Our group has two main areas of laboratory and clinical investigation, the common denominator being the application of basic research and new technologies to the management of prostate cancer.
First, we are focused on understanding the fundamental mechanisms that lead to prostate cancer metastasis and progression to castration resistance (in which prostate cancers become resistant to testosterone inhibition using drugs such as Lupron, Enzalutamide and Abiraterone). In particular, we are developing novel therapies to intervene in these pathways of resistance. These include development of antibody therapies that we are hoping to take into the clinic. These also includes the use of approved cancer drugs in clinical trials of men with high risk and metastatic prostate cancers.
Second, we are focused on improving the ability to detect prostate cancer in patients using PET (positron emission tomography), MRI, and other forms of imaging. We have made major contributions in the development of MRI to diagnose and manage prostate cancer, being among the first to use this technology to plan and perform robotic surgery. In the laboratory, we have developed novel probes (proteins or small molecules that can hone in on prostate cancers anywhere in the body and enable visualization/detection by PET scans) for PET and other imaging. Specifically, we developed antibody scaffolds called minibodies that can detect prostate cancer proteins such as PSCA (prostate stem cell antigen) and PSMA (prostate specific membrane antigen). In addition, we are developing methodologies to see prostate cancers during surgery using fluorescent probes, a major unmet need.
1. Mechanisms and therapeutics of castration and therapy resistance: The overall goal of our work is to determine how prostate cancers become resistant to hormonal therapies that block the androgen (testosterone) receptor pathways, particularly the problem of resistance to newer drugs such as Enzalutamide and Abiraterone. We have a number of projects exploring this area of research:
(a) We have identified a cell surface protein called N-cadherin that can lead to hormone resistance, as well as drug resistance in advanced prostate cancer. We are working on understanding how N-cadherin causes resistance at the molecular level and have designed therapeutic antibodies that can bind to and inhibit N-cadherin, which in animal models can prevent or delay progression of prostate cancer. We have recently selected a lead antibody to take to the clinic. We have also elucidated some of the pathways by which N-cadherin can cause treatment resistance and are testing drug combinations that can block this.
(b) We are working to identify novel pathways that lead to treatment resistance by sequencing the tumors of 200 men who underwent biopsy of their resistant and metastatic cancers. To date, we have found a number of potential targets and pathways that may cause resistance, including activation of signals that lead cancers to change to a more primitive or stem-like phenotype that is highly treatment resistant. We have identified putative pathways that are critical for this process and used existing drugs to try to intervene. We recently completed a clinical trial in men with high risk cancers prior to surgery in which men are treated for two months with the newest forms of testosterone blockade in addition to one of two novel “targeted” therapies in order to determine if the study drugs can block the resistant pathways from emerging. We are in the process of analyzing the genomic and clinical outcomes of this trial. Finally, with an interest in the emerging area of immunotherapy, we completed a clinical trial which men are being treated with radiation PRIOR to surgery. The goal of the trial is to determine if radiation can trigger an immune response that may then be abetted with additional drugs. We are in the process of analyzing the clinical and genomic outcomes of this study and developing new preclinical and clinical studies based on these results. To date, our studies have shown that radiation does induce an immune response characterized by the infiltration of both anti-tumor and pro-tumor cell types. Therefore, one goal is to augment to good response and suppress the deleterious one using existing drugs.
2. Imaging prostate cancer: As mentioned above, our interest is to fundamentally change the way we manage prostate cancer. Historically, we have had few ways to detect cancer either in the prostate or when it spread. This led to the performance of “blind” biopsies, lack of visualization to guide surgeries and guessing where a cancer was when it recurred after radiation and surgery. Also, this led to an inability to monitor the effectiveness of drugs because we could not visualize tumor progression or regression. To solve these problems, we have worked in three areas over the past 15 years.
(a) MRI—we were among the first to use MRI of the prostate to detect and manage prostate cancer. In particular we showed that MRI is able to detect more than 80% of tumors and that radiologic features found on MRI can correlate and predict the aggressiveness of tumors. The flip side of this coin is that 20% of tumors cannot be visualized. We are currently engaged in projects to determine why some cancers are visualized and others are not by sequencing the DNA and RNA of such tumors and determining whether tumor biology can explain this phenomenon. Our goal is to sequence up to 300 visualized and non-visualized tumors comprehensively and to develop a new predictive tool that combines imaging and genomic features of tumors to make treatment decisions. We have two studies that were recently published and first-in-field. Our goal now is to increase the power of our observations, extend them to include proteomics in addition to genomics, and to develop an algorithm incorporating ALL data to predict prostate cancer aggressiveness and guide management
(b) PET—PET scans can detect positrons emitted by cancer specific probes that target cancers. Until recently there were no available probes that could detect prostate cancers reliably. In this domain, we have developed a novel antibody probe that binds to PSCA, a protein our lab discovered that is present in almost all prostate cancers as well as pancreatic and bladder cancers. We are exploring the use of this probe for clinical use now that animal studies have been completed. We have also worked with the department of Nuclear Medicine at UCLA to bring another novel probe to the clinic that targets another prostate cancer program, PSMA. This test has now been available at UCLA for three years now and is radically changing how we manage prostate cancer. However, we do not yet know how to use this new information accurately and are developing clinical studies to determine how to apply the information in men with newly diagnosed and recurrent prostate cancers.
(c) Imaging during surgery—One problem we have as surgeons is that we cannot see cancers during surgery. So a PSMA PET scan (above), for instance, could show that there is a single lymph node that might harbor prostate cancer, but when we look inside the patient we cannot easily find that lymph node because it might be of normal size or texture. Likewise, because we cannot see the cancer in the prostate, we are always in the dilemma of not knowing how much tissue to take out to remove all cancer. Tradeoffs of taking too much tissue or too little tissue include the risk of impotence and incontinence on the one hand or leaving residual cancer tissue on the other. To solve this problem, we have developed PSCA and PSMA fluorescent probes that can be detected with fluorescent cameras during surgery. We recently published that we can reduce the chances of cancer recurrence in animal models of prostate cancer by using these probes and hope to bring this new technology into the clinic soon. We have also created dually functional probes that can be used for both PET and fluorescent imaging so that a patient can receive one injection for both purposes. And finally, we are also attaching therapeutic radioisotopes to the PSCA probes for therapeutic purposes.