Developmental Research Program (DRP)

Title: Novel Thorium-227 agents for targeted alpha therapy of advanced prostate cancer 

Prostate cancer remains a leading cause of cancer-related death in men in the United States. Although most patients initially respond very well to chemical castration with drugs that lower the body’s testosterone levels, eventually, cancer comes back in nearly all men treated. Recurring tumors typically reappear at various places around the body, showing more aggressive traits like resistance to chemical castration. This stage of the disease, called metastatic castration-resistant prostate cancer mCRPC, is the lethal form of prostate cancer. Because more than half of mCRPC patients die within three years despite intense chemotherapy, there is an urgent need for better treatments to treat this stage of disease more effectively. Therefore, we aim to develop a highly effective therapy regime that will eradicate lethal mCRPC. A unique feature of mCRPC cells is that they express elevated levels of the membrane protein prostate-specific membrane antigen (PSMA). Radiopharmaceutical therapy is a therapeutic modality that employs radioactive molecules to target PSMA and deliver lethal radiation to cancer cells selectively. A recently FDA-approved radiopharmaceutical Lu PSMA-617 showed encouraging therapeutic activity in advanced mCRPC, but not all patients benefited from the treatment, and those who did eventually recurred. A more potent version of this agent using Ac, an isotope emitting alpha particles, has been shown to increase the efficacy of the therapy but at the expense of increased normal tissue toxicity. Additionally, the limited availability of Ac hinders the widespread implementation of these targeted alpha therapy (TAT) agents. The goal of our proposal is two-fold. First, we will develop a novel series of PSMA targeting TAT agents addressing the toxicity concerns of PSMA-617 as a delivery vector for alpha-emitting radionuclides. Second, we will design these agents to carry Th as an alternative alpha-emitting payload. Compared to Ac, Th supply is robust as it is a precursor of the ubiquitously used drug Xofigo. To this end, we will synthesize a series of structurally related compounds (ART-100) which we will radiolabel with Th and test in mouse models of prostate cancer. If successful, the agents arising from the proposed studies will be ideal in terms of targeting properties, safety, and scalability. Finally, preliminary data from these studies will support the submission of larger funding applications focusing on translating the most promising candidates into early clinical testing. 

Title: Targeting NSD2 in advanced prostate cancer 

To date the majority of treatments focus on altering behavior of the androgen receptor, a key target in prostate cancer progression. New targets are required as more frequently advanced cancers are developing androgen receptor resistance. One major regulator of cell behavior involves a series of enzymes called lysine methyltransferases. Enzymes are excellent cancer targets. We have discovered that unique histone patterns result in androgen resistant cells that are controlled by these enzymes. In this proposal we will examine one of these enzymes, NSD2, as a potential “Achilles heel” that plays a key role in the resistance response of prostate cancer cells after hormone removal. Specifically, we will test this novel approach in cell culture models and clinically relevant human prostate cancers, and test a new drug being developed in a collaboration with a local biotechnology company. Our studies will lead to a new treatment paradigm for prostate cancer to eradicate resistant cells after hormone removal that has the potential to dramatically improve treatment outcomes. This study addresses the development of cancer resistance in men, and furthermore could be readily translated into the clinic since the agents are in later stage development and the combinations proposed, including androgen-deprivation therapy already in use. 

Title: Development of Novel Tumor-selective and BRD4-specific Degraders for the Treatment of Prostate Cancer 

Due to a limited ability to elicit long-term responses, current targeted therapies for castration-resistant prostate cancer (CRPC) have only contributed to a marginal 5% decrease in mortality in the last decade. De novo and acquired resistance to conventional therapies and the risk of severe toxicities are common factors that reduce drug efficacy. We propose to develop novel therapy will improve the overall survival and quality of life of CRPC patients by a) increasing the efficacy of the treatment compared to current therapies, b) reducing toxicity compared to other monotherapies, and c) overcoming resistance to second-generation AR therapies. Our proposed therapeutic reagents will induce genomic instability in CRPC cells that can be leveraged in combination with other targeted therapies such as chemotherapy, radiopharmaceutical, and immunotherapies. Upon demonstration of therapeutic benefit, we will initiate clinical translational efforts quickly by collaborating with other partners. 

Title: Next-generation whole-body diffusion MRI to detect metastatic disease from prostate cancer 

This application will develop and evaluate a new magnetic resonance imaging (MRI) method for the detection of metastatic lesions in patients with prostate cancer. Clinical care for patients with prostate cancer requires accurate detection of metastases, which affects the patient’s therapy. Current methods such as those that use positron emission tomography (PET) to detect metastases often fail to detect all lesions, for example when the lesions are small. Our proposed method has the potential to detect currently missed lesions, and is highly compatible with current PET methods (for example, in PET-MRI systems such as the one available at the University of Wisconsin). This application will develop the proposed MRI-based method and validate it in healthy subjects and patients with prostate cancer. 

Title: Molecular mechanisms and therapeutic targeting of DDX3X in castration resistance 

There is a knowledge gap for identifying which prostate cancers (PC) develop into lethal castration resistant PC (CRPC), and which PCs will be responsive to therapies. CRPC is characterized by the ability to grow in a “castrate” host. There are several mechanisms that have been described for how CRPC manifests including, AR amplification, AR mutations, intra-tumor androgen synthesis, ligand independent AR activation, and AR variants. While these mechanisms explain how cancers can grow under castrate conditions, they all center on the activation of AR.  What is significantly overlooked is: AR negative cancer cells, which are the ideal cell type to grow in castrate conditions because these cells lack the ARs and do not need androgen ligands to proliferate or survive. However, few studies have evaluated CRPC with AR negative cells. A mounting body of evidence has shown that CRPC, especially AR negative [aka double negative PC (DNPC)] is increasing in men treated for PC. Currently, 2nd generation therapies to treat CRPC serve to severely reduce AR signaling (e.g. enzalutamide) and although highly effective, these therapies commonly act on, or create, a population of AR negative cells, a key feature of the disease.  Therefore, if the current therapies are to be more efficacious, identifying how these AR low/negative cells escape therapy by decreasing AR expression is necessary; additionally, therapeutically targeting them is clinically needed. By identifying the mechanisms underlying this decrease of AR expression, it may be possible to prevent the down-regulation of the receptor and re-sensitize CRPC to current therapies.  We have recently discovered that the RNA binding protein/helicase, DDX3X, binds AR mRNA directly. We found that DDX3X is overexpressed in PC, especially in DNPC. These cells appear to be AR negative at the protein level (not mRNA level), resulting in growth during castrate conditions (e.g. androgen deprivation). We have also observed that therapeutics to inhibit DDX3X promote AR protein positivity. Moreover, by inhibiting DDX3X with DDX3X inhibitors, these cells become susceptible to current therapies, i.e. they are no longer castration resistant. We hypothesize that CRPC occurs, in part, due to increased levels of DDX3X, and that inhibition of DDX3X function may re-sensitize DNPC to highly clinically effective antiandrogen therapies. The proposed research will provide a better understanding of molecular and cellular mechanisms of CRPC/DNPC and provide a novel co-treatment therapeutic approach for men diagnosed with CRPC/DNPC. Patients with CRPC/DNPC would be the immediate recipients of the proposed research. Additionally, diseases involving AR pathways (e.g. prostate cancer, liver cancer, benign prostate 26 diseases, bladder cancer, sarcopenia, breast cancer, and others) may benefit from this research.  Since the proposed therapeutics are well tolerated and FDA approved, translation to the clinic is expected to be relatively quick (<5 years). A new multidisciplinary team [Biomedical (Ricke) and Chemistry (MacGillivray)] will be formed with the proposed research; furthermore a 2024 R01 submission will result from this work.