Kerry L. Burnstein, Ph.D., Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine
Targeting KIF20A a critical promoter of castration resistant prostate cancer in robust pre-clinical models
Although prostate cancer (PC) patients respond favorably to androgen deprivation therapy (the gold standard of treatment), tumors almost always develop the ability to evade drugs, resulting in castration resistant prostate cancer (CRPC), which is incurable. In CRPC, androgen receptors (proteins normally responsible for regulating the effects of androgens such as testosterone) acquire the ability to promote uncontrollable tumor growth. To improve patient outcomes, new treatment strategies are required to specifically combat CRPC and metastatic CRPC (when tumors have escaped the prostate and initiated growth at remote sites, most commonly the skeleton).
By analyzing publicly available data obtained from patients with PC and by our laboratory experimentation, we identified a protein termed KIF20A that is present at high levels in CRPC and even more so in metastatic CRPC (compared to primary [early stage] PC and normal prostate tissue). In our studies conducted in mice bearing human prostate tumors, we demonstrated that increasing KIF20A (by genetic manipulations) causes primary PC cells to undergo the devastating transition to CRPC tumors. Our cell-based preliminary data showed that blocking KIF20A (either by genetic experiments or by treatment with pre-clinical drugs) stopped the growth of CRPC cells.
We hypothesize that KIF20A promotes the transition to CRPC and aggressive tumor growth by enhancing androgen receptor function (a critical component of most lethal PCs). Given the current availability (and continuing development) of experimental drugs that inhibit KIF20A, we propose that targeting KIF20A offers a promising and novel approach for treating CRPC and metastatic CRPC. We will evaluate a pre-clinical drug that inhibits KIF20A in an array of human prostate tumors transplanted to mice, which closely represents CRPC features found in men.
By directly targeting KIF20A (for which non-toxic inhibitors are currently available), successful discoveries will translate rapidly to clinical trials and near-future new therapies.
Daniel E. Frigo, Ph.D., University of Texas MD Anderson Cancer Center
Targeting Myeloid Cell Metabolism to Sensitize Advanced Prostate Cancers to Immunotherapy
While the androgen receptor remains the central driver of the majority of incurable, castration-resistant prostate cancers, sustained inhibition of AR remains a clinical challenge. Moreover, promising new treatments such as immune checkpoint therapy have, to date, failed to demonstrate significant single agent efficacy in prostate cancer patients and hence, overcome the known immunosuppressive prostate tumor microenvironment. As such, novel therapeutic approaches are needed to improve current clinical outcomes.
Our prior work established an important role for the metabolic process autophagy, a cellular recycling mechanism, in prostate cancer cell biology as targeting autophagy in cancer cells impaired hormone therapy-refractory prostate cancer. Surprisingly, new data indicate that our understanding of autophagy in prostate cancer was incomplete. To that end, upstream activators of autophagy in the surrounding tumor microenvironment also blocked tumor growth, an effect we anticipate will create additional therapeutic opportunities. The goal of this study is to explore new roles for autophagy in prostate cancer and the immune system. It is our central hypothesis that autophagy promotes prostate cancer in part through creating an immunosuppressive tumor microenvironment and therefore, autophagy inhibitors can sensitize advanced prostate cancers to existing immunotherapies. These studies are highly significant because they would provide the validation needed to warrant deeper mechanistic interrogation using more sophisticated models of prostate cancer and drive drug development targeting autophagy to overcome the immunosuppressive prostate tumor microenvironment.
Brian Ruffell, Ph.D., H. Lee Moffitt Cancer Center & Research Institute
Evaluating TIM-3 combination therapies in castration-resistant prostate cancer
Immune checkpoint blockade therapy with anti-CTLA-4 (i.e. ipilimumab) or anti-PD-1/L1 (i.e. atezolizumab) have failed to show a survival benefit in phase III trials in castration-resistant prostate cancer (CRPC). Although it is possible that ongoing combination trials with these agents will provide some benefit, there remains a large unmet need to enhance the efficacy of immunotherapy in prostate cancer by boosting the strength of the antitumoral T cell response.
TIM-3 (T-cell immunoglobulin and mucin domain containing-3) is an immune checkpoint molecule currently being evaluated in clinical trials in combination with anti-PD-1 antibodies in lung cancer and melanoma. These trials are being conducted in highly immunogenic tumors based upon dual expression of PD-1 and TIM-3 by cytotoxic T cells, the immune population largely responsible for the efficacy of immunotherapy. However, we found that TIM-3 is not expressed at high levels by cytotoxic T cells in poorly immunogenic tumors. Instead, we have recently described a unique mechanism of action whereby blocking TIM-3 functions by activating a rare population of dendritic cells, the immune subset that is responsible for controlling cytotoxic T cells.
Critically, we have found that dendritic cell activation only occurs when tumor cells are killed in a manner that releases DNA. Therefore, we propose to identify combinations of cytotoxic therapy that are efficacious with TIM-3 blockade, and determine if these combinations can elicit a response to immune checkpoint blockade. As TIM-3 is constitutively expressed by dendritic cells, the therapeutic combinations we identify should be applicable to the majority of patients with CRPC. Furthermore, there exists the potential for enhanced cytotoxic T cells responses resulting from anti-TIM-3 and cytotoxic combinatorial therapies to increase the rate of response to other forms of immune checkpoint blockade, such as anti-PD-1. Results from these studies could therefore alter the landscape of prostate cancer immunotherapy.
Qianben Wang, Ph.D., Department of Pathology, Duke University School of Medicine
FOXA2-targeted organ-selective nanotherapy for neuroendocrine prostate cancer visceral metastasis
While approximately 80% of prostate cancer patients can be cured in the early stages, about 20% eventually reach a lethal, advanced stage that is resistant to all currently available treatments. The medical field is eagerly researching new treatments for advanced prostate cancer, especially to help patients whose cancer has spread to a key organ such as the liver or the lungs. Researchers have discovered a vulnerability of advanced prostate cancer: It requires a molecule called FOXA2 to spread and survive. Evidence suggests that blocking FOXA2 causes advanced prostate cancer cells to die. Creating a traditional chemotherapy to block FOXA2 has proven to be very challenging, but a new type of treatment called gene therapy appears to block FOXA2 much more effectively. The obstacle remaining is that researchers have not yet discovered a way to deliver gene therapy directly to prostate cancer cells in the liver and lungs, so that anti-cancer activity is maximized and side effects are minimized.
This project has created a small nanoparticle that travels specifically to the liver and lungs and is designed to deliver gene therapy to block FOXA2. The sphere-shaped particles contain gene therapy materials in the center, surrounded by an outer layer that strongly attracts them to advanced prostate cancer cells, but not to normal liver or lung cells. This outer layer will help to avoid any side effects in the liver or lungs. This project will test the safety and effectiveness of this new nanoparticle therapy. If the nanoparticles are both safe and effective, a clinical trial will follow to evaluate their potential to benefit patients. The goal is to provide doctors with a way to destroy metastases and improve the lives of the most advanced prostate cancer patients.
Exploiting ferroptosis for the treatment of lethal neuroendocrine prostate cancer
Neuroendocrine prostate cancer (NEPC) is a subtype of prostate cancer that tends to grow quickly and spread to vital visceral organs such as the liver and lung. It accounts for up to 25% of prostate cancer related deaths. Currently, there are no effective therapies for NEPC and people who are diagnosed with NEPC have a grim outlook (average survival = 7 months).
A gene called RB1 often doesn’t work properly in NEPC. This gene is part of a cell circuit that controls cell division. In laboratory-based experiments, we have found that when the RB1 gene goes wrong, cancer cells are sensitive to a special type of cell death (a process known as ferroptosis), especially for NEPC cells. Our aim now is to test whether the ferroptosis inducer can help slow or stop the growth of NEPC and determine how it works. To address this, we propose several animal and prostate cancer cell biology studies aimed at answering the following two questions:
Whether the ferroptosis inducer works in NEPC. This will be investigated with powerful animal studies that allow us to test the efficacy of the ferroptosis inducer in human patient-derived NEPC tumor models as well as in genetically engineered mice that develop similar NEPC as humans.
What mechanisms render NEPC cells more sensitive to ferroptosis? This will involve a detailed analysis of how the absence of the RB1 gene affects the key players that regulate ferroptosis.
This is a unique line of investigation that seeks for a key weak spot in NEPC cells, allowing us to test a drug candidate for future clinical trials of NEPC and study the underlying mechanisms driving ferroptosis. Our hope is that these investigations can eventually contribute to finding a cure for prostate cancer.
Pratip Bhattacharya, PhD – MD Anderson Cancer Center, University of Texas
Overcoming ADT Resistance in Metastatic Castration Resistance Prostate Cancer (mCRPC) By Targeting Monocarboxylate Transporter (MCT) Pathway
Prostate cancer (PCa) is the second most common cause of cancer mortality in men. Patients with advanced disease receive anti-androgens (Enzalutamide) as the first line of treatment. Unfortunately, many patients develop resistance, and the disease relapses with aggressive histology and transforms to metastatic castrate-resistant prostate cancer (mCRPC). Treatment options for mCRPC patients are limited with an alarming low survival rate of only 28%. Metabolic biomarkers are urgently needed to access the treatment response of the patients receiving antiandrogen therapy as well as classifying different metabolic sub-types of PCa. The overarching goal of this proposal is to develop personalized metabolic imaging modality to target treatment strategies of different metabolic sub-types of PCa. Recent studies from our group has shown that the tumor’s metabolic profile that impacts anti-androgens response can be identified early on by using hyperpolarized Magnetic Resonance Imaging (HP-MRI). HP-MRI offers unprecedented insights into cellular metabolism in real-time by enhancing signal of conventional MRI by over 10,000-fold. We also discovered that Monocarboxylate Transporter (MCT) pathway is dysfunctional in mCRPC and may be a viable target for therapeutic intervention. We will therefore, employ HP-MRI to interrogate glycolysis in PCa and to evaluate the treatment response of antiandrogen drug, Enzalutamide in four clinically relevant well characterized patient derived mouse models of PCa. Of these four models, two are resistant to treatment, while the other two are sensitive. In the resistant models, we will attempt to restore Enzalutamide sensitivity by targeting the MCT pathway by inhibiting that pathway with the drug, Syrosingopine. We will correlate imaging data with comprehensive metabolomics, transcriptomics and immunohistochemistry analysis of the ex vivo tissue samples to elucidate the metabolic drivers of treatment resistance, and an in-depth characterization of the tumor sub-types. Thus, this grant thus presents an exciting opportunity to realize imaging-based personalized medicine in prostate cancer.
Functions of the CDK8 module in prostate cancer cells
The Androgen Receptor (AR) plays critical roles in pathogenesis of prostate cancer. After binding to male hormones, AR is activated and functions as a transcription factor that regulates the expression of genes required for cell proliferation in both the normal prostate or prostate cancer cells. Accordingly, androgen-deprivation therapy aimed at reducing androgen levels by surgical or pharmacological castration has been the standard option to treat metastatic prostate cancer. However, after this initial hormone therapy, prostate cancer cells eventually stop to respond to low androgen levels. Nevertheless, the proliferation of the castration-resistant prostate cancer cells is still dependent on AR. Thus, finding new approaches to reduce the levels of AR may hold the key to slow the proliferation of castration-resistant prostate cancer cells in patients with advanced prostate cancer. In this project, we will study the role of the CDK8 module, part of the transcription cofactor Mediator complex, in regulating AR expression in prostate cancer cells.
Targeting the androgen receptor axis affects macrophage polarization in castration-resistant prostate cancer
It is estimated that in 2020, approximately 192,000 new cases of prostate cancer and more than 33,000 prostate cancer-related deaths will occur in the United States. A disappointing irony is 1 in 9 men will be diagnosed with prostate cancer in lifetime, as every 20 minutes another American man dies from this malady. Although early diagnosis and aggressive therapies extend survival, unfortunately a lethal form of advanced disease known as castration-resistant prostate cancer ensues to which no treatment options are effective. From current understanding, it is clear that not only the tumor cells escape therapy and develop resistance, but also tumor-fighting immune cells in patients’ bodies follow signals from the tumor and become tumor-assisting cells rather than tumor-eliminating cells. Thus, it is critical to identify mechanisms that trigger conversion of normal cells in the body so treatments can combine effective modifications to prevent such resistance.
In our efforts to identify the cause for this problem and improve therapy measures, we discovered this unique resistance, in fact, occurs as a bystander effect of current treatment itself, involving a key tumor fighting immune cell type called macrophage. We found that side effects of frontline therapies intended to manage patients unfortunately blunt the capacity of the immune cells, but turn them into a group of cells that support metastatic growth. With an ultimate goal of blocking the onset of resistance and improving treatment combinations for men with metastatic disease, studies proposed in this application will uncover molecular mechanisms that trigger this phenomenon and test a combination therapy to prevent this important, yet unaddressed issue, in a preclinical mouse model of prostate cancer.
Results from the pilot studies will lead to a high-impact publication and form a solid basis as supportive preliminary data for an extramural R01 grant application to the National Cancer Institute.
Validating and tailored targeting of identified immune signature in the tumors of African American Prostate cancer patients
Prostate cancer is the second leading cause of cancer-related deaths among men in the United States. African American men are known to suffer a higher burden of the disease evidenced by increased morbidity and mortality in this minority population. In recent decades, there is increasing appreciation for the contribution of the immune system to mounting an attack against cancer cells. Despite this knowledge, we still do not have a solid understanding of whether the immune composition of prostate cancer is different in African American patients in a manner that might support a more aggressive disease and poorer outcomes compared to Caucasian men. This outstanding issue is what led us to begin to investigate the presence and attributes of immune cells that are present in surgically-removed prostate cancer tissue of African American men relative to their Caucasian counterparts. In this preliminary study, we found striking differences that suggest that the immunological profile of prostate cancer in African American men harbors features that tend to inhibit immune response and this may be a major contributory factor to disease severity in this minority group. In the proposed project, we hope to confirm the presence of these features in a larger cohort of patients from both racial groups leveraging the previously stored cancer specimens available in our institution’s repository. Beyond this, we will also test the idea that targeting these immune features with certain drugs will likely improve the functionality of the immune cells against the cancer cells in the tumors of African American patients while comparing any observed effects with those from tumors of Caucasian patients. Rather than a one-size-fits-all approach, it may just be that we need tailored treatments for African American prostate cancer patients, and this is essentially what this study hopes to shed some light on.
Runhua Liu, MD, PhD – UAB O’Neal Invests Partnership Grant Recipient
CD24-mediated Tumor Metastasis and Targeted Therapy in Prostate Cancer
Prostate cancer is slow-growing and relatively harmless. However, in some patients prostate cancer becomes very aggressive, turning lethal as it spreads throughout the body. Once the spread of cancer occurs, chemotherapy is the viable treatment option, but chemotherapy causes severe adverse effects and does not cure this disease. In fact, many patients opt for not treating advanced prostate cancer. For this reason, prostate cancer has become the second leading cause of cancer-related deaths in American men. Unfortunately, the mechanisms within the prostate cancer cells that lead to aggressive spreading are not completely understood. A more thorough understanding of these mechanisms and how they differ from the normal processes in healthy cells is necessary to inform the design of safe and effective treatment strategies. Recently, we discovered a CD24 expressed in spreading prostate cancer cells but not in normal prostate cells. CD24 can inactivate the normal function of p53 and is responsible for keeping the prostate cancers from spreading to other areas of the body, especially if p53 is mutated, which is often the case in prostate cancer. Therefore, we can block the spread of prostate cancer cells in laboratory-based studies by deleting the portion of DNA that encodes for CD24. Based on these novel observations, we hypothesize that the CD24 and p53 regulate the spreading of prostate cancer and that targeting these genes can eliminate the aggressive, lethal spreading of prostate cancer cells. Our first goal is to determine how CD24 contributes to the spreading of prostate cancer using animal models. Our second goal is to develop an effective cancer cell-targeted therapy for metastatic prostate cancer by a combination of an anti-CD24 (targeting) antibody with a drug (PRIMA1) that reactivates the tumor-suppressive function of mutant p53. We will validate the ability of this novel therapy to safely and effectively eliminate metastatic prostate cancer in preclinical animal models. If our hypothesis is correct, then our findings will lead to the development of more effective treatment options by eliminating metastatic tumors with minimal toxicity to normal cells. This will benefit patients with metastatic prostate cancer, especially CD24+ and/or p53 mutant prostate cancer.
Developing Culturally-Tailored Interventions to Increase Prostate Cancer Screening Among African-American Men
Prostate cancer (PCa) disproportionately affects African American (AA) men and is the leading cause of cancer incidence and second leading cause of mortality among AA men in the United States (US). Several factors including environmental, genetic and social contribute to this disparity. While the overall PCa incidence and mortality rates in Alabama have decreased overtime, large pockets remain where the disparity between AA and non-Hispanic White men remain significantly high. Despite being at high risk for early development of PCa and early transformation to more aggressive disease compared to other races, AA men have much lower rates of early screening for PCa than other racial groups.
The renewed attention by the U.S. Preventative Services Task Force to recommend early PCa screening for AA men paves the way for developing and delivering culturally- and geographicallytailored health promotion interventions. However, we have insufficient information about the reasons for lower screening among these groups at highest risk. The proposed study will capture data directly from AA men, aged 35 to 70 years in Alabama to: (a) identify barriers and facilitators that relate to early detection screening PCa among AA men; (b) understand the relative importance of these factors to different health-seeking behaviors; and (c) understand the relationship between these factors and how they impact health-seeking behaviors and (d) develop message approaches and communication channels that increase PCa screening among AA men in both urban and rural settings. Using the participatory approach, we will conduct focus groups (FG) with 120 AA men (50% rural; 50% urban) and key informant interviews with 24 men and their spouses/partners to learn more about how to best reach this target population. Findings from this “seed” grant will provide preliminary data to support a larger grant to test the intervention in multiple areas throughout the state.
Targeting the CD24/p53 axis for Lethal Metastatic Prostate Cancer
Generally speaking, prostate cancer is slow-growing and relatively harmless. However, in some patients prostate cancer becomes very aggressive, turning lethal as it spreads throughout the body. Once metastasis occurs, chemotherapy is the only viable treatment option, but chemotherapy causes severe adverse effects and does not cure this disease. Recently, we discovered a protein expressed in spreading prostate cancer cells but not in normal prostate cells. We found that this protein, CD24, can promote inactivation of mutant p53 gene, which is often the case in prostate cancer. We can block the spreading of prostate cancer cells in laboratory-based studies by deleting the CD24. Based on these novel observations, we hypothesize that the CD24 and mutant p53 regulate the spreading of prostate cancer and that targeting these genes can eliminate the aggressive, lethal spreading of prostate cancer cells. Our goal is to develop an effective cancer cell-targeted therapy for metastatic prostate cancer by conjugating an anti-CD24 (targeting) antibody with a drug (PRIMA1) that reactivates the tumor-suppressive function of mutant p53. We have confirmed that our developed anti-CD24 antibody-PRIMA1 drug specifically targets CD24+ prostate cancer cells but not normal cells. We will validate the ability of this novel therapy to safely and effectively eliminate metastatic prostate cancer in preclinical animal models. If our hypothesis is validated, then our findings will lead to the development of more effective treatment options with minimal toxicity to normal cells, which will benefit patients with metastatic prostate cancer. Our results could lay the groundwork for prostate cancer clinical trials in which this anti-CD24 antibody-PRIMA1 drug is administered alone or in combination with surgery.
Impact of Physical and Cognitive Function on Treatment Selection and Outcomes of among Older Patients with Prostate Cancer
Prostate cancer is the most common cancer in American men. The risk of getting prostate cancer increases as a man gets older and the median age of diagnosis is 66. Due to the earlier detection and innovative treatments, the overall survival rate for prostate cancer patients has been greatly improved. However, older patients with prostate cancer usually live with multiple comorbidities that have great impact on patient’s physical and cognitive function and clinical outcomes. Oncologist experts have recommended adding a formal assessment of patient’s physical and cognitive status to help clinicians select the most appropriate treatment for older men diagnosed with prostate cancer. The objective of the proposed research is to study the impact of patient’s physical and cognitive function on treatment selection and outcomes of among older patients with prostate cancer. To achieve this, we propose the following two specific aims: Aim 1: To assess the association between older patients’ physical and cognitive function before prostate cancer diagnosis and treatment selection. Aim 2: To examine the impact of treatment selection on physical and cognitive function and clinical outcomes after cancer diagnosis among older patients with prostate cancer. We will use the existing 1998-2017 SEER-MHOS data files to focus on prostate cancer patients aged 65 years and older who completed the MHOS survey both before and after their cancer diagnosis (n=2380). Patient’s physical and cognitive function will be measured using the survey questions regarding the activities of daily living (ADL) scale and memory issues, respectively. Patient’s outcomes will include survival and quality of life. The expected outcomes of this proposed study are ultimately intended to improve the evidence base in patient’s physical and cognitive function so that clinicians could tailor treatment recommendations and improve outcomes for older men diagnosed with prostate cancer.
Identification of NCOA6 as a New Oncogenic Driver of Neuroendocrine Prostate Cancer (NEPC)
More than 10% of men in US develop prostate cancer (PC) in their lifetime, and PC is the second leading cause of cancer death in US men. About 95% of PC is adenocarcinoma and the less common subtypes include neuroendocrine PC (NEPC) and squamous cell carcinoma. Pure NEPC is less than 2% of all PC, whereas focal NEPCs mixed with adenocarcinomas are commonly observed in ~30% of patients after androgen deprivation therapy (ADT). Both pure and mixed NEPCs are aggressive and often metastasize to internal organs to kill patients. NEPC is also resistant to ADT and lacks targeted therapies. Therefore, it is important to identify new oncogenes that drive NEPC development as therapeutic targets. We found that the NCOA6 gene is amplified in human NEPCs, NCOA6 is increased in NEPC developed in a PC mouse model, and overexpression of human NCOA6 in the mouse prostate cells significantly increased the number of neuroendocrine cells (NECs). Thus, we hypothesize that overproduced NCOA6 drives NEPC development. To test this hypothesis, we will make mouse models with NCOA6 overexpression in each of the three types of prostate epithelial cells termed basal cells (BCs), luminal cells (LCs) and NECs. We will examine what type of these cells with NCOA6 overexpression will develop NEPC. We will also make prostate progenitor cells with or without NCOA6 overexpression in culture to test whether NCOA6 overproduction induces NEPC.
Furthermore, we will analyze the genes and mechanisms regulated by NCOA6 in these mouse and cell culture models during NEPC development to define the role of NCOA6 in NEPC. With these data, we will apply for a NIH grant to support our second phase research, in which we will study NCOA6 in human NEPC tumors, explore NCOA6-regulated pathways in NEPC, and develop NCOA6 inhibitors to treat NEPC for reducing PC death.
Jiaoti Huang, M.D., Ph.D. and Jung Wook Park, Ph.D. – Duke
Unveiling the roles of neuroendocrine cells in prostate cancer development.
For prostate cancer, current hormone therapies targeting either the cancer-driving protein called androgen receptor (AR) or proteins that interact with it extend patients’ lifespans and improve their quality of life. However, resistance to these hormone treatments usually occurs.
These advanced prostate cancers are referred to as castration-resistant prostate cancer (CRPC) or AR-independent prostate cancer. Understanding the mechanisms by which these advanced prostate cancers develop is an urgent need, because no effective treatment exists for this disease.
Our research focuses on a cell type called neuroendocrine cells which is AR-negative.
Although they are found in normal prostate tissue, an increased number of these neuroendocrine cells is positively correlated with prostate cancer aggressiveness. Currently, their roles in prostate cancer development remain unclear. Animal studies have provided evidence that metastatic prostate cancer can be initiated from neuroendocrine cells. However, there are no studies using human neuroendocrine cells due to difficulties in handling and manipulating fresh human cells.
To overcome these limitations, we have established a novel efficient cancer-initiating assay using fresh human prostate cells, which allows us to identify 1) which cell types can be cells of origin for prostate cancer and 2) which mutant genes can initiate prostate cancer. Using this powerful assay and our efficient gene delivery system with fresh human neuroendocrine cells, this research proposal will reveal the contribution that these mysterious neuroendocrine cells play in prostate cancer development.
The foreseeable benefits from this research proposal are: 1) the understanding of cancerinitiating genes in neuroendocrine cells and 2) the generation of new and diverse preclinical disease models that potentially recapitulate human prostate cancer. We hope that our research provides insights into developing new therapeutic interventions to combat CRPC or ARindependent prostate cancer.
Psma-pet/mri for Radiation Treatment Planning in Patients With Locally Metastatic Prostate Cancer
Prostate cancer is common and affects about 1 in 10 men. However, there is considerable variation in how prostate cancer progresses. Some prostate cancers are slow-growing and do not pose a threat to life while others are more aggressive and require early treatment to avoid spread of cancer and death. In contrast to localized disease, the 5-year survival for patients with distant metastatic disease is 29%. This is largely because it is difficult to detect disease outside the prostate at the time of diagnosis using conventional imaging. CT and MRI require that lymph nodes become enlarged before they are suspicious for having cancer within them, however normal size lymph nodes can also harbor cancer. If suspicious lymph nodes could be detected at the time of initial diagnosis regardless of their size, additional radiation to these lymph nodes would potentially decrease the rates of cancer recurrence and more effectively treat metastatic cancers. Thus, there is a great need for more accurate staging of extra-prostatic disease at the time of initial diagnosis to guide therapy and thereby reduce the rates of recurrence and death from prostate cancer.
This project proposes to use a novel molecular imaging method that detects Prostate-specific membrane antigen (PMSA-PET), in combination with MRI to identify metastatic prostate cancer at the time of diagnosis. The objective of this study is to (1) demonstrate that PSMA-PET/MRI can detect more lymph node metastases than CT or MRI alone and (2) to evaluate the ability for the radiation oncologist to use the results from this PET/MRI to provide additional radiation to suspicious lymph nodes. After getting the results of the PSMA-PET/MRI, the radiation oncologist will be able to design a unique radiation treatment plan for each patient and evaluate if it is possible to give extra radiation to the suspicious lymph nodes. If the treatment plan is feasible, the radiation oncologist will deliver additional radiation to the suspicious lymph nodes in addition to standard radiation treatments.
Suzanne Lapi, PHD and Jonathan McConathy, MD, PHD – UAB
Targeting the Amino Acid Transporter Lat1 to Treat Aggressive Prostate Cancer
Obesity is a clear risk factor for 13 different cancers, but for prostate cancer, this relationship is complex. The most recent data shows that is related to aggressive prostate cancer, prostate cancer progression and prostate cancer death. These data come from many observational studies in humans, as well as experiments in preclinical models. Dr. Demark-Wahnefried and team will be studying randomized controlled trial data on weight loss among obese and overweight prostate cancer patients to determine if slower weight loss/or less intensive physical activity exerts a beneficial impact on tumor biology.
Dr. Jonathan McConathyThe wide spectrum of aggressiveness of prostate cancer presents major clinical challenges, leading to overtreatment of slow-growing prostate cancers and undertreatment of more aggressive prostate cancers. This study proposes the creation of a new targeted treatment that delivers cancer-killing radiation directly to prostate cancer cells. LAT1is a protein that is associated with aggressive, castration-resistant prostate cancers but has low levels in most normal tissues. These properties make LAT1 a very promising target for PET imaging and for targeted therapy. In mouse models of prostate cancer, LAT1 levels were detected and quantitated with high sensitivity and specificity using a LAT1 antibody.
In this proposal, radioactive elements (the lutetium-177 and yttirum-90) will be attached to the LAT1 antibody which will then home to prostate cancer cells and deliver radiation in a very focused manner. For men with cancers that have spread beyond the prostate gland with high levels of LAT1, our approach can be used to selectively deliver lethal radioactivity to metastatic prostate cancer cells. This therapy could be used with established prostate cancer therapies such as androgen deprivation and chemotherapy. A key advantage of this approach is the use of PET imaging to select patients most likely to benefit from the therapy based on the presence of the LAT1 target. Support from the Mike Slive Foundation will be used to create the lutetium-177 and yttirum-90 labeled therapeutic agents and to perform therapy studies in mouse models to determine if they can be used to treat prostate cancer. Our long term goal is to translate the most promising agents into first-in-human studies in an effort to better target effective treatments for patients with high levels of LAT1.
Targeted Therapy for Nuclear Receptor Resistance Mechanisms in Prostate Cancer
The androgen receptor (AR) protein promotes aggressive growth and metastasis of prostate cancer (PCa). New drugs are designed to target AR to inactivate its function, but unfortunately spontaneous mutations and reactivation of other receptor proteins in AR family enable progression and patients die from metastatic disease. Further, when PCa develops resistance to androgen deprivation therapy, it promotes oxidative stress causing cells to become much more aggressive than the slow-growing primary tumor. Hence, development of novel therapies should focus on identifying, and using inhibitors that can overcome these limitations without provoking resistance.
In a preclinical mouse model of PCa, this proposal will test a unique approach using a biologically produced molecule called endostatin. So far, endostatin is known to arrest the growth of blood vessels that supply oxygen and nutrients to the growing tumor. However, recently we made a striking discovery that endostatin efficiently internalizes into PCa cells and binds to AR, causing a significant decrease in AR levels and its tumor-promoting functions. We also found that endostatin could bind to an alternate receptor (GR) that is activated in resistant PCa cells. Indeed, endostatin significantly reverses oxidative stress mechanisms within PCa cells by arresting GR functions. Thus, we strongly believe that endostatin can be effectively used in combination with existing therapies (e.g. enzalutamide and docetaxel) to increase patient survival. Combination therapy with endostatin is expected to reduce the growth of resistant tumors not only by arresting AR and alternate receptor functions, but also by blocking the growth of tumor blood vessels. Hence, this combination therapy will act as a double-edged sword against the growth of tumors that are resistant to current therapies.
Mechanism of Tumor Immune Escape and Metastasis in Lethal Prostate Cancer
In the United States, prostate cancer is the second-leading cause of cancer-related death of men. Lethal prostate cancers can be defined as tumors that spread to other organs, such as the bones, lungs, and liver. Several studies have reported mutations in two genes, MYC and PTEN, that accelerate the aggressive metastasis of prostate cancer to such organs. In our preliminary studies, we developed a metastatic prostate cancer mouse model that contains mutations similar to those found in lethal prostate cancer in humans. Analysis of the cancers from this model suggested a synergy between the two altered genes and the first evidence that this synergy occurs through the increased expression of specialized, secreted proteins called CXCL3/7 that help the tumor escape the body’s anti-tumor immune responses and facilitate the spread of cancer to distant organs. Therefore, our central hypothesis is that the dysfunction of MYC and PTEN promote escape and spreading of prostate cancer cells through increases in the secreted CXCL3/7 proteins. Our overall goal is to define the molecular mechanism underlying the synergy between these genes that cause the tumors to spread. We are also focused on improving existing therapeutic strategies for patients who are suffering from lethal prostate cancer. In this proposed work, we will use animal models to determine the role and mechanism of two altered genes that underlie the regulation of CXCL3/7 proteins that promote the spreading of prostate cancer. We will validate the abnormalities detected in the lethal, spreading prostate cancers, and our results will help to guide therapy for men who suffer from cancers of this type. If our hypothesis is validated, our discoveries will immediately help doctors develop more effective treatment options for patients with lethal prostate cancer.
Impact of Tet Protein With Aggressive Prostate Cancer
Dr. Sudarshan is a urologic surgeon-scientist dedicated to the further understanding of the molecular basis on genitourinary malignancies and to translate these findings to the development of novel treatments that will impact the care of affected patients. His particular area of interest is the role the TET enzyme (ten-eleven translocation methylcytosine dioxygenases) to prostate cancer. Dr. Sudarshan believes this grant will validate the finding that the loss of the TET protein promotes the development of aggressive prostate cancer. Dr. Sudarshan will determine how TET is lost, and how it can be turned back on. Identifying the target genes of TET will allow the documentation of the characterization of protein and their effects on prostate cancer progression. This in turn will lead to new and novel therapeutic approaches to the disease.
Wendy Demark-Wahnefried, PHD, RD, Soroush Rais-Bahrami, MD, Robert Oster, PHD, and Andrew Frugé, PHD, RD – UAB
Solving the Obesity Paradox in Prostate Cancer
Obesity is a clear risk factor for 13 different cancers, but for prostate cancer, this relationship is complex. The most recent data shows that is related to aggressive prostate cancer, prostate cancer progression and prostate cancer death. These data come from many observational studies in humans, as well as experiments in preclinical models. Dr. Demark-Wahnefried and team will be studying randomized controlled trial data on weight loss among obese and overweight prostate cancer patients to determine if slower weight loss/or less intensive physical activity exerts a beneficial impact on tumor biology. In addition, they will to determine if rapid weight loss fuels the aggressiveness of tumor growth in the prostate. The NCI-supported trials (one in breast cancer and one in prostate cancer) of weight loss interventions convened during the presurgical period yielded incredibly interesting results that suggest that a slow, steady weight loss that includes exercise may be the best to reduce prostate cancer cell proliferation. Through additional testing of RNA expression data and some circulating biomarkers, we hope to better understand the mechanisms by which slow weight loss and exercise may help men with prostate cancer and arrive at some idea of the rate of weight loss and the amount and kind of exercise needed.
Novel Functions of Mitochondria Localized Androgen Receptor in Prostate Cancer
The androgen receptor plays a central role in the normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer to advanced metastatic disease. Nuclear localization of androgen receptor upon binding to testosterone directs regulation of a host of nuclear genes. Traditional thinking is that nuclear localization of androgen receptor plays a key role in prostate tumorigenesis. Although this is certainly true, we have discovered that additional action(s) of androgen receptor outside the nucleus can contribute to prostate cancer. Surprisingly, we have found that the besides in the nucleus androgen receptor localizes into mitochondria and contains authentic mitochondria localization signal capable transporting other proteins into the mitochondria. Our study suggests that mitochondria-localized androgen receptor is a novel player in promoting prostate tumor growth and metastasis. It is conceivable, that androgen receptor in mitochondria acquires novel mitochondrial function(s) and provides energy needed to fuel prostate cancer aggressiveness, but this remains to be investigated. This grant will seek to 1) determine the novel function(s) of androgen receptor in the mitochondria and evaluate the tumor growth and metastatic potential of mitochondria-localized androgen receptor in mouse xenograft model.
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