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Developing CAR-NKT cells to reprogram the Tumor Microenvironment in Prostate Cancer, Tonya J. Webb, University of Maryland, Baltimore
Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in men older than 40 years in the United States. PCa is a significant health concern particularly in patients who are resistant to standard hormone therapies, such as androgen deprivation. These patients have developed castration-resistant prostate cancer (CRPC), which has a median survival rate of only 14- 15 months, thus the development of novel therapeutic targets is critical. It is known that the host’s immune system can often recognize cancerous cells and destroy these transformed cells. One of the earliest pathways in immune activation is the presentation of lipid antigens by CD1d molecules to a unique subpopulation of T cells called natural killer T (NKT) cells. NKT cells are primed cells which can, if appropriately activated, lead to the development of a robust anti-tumor immune response. However, the immune system in PCa may be compromised as we have observed a profound reduction in circulating NKT cells in the blood of PCa patients. Studies in our lab have further demonstrated that blockade of sphingosine phosphate, a key regulator in cellular metabolism, can restore NKT cell responses to PCa. Therefore, the goal of our proposed studies is to test the hypothesis that lipid metabolism regulates immune responses to PCa, and understanding the mechanism will lead to the development of novel therapeutic targets.
Murine Modeling and Immunotherapeutic Targeting of GPC3 Positive Prostate Cancer, Dr. Christopher J. Pirozzi and Dr. Jiaoti Huang, Duke University Medical Center
Despite a decrease in Prostate Cancer (PCa) incidence over the past decade, there has been an increase in metastatic PCa. This transformation into a lethal disease is expected to raise the current burden of PCa by 42%. We hypothesize that by understanding the differences between primary and metastatic PCa through establishment of genetically faithful and biologically relevant model systems, that we will reduce this burden and the deaths associated with metastatic disease. Our models will enable an understanding of primary and metastatic PCa through the biological and transcriptional characterization of the tumor microenvironment (TME) among primary and metastatic lesions. Additionally, following our discovery of tumor-specific expression of the oncofetal protein, GPC3, in neuroendocrine cells, we seek to identify the role of GPC3 in tumor biology, but also in how it modulates the TME to promote resistance and ultimately, recurrence. As GPC3 is expressed in therapy resistant neuroendocrine cells, we will apply what is known in targeting GPC3 in hepatocellular carcinoma to our murine models and determine the therapeutic efficacy of GPC3 peptide vaccination. We will assess the ability to augment the immunogenicity of peptide vaccination with DRP-104, a prodrug known to activate CD8+ T cells. These studies will 1-provide a faithful murine system that can be adapted to study the contribution of specific genes or mutations to tumorigenesis and the TME, 2. provide a foundation for comparing the TME between primary and metastatic tumors that can be therapeutically exploited, and 3. provide a rationale for co-therapy of GPC3 peptide vaccination and DRP-104 for prostate cancer. As the TME is imperative to the overall success of a metastatic lesion, we provide the systems to perform a thorough comparison between primary and metastatic PCa in the context of GPC3 that can illuminate therapeutic sensitivities to be utilized for therapeutic benefit.
Investigating PTGES3 as a Novel Therapeutic Target in Advanced Prostate Cancer, Dr. Haolong Li, Fred Hutchinson Cancer Center
The androgen receptor (AR) is a major driver of prostate cancer growth and progression. While therapies targeting AR have shown significant benefits for patient survival, aggressive prostate cancers frequently develop resistance by reactivating AR signaling. This highlights the urgent need for new strategies to inhibit AR and improve outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC).
To identify new regulators of AR, we developed a unique AR reporter system using CRISPR-Cas9 to tag AR with a fluorescent protein in prostate cancer cells. This novel approach allows precise monitoring of endogenous AR levels without the disruptions caused by traditional overexpression models. Using this reporter, we conducted genome-wide CRISPR interference (CRISPRi) screens to identify genes that control AR protein levels.
Our screens revealed several known AR regulators, such as HOXB13, GRHL2, and GATA2. However, a less-characterized gene, prostaglandin E synthase 3 (PTGES3), emerged as a top candidate. We found that PTGES3 physically interacts with AR in the nucleus and significantly increases AR protein levels and activity. These results nominate PTGES3 as a novel target for therapeutic development in mCRPC.
We propose two specific aims to further investigate the role of PTGES3 in regulating AR:
Aim 1: Investigate the dual mechanisms by which PTGES3 regulates AR. We will explore its roles in prostaglandin E2 synthesis and as a protein chaperone using biochemical and genetic assays.
Aim 2: Validate PTGES3 overexpression as a biomarker of resistance to AR-targeted therapies. We will analyze its impact on treatment resistance using in vivo models and patient samples from clinical trials.
Overall, this study will deepen our understanding of how prostate cancer adapts to current therapies and provide a basis for developing new PTGES3-targeted treatments for patients with advanced prostate cancer.
Targeting dopa decarboxylase (DDC)-dependent metabolic reprogramming to overcome immunotherapy resistance in NEPC, Dr. Guocan Wang, The University of Texas MD Anderson Cancer Center
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that accounts for 20- 30% of lethal cases. While de novo NEPC is rare, it often arises as a resistance mechanism in patients treated with androgen pathway inhibitors (ARPIs). Due to the increasing use of ARPIs, the incidence of NEPC is on the rise. Currently, no effective therapies are available for NEPC, highlighting a critical need for new treatment strategies.
Although immunotherapy has transformed cancer treatment, most prostate cancer patients, especially those with NEPC, respond poorly. A major factor limiting its efficacy is the metabolic stress imposed on T cells by the tumor microenvironment (TME), resulting from cancer-driven metabolic reprogramming. Targeting these metabolic pathways is a promising approach to improve immunotherapy responses.
Tryptophan, an essential amino acid, is catabolized via kynurenine, serotonin, and indole pathways. Tryptophan plays a crucial role in tumor progression and immune evasion. While the kynurenine pathway has been extensively studied, the serotonin and indole pathways are less understood. We have identified overexpression of dopa decarboxylase (DDC), an enzyme involved in serotonin and indole pathways in tryptophan metabolism and dopamine production, in NEPC. Preliminary data suggest that DDC contributes to a “cold” TME and immunotherapy resistance via metabolic reprogramming.
In Aim 1, we will test whether targeting DDC, either genetically or pharmacologically, can delay NEPC progression and enhance NEPC response to ICT. In Aim 2, we will explore the mechanisms by which DDC drives NEPC progression and immunotherapy resistance.
If successful, our study will establish a novel therapeutic strategy by targeting DDC to improve NEPC clinical outcomes. Given that DDC inhibitors are already approved for Parkinson’s disease and have a well-established safety profile, they could be repurposed for NEPC treatment, either as monotherapy or in combination with immune checkpoint therapy (ICT), enabling rapid translation into clinical trials.
Harnessing TMPRSS2-ERG Fusion-Derived Neoantigens for an Off-the-Shelf Prostate Cancer Vaccine, Dr. Nina Bhardwaj and Dr. Mesude Bicak, Icahn School of Medicine at Mount Sinai
Prostate cancer, despite having a relatively low mutation burden, harbors a high frequency of gene fusions, particularly the TMPRSS2-ERG fusion, present in up to 70% of patients. This fusion generates unique, tumor-specific proteins, making it a promising neoantigen source for immunotherapy. Our preliminary analysis of the TCGA-PRAD cohort demonstrates the significant impact of incorporating TMPRSS2-ERG fusions alongside single nucleotide variants (SNVs), substantially enhancing potential patient coverage from 9% to 46%. Notably, we observed that TMPRSS2-ERG fusion-derived neoantigens were immunogenic and elicited CD4+ T cell responses, underscoring the viability of TMPRSS2-ERG fusions as effective targets for immunotherapy in prostate cancer.
If awarded, we will evaluate the therapeutic potential of TMPRSS2-ERG fusion-derived neoantigens for the development of an off-the-shelf prostate cancer vaccine. We will combine (i) comprehensive bioinformatics analysis of TMPRSS2-ERG fusions across in-house matched blood, tumor and adjacent normal samples from primary prostate tissue, as well as the TCGA-PRAD dataset, and (ii) immune monitoring to assess the immunogenic potential of these neoantigens. Our key resources include OpenVax, our in-house bioinformatics pipeline successfully utilized in multiple clinical trials, which we now extend to predict fusion-derived neoantigens and their MHC-I binding potential, as well as our in-house immune monitoring platform, which will determine their ability to elicit robust CD4+ and CD8+ T-cell responses.
By pioneering the combination of TMPRSS2-ERG fusions with SNVs, we aim to significantly broaden the scope of prostate cancer immunotherapy. If successful, our approach could revolutionize prostate cancer treatment by offering a precision-based, off-the-shelf vaccine that provides durable, robust immune responses, ultimately benefiting a significantly larger patient population. Moreover, this work could also establish fusion neoantigens as critical components of cancer immunotherapies, which is currently underexplored.
PSMA targeted sialidase for prostate cancer immunotherapy, Dr. James D. Brooks, Stanford University
A growing body of evidence suggests a vital role for interactions between Sialic acid (SA)-binding immunoglobulin-type lectins (Siglecs), expressed in immune cells such as NK cells, T cells, macrophages and their ligands, SA-containing glycoproteins, expressed in cancer cells, in suppressing immune cell functions within the tumor microenvironment (TME). Efforts on developing novel therapies targeting Siglec/SA axis as a new immune checkpoint in cancer to overcome immune evasion have increased dramatically in recent years. For example, in breast cancer, a novel targeted therapeutic (Tia-2) comprised of anti-HER2 antibody conjugated to Salmonella typhimurium sialidase (STS) that cuts off SA from glycoproteins on the cancer cell surface has been shown to increase cancer-killing by NK cells. An optimized version of Tia-2, E602, with two units of sialidase, is currently being evaluated in phase I/II clinical trials for several HER2-expressing solid tumors. We hypothesize that removing SAs from PCa cell surface using STS conjugated to an antibody against prostate-specific membrane antigen (PSMA) will block Siglec/SA axis and improve NK, macrophage, and T cell-mediated PCa killing. In Aim 1, we will develop a genetically engineered PSMA-STS fusion protein by coupling a commercially available PSMA antibody to STS. In Aim 2, we will determine the efficacy of PSMA-STS in inhibiting tumor growth and metastasis using three PSMA-positive and two PSMA-negative patient-derived xenografts (PDXs). Mice carrying PDXs will be randomized and treated with PSMA antibody alone, STS alone, or PSMA-STS. Tumor volume will be monitored by MRI. At the end of the experiment, tumor cell proliferation and apoptosis will be evaluated by immunohistochemistry using antibodies against Ki67 and cleaved Caspase-3, respectively. Lung, liver, and bone will be snap-frozen for metastatic burden evaluation using human-specific GAPDH qPCR. The number of intratumoral cytotoxic NK, T cells, and macrophages among different groups of mice will be examined by flow cytometry.
Elucidating Circulating Tumor and Immunological Phenotypes Following Treatment with SBRT +/- 177Lu-PNT2002 in Men with Oligometastatic Recurrent Prostate Cancer, Luca Valle, M.D., University of California Los Angeles
Treatments for prostate cancer are excellent, but sometimes the prostate cancer can unfortunately come back after treatment. When the prostate cancer comes back in a location far away from the prostate (like a lymph node or a bone), but there are only a few areas (less than 5) where the cancer has spread, this is referred to as “oligometastatic” prostate cancer. We used to think that these men were incurable, but recent studies have shown that treating these few metastatic sites with targeted radiation improves outcomes and can even lead to cure. However, sometimes the cancer still comes back even after these focused radiation treatments. As a result, we have been exploring whether adding another form of systemic radiation therapy that travels throughout the body and seeks out prostate cancer cells in a targeted manner will be able to further prevent the disease from coming back.
We have seen very promising results, but we want to better understand why this combination treatment works so well. Looking at the immune systems of men with oligometastatic prostate cancer as well as prostate cancer cells circulating in the blood may unlock our ability to understand this better. The success of this project will enable the development of tools that can be directly translated clinically to help improve the treatment of men with oligometastatic prostate cancer. It will enable a more sophisticated approach for microscopically monitoring and prognosticating disease progression while simultaneously improve our understanding of how the biology of the immune system of men with prostate cancer may be driving the favorable results we have seen so far (in terms of preventing the disease from progressing) when we add radionuclide therapy to targeted radiation treatments for prostate cancer that has spread to only a few areas of the body.
Artificial Intelligence (AI) based Radio-Pathomic nomogram to prognosticate treatment outcomes in prostate cancer patients following radical prostatectomy, Rakesh Shiradkar, Ph.D., Emory University
Prostate cancer patients with localized and intermediate/high risk disease typically undergo surgery or radical prostatectomy. Of these, about 30% experience cancer reoccurrence and such patients with aggressive disease are at high risk of metastasis and death. Therefore, pre-emptively identifying patients who are likely to experience reoccurrence even before undergoing surgery will allow for administering more aggressive, alternative therapies thereby improving treatment outcomes. Magnetic Resonance Imaging (MRI) and biopsy are routinely used as standard of care for prostate cancer diagnosis. We have previously demonstrated that Artificial Intelligence (AI) based approaches leveraging prostate MRI and digitized pathology, separately, can predict which patients would experience cancer reoccurrence following surgery. These AI methods outperformed extant prognostic assays such as CAPRA nomogram and genomics based Decipher test which are also expensive at tissue destructive.
However, there is a need for more advanced and comprehensive qualification of patters associated with prostate cancer reoccurrence through integration of pre-treatment MRI and biopsy data. This is particularly relevant in the context of disparities wherein biological differences in tumor biology exist between different populations. For instance, African American men experience significantly adverse prostate cancer outcomes compared to Caucasian counterparts. In this project, we will leverage routine standard of care data modalities, including MRI (radiology) and digitized biopsy (pathology), and develop AI based methods that can identify and integrate complementary patterns associated with prostate cancer reoccurrence post-surgery. We will validate the integrated AI based ‘radio-pathomic’ model in a diverse cohort of patients at Emory University including African American and Caucasian American men. This project will demonstrate feasibility of using AI to integrate multiple data modalities (MRI and biopsy) prior to surgery that can be leveraged in future projects to address health disparities in prostate cancer.
Elucidating the functional significance of full-length androgen receptor in castration-resistant prostate cancer, Selvarangan Ponnazhagan, Ph.D., University of Alabama at Birmingham
Prostate cancer is the second leading cause of all cancer-related deaths and ranks as the highest among cancer types in men. The American Cancer Society (ACS) estimates that about 288,300 new cases and 34,700 new deaths will occur from prostate cancer in the United States alone in 2023. According to the ACS, approximately 5,320 new cases of prostate cancer will be diagnosed in Alabama in 2023, which is alarmingly higher than projected new cases of breast cancer in our state this year. Epidemiological data highlights important disparities in cancer outcomes, including death rates among the African American population. For example, the fatality rate is higher in African Americans for most of the cancers, compared to other racial and ethnic categories. This disparity is most pronounced for breast, colon, and prostate cancers. Although early diagnosis and aggressive interventional therapies extend the survival rate for prostate cancer patients, unfortunately, a lethal form of advanced disease known as castration-resistant prostate cancer (CRPC) ensues to which no treatment options are effective. Hence, defining how prostate cancer progresses to lethal disease will shed more light on developing targeted therapies and thus improve survival of men with CRPC.
It is widely known that prostate cancer is driven by the androgen receptor, which regulates the expression of genes involved in tumor growth and metastasis. Targeting the androgen receptor is the mainstay for controlling the disease. However, the tumor relapses by acquiring mutations in the androgen receptor. Despite the identification of mutant androgen receptors in patients with resistant disease, molecular events that lead to the development of recurring prostate cancer are not clearly understood. Hence, there is an imminent challenge for identifying mechanisms that are responsible for the aggressive growth of CRPC. We recently identified that following androgen deprivation therapy and enzalutamide treatment (used in men with pre-metastatic and metastatic prostate cancer to minimize aggressive growth of prostate cancer), tumor repopulating stem cells, which are otherwise dormant, reactivate their androgen receptor function and become aggressively growing cells with resistance mechanisms. We further identified that cooperation between normal and mutant androgen receptor types in this scenario provides survival signals for tumor cells while developing resistance. Based on these clues, we will investigate how current therapy promotes unintended activation of otherwise dormant prostate cancer stem cells and identify key regulatory elements that are responsible for androgen receptor reactivation in CRPC. Outcomes of this study will shed important light on how survival signals in resistant tumors are regulated. This can be used in new, targeted therapy combinations to extend patient survival.
Immunotherapy with γδ T cells for Neuroendocrine Prostate Cancer, Craig Morita, M.D., Ph.D., University of Iowa
In the USA in 2023, it is estimated that there will be 288,300 new cases of prostate cancer and 34,700 deaths. For men, prostate cancer is the second most deadly cancer, behind lung cancer. Early-stage prostate cancer can be effectively treated, but in advanced cases, with the most common treatment being androgen deprivation therapy, resistance invariably develops within 2-3 years. About 20-25% of the time, this resistance is due to the transition of the cancer to a neuroendocrine prostate cancer (NEPC), where median survival after diagnosis is only 7 months with almost no long term survivors. Despite advances in cancer treatment, progress is still limited for many types of cancers, especially solid tumors such as prostate cancer.
Our proposal will develop a new treatment for NEPC using immunotherapy. Immuno- therapy is an exciting approach where the patient’s immune system is used to fight cancer cells. A new tool for immunotherapy is the bispecific antibody. As opposed to the classical antibody that binds one site, a bispecific antibody will bind to two sites. For our proposal, we have prepared a bispecific anti- body that binds to prostate cancer cells and to a specific type of lymphocyte, that is part of the immune system. We propose to demonstrate that when the bispecific antibody binds to the two sites, the lymphocyte will be activated and will kill the neighboring prostate cancer cell. Using a cell free system, we will be mixing the bispecific antibody with a prostate cancer cell line and purified lymphocytes. In mice, we will implant the mice with a prostate cancer tumor and then introduce the bispecific antibody and lymphocytes by injection. If successful, the bispecific antibody will provide a significant advance in prostate cancer treatment and will next be tested in monkeys and then humans.
Novel epigenetic therapies for bone metastatic castrate-resistant prostate cancer, Juan Arriaga, Ph.D., Icahn School of Medicine at Mount Sinai
Prostate cancer may spread to bones in a process called metastasis and when it does patient survival drops dramatically. Moreover, bone metastasis leads to debilitating symptoms such as pain, fatigue and susceptibility to fractures that drastically affect quality of life. A treatment modality called immune checkpoint blockade leverages a patient’s immune system to attack tumors and although it has shown remarkable success in many cancer types, marginal responses are observed in prostate cancer. Therefore, a major unmet need in prostate cancer is to develop new treatments against bone metastatic disease, as well as to improve responses to immune checkpoint blockade, to ultimately improve patient survival.
In order to develop much needed new treatments, we need to understand how prostate cancer evolves into bone metastatic disease. For this purpose, we have recently developed novel models of prostate cancer bone metastasis in mice with intact immune systems, that also expand our tools to study responses to immune checkpoint blockade. Such studies are challenging to perform in human models before getting to clinical trials. By integrating findings in mouse models and human prostate cancer tissues we have identified a gene called ATAD2 which we show may be involved in blunting immune responses. We therefore hypothesize that ATAD2 expression in bone metastases can favor resistance to immune checkpoint blockade and that specific small molecule inhibitors of this protein can revert this. Therefore, our goal in this proposal is to test whether ATAD2 inhibitors can improve responses to immune checkpoint blockade using our unique models of lethal bone metastatic prostate cancer, as well as to study the biological mechanisms of how this occurs.
If successful, this proposal will develop and test novel therapeutic strategies that may lead to transforming the therapeutic options for patients with bone metastatic prostate cancer.
OGDHL as a new target in neuroendocrine prostate cancer, Andrew Goldstein, Ph.D., University of California Los Angeles
While localized prostate cancer is often treatable with surgery or radiation therapy, the disease becomes much more difficult to treat when it spreads to other tissues in the body. Advanced metastatic prostate cancer is typically treated with therapies targeting the androgen receptor. Androgen receptor targeted therapies are effective for some patients, but eventually most advanced metastatic prostate cancers develop resistance. Treatment-resistant prostate cancer is responsible for the majority of prostate cancer-associated deaths, which amounts to more than 30,000 annual deaths in the United States alone. There is a critical need to develop new therapies that can halt the progression of treatment-resistant prostate cancer. In order to develop new therapies, we need to identify important molecules that fuel the growth of treatment- resistant prostate cancer cells.
Neuroendocrine prostate cancer is one of the most resistant and difficult-to-treat forms of prostate cancer. While neuroendocrine prostate cancers were previously considered rare, Oncologists and Pathologists are increasingly finding neuroendocrine disease in patients who have been heavily treated with therapies targeting the androgen receptor. We looked at patient tumors and experimental models of different forms of prostate cancer and identified a molecule called OGDHL that is found specifically in neuroendocrine prostate cancer but not in other stages of the disease or in the normal/healthy prostate. Because OGDHL is found in neuroendocrine prostate cancer cells but not in other prostate cells, blocking its function would likely have a specific effect on neuroendocrine cells, making it a good therapeutic target. In this proposal, we will specifically evaluate the role of OGDHL in neuroendocrine prostate cancer. We hypothesize that interfering with OGDHL will block the growth of neuroendocrine prostate cancer. In preliminary experiments, we found that cell growth was stalled when we blocked OGDHL. Identifying a new therapeutic target could improve outcomes for patients with treatment-resistant prostate cancer.