved in the majority of all human cancers.
PI: Qi Cao, PhD, Associate Professor of Urology, Feinberg School of Medicine
Cancer results from defects in many cellular functions and pathways, including the maintenance of genetic memory that is important for cellular identity. Polycomb Group (PcG) and trithorax group (TrxG) proteins play a major role in maintaining genetic memory and cellular identity. They are also known to be involved in cancer initiation and progression.
The Cao lab discovered that BMI1, a member of the PcG family of proteins, is overexpressed in prostate cancer, particularly in aggressive and/or metastatic prostate cancers. Importantly, prostate cancer patients with high BMI1 levels have worse clinical outcomes compared to patients with low BMI1 expression. Furthermore, there is a significant body of evidence indicating that dysregulated BMI1 and other PcG proteins, along with the hormone-regulated androgen receptor (AR), contribute to prostate cancer development and progression.
This study will explore the functional relationship between BMI1 lipogenesis genes that may cause prostate cancer development. The investigators will characterize the novel BMI1-lipogenesis regulation axis, and dissect how BMI1 regulates metabolism in castration-resistant prostate cancer. They will also test the newly developed BMI1 inhibitors and AMPK activators in prostate cancer cells and use animal models to determine whether combinational inhibiting BMI1 and activating AMPK has the best therapeutic efficacy to kill prostate cancer cells and inhibit tumor growth.
Once this project is completed, it will yield new insights into the cellular mechanisms of prostate cancer development, including disease initiation and progression. This data will provide a strong rationale to develop therapies using BMI1 inhibitors for prostate cancer treatment.
Dysregulation of Mitochondrial MnSOD Acetylation in Prostate Carcinogenesis and Castrate-Resistant Prostate Cancer
PI: David Gius, MD, PhD, Professor of Radiation Oncology and Pharmacology, Feinberg School of Medicine
A fundamental theme in personalized or precision cancer medicine is to identify specific tumors, based on molecular biomarkers and/or tumor signatures that will subsequently benefit from new therapeutic strategies, including targeted agents. An important, and longstanding, example of this concept is the dependency of prostate tumor cells on the androgen receptor (AR), i.e. the AR signaling axis. While the majority of men will initially exhibit an excellent response to androgen-deprivation therapy (ADT), with time, nearly all men develop enzalutamide resistance (ENZR) tumor cells, as such, new therapeutic interventions are a necessity. There is an ongoing intense search, using molecular analyses, to define the pathways leading to ADT resistance (ADTR), including ENZ, a primary therapy for prostate malignancies. One of the central themes in cancer medicine is “oncogene addiction”, a phenomenon that implies while tumors contain multiple genetic, signaling, and metabolic abnormalities, and despite this tumor complexity, growth and survival of cancer cells are often impaired by the inactivation of a single driver or signaling pathway. Thus, the phenomenon of oncogene addiction (i.e., the “Achilles heel”) in cancers provides a scientific rationale to identify new molecular targets. This is of importance since the disruption of the physiological crosstalk between the AR signaling and these oncogenic addiction survival pathways are hallmarks of progression to ENZR. Thus, it is proposed that the disruption of mitochondrial physiology by the prolonged exposure to ENZ is a novel cancer model by which prostate tumors metabolically re-program cellular processes leading to an oncogenic addiction phenotype.
Thus, the goal of this proposal is to validate if manganese superoxide dismutase (MnSOD), a key detoxification enzyme that maintains metabolic redox balance, is dysregulated due to prolonged ENZ exposure by accumulating lysine 68 (K68) acetylation (Ac), which may function as a locus of “oncogenic addiction” in ENZR tumors. In this regard, several other laboratories have recently also shown that mitochondrial reprogramming plays a significant role in how tumor cells develop resistance to anti-cancer agents. Based on these results, it is proposed that mitochondrial reprogramming may play a significant role, at least in some significant part, in how tumor cells gain resistance to anticancer agents used in PCa, including ENZ. This is of importance since there is no cure for metastatic prostate cancer; while second generation anti-androgens, such as ENZ, prolong survival in these men, their PCa invariably relapses. In this regard, the researchers hypothesize that prolonged ENZ exposure dysregulates the MnSOD-K68 axis, reprograms mitochondrial metabolism, and triggers the development of an EZNR phenotype. It is thought that GC4419, a chemical substitute for the catalytic SOD activity of MnSOD, converts the observed ENZR to a sensitive phenotype in mCRPC (Fig. 1). Thus, the long-term goal of this research is to determine if GC4419 is a potential therapeutic agent in men with prostate tumors that have fail systemic therapy with ENZ.
PI: Shilajit Kundu, MD, Associate Professor of Urology, Feinberg School of Medicine
Co-PI: John S. Witte, PhD, Professor of Epidemiology/Biostatistics and Urology, UCSF Helen Diller Family Comprehensive Cancer Center
Previous studies have noted an associated between chronic inflammation and prostate cancer, yet the risk of prostate cancer in men with chronic inflammatory conditions, specifically inflammatory bowel disease (IBD), is not known. This project will conduct genetic studies to identify the mechanisms that drive prostate cancer development in men with inflammatory bowel disease. The investigators will determine whether the individual genes that are associated with IBD are also associated with prostate cancer. Additionally, since one single gene may not explain genetic commonalities between prostate cancer and IBD, they will develop a risk score to determine if multiple genes acting together result in a stronger link between the two diseases.
This study aims to identify the shared underlying genetic basis of IBD and prostate cancer. The findings will help provide important advances in our understanding of prostate cancer development and will also indicate whether men with IIBD should undergo more active prostate cancer screening.
PI: Joshua Meeks, MD, PhD, Assistant Professor of Urology and Biochemistry and Molecular Genetics
Metastatic bladder (urothelial) cancer is one of the most aggressive, treatment refractory solid tumors and female gender is associated with a 20% worse survival than males. The biological causes of this disparity is unknown. This proposal aims to investigate the gender disparity of bladder cancer. The Meeks lab hypothesizes that cells and tissues of the stroma microenvironment may contribute to the gender differences in tumor aggressiveness between males and females with bladder cancer. The overall objective of this application is to dissect the tumor and immune mechanisms of resistance to chemotherapy and immunotherapy in muscle invasive bladder cancer to determine the differences in response to therapy between men and women. The investigators will first determine how gender impacts response to chemotherapy in both epithelial and stromal tissue compartments of bladder cancer, and will then investigate how gender affects immune cell activity prior to radical cystectomy. Lastly, they will validate these signatures and investigate those found in the tumor immune microenvironment of cancers resistant to immunotherapy. Collectively, this work will identify novel pathways and potential therapeutic targets of the stroma to improve survival of both men and women with bladder cancer and translate into improved outcomes for female patients of the Polsky Urologic Cancer Institute.
PI: Chad Mirkin, PhD, Professor of Chemistry, Weinberg College of Arts & Sciences
Immunotherapy vaccination is a powerful emerging treatment strategy for a variety of malignancies. Like an influenza vaccine, an effective cancer vaccine would specifically recognize and activate the immune system against a specific cancer cell marker. Dr. Mirkin is investigating the development of vaccines which target metastatic castrate-resistant prostate cancer (mCRPC), a deadly cancer with few viable treatments. Since vaccination efforts in ongoing clinical trials have not been effective at eliminating the disease burden, the Mirkin group is utilizing Spherical Nucleic Acids (SNA), a nanoscale architecture that consists of DNA that is spherically oriented around a nanoparticle core. These structures greatly increase the efficacy of immunostimulatory agents owing to their novel 3-dimensional architecture and are currently part of four human clinical trials. Using SNAs, Dr. Mirkin and his team will strengthen antitumor immune responses and ultimately improve immunotherapy through the rational design of the SNA construct. They plan to do this by designing and synthesizing SNAs capable of targeting multiple tumor cancer markers, thus improving the range and breadth of the stimulated immune responses. By investigating SNA vaccine efficacy in both mouse tumor models and patient samples, they hope that this will be easily transferred to clinical practice.
PI: Milan Mrksich, PhD, Professor of Biomedical Engineering, McCormick School of Medicine, Professor of Chemistry and Cell and Molecular Biology, Weinberg College of Arts & Sciences
Antibody therapeutics that target protein markers on cancer cells and deliver cytotoxic agents hold significant promise as prospective treatments for prostate cancer. These drugs contain highly specific binding domains that target proteins that are overexpressed on the cancer cells, and deliver radioactive atoms that emit high-energy particles (e.g. alpha particles) to kill the cancer cells. The current therapeutics show promise but still have significant side effects because they bind to healthy cells that also present the target proteins, albeit typically at lower levels. This project will develop a new class of antibody mimics, called ‘megamolecules’, that are more selective in targeting prostate cancer cells because they are designed to bind to two overexpressed proteins on the cancer cells (so called bi-specific recognition) and that have multiple copies of each binding domain (i.e. multi-valent), and that deliver the radionuclide. The synthesis of therapeutics with multiple types of binding domains or with multiple copies of each binding domain, along with the alpha particle emitter is impractical with most current production methods. However, the megamolecule platform, developed in the Mrksich laboratory, provides a facile method for producing therapeutics with this complexity. A unique aspect of this platform is the method for connecting protein domains, which uses reactions between enzymes and inhibitors to snap the pieces together in arrangements that are not feasible with traditional protein engineering methods, enabling the creation of, for example, branched and cyclic structures. The investigators will use the megamolecule platform to test dozens of design variations of targeted alpha therapeutics. The therapeutics will contain separate binding domains that target either prostate-specific membrane antigen (PSMA) or epidermal growth factor type II receptor (HER2), and will vary in the number, binding strength, and arrangement of binding domains. The therapeutics will also incorporate a chemical binder for the radionuclide actinium 225 (225Ac). The hypothesis is that structures that target multiple overexpressed targets on cancer cells will be more selective for the prostate tumor cells, and that this selectivity can be optimized by adjusting the number, binding strength, and relative positioning of binding domains on the megamolecules. These structures offer a completely novel opportunity to boost the efficacy of targeted alpha immunotherapeutics.