Prostate Cancer Research
Young Investigator Award Recipients 2012
The PCF Young Investigator Award-Class of 2012 recipients are:
The 2012 Robbins Family – PCF Young Investigator Award
Dr. Bismar earned an MD degree from the University of Damascus and then performed two fellowships in surgical and genitourinary pathology at Wayne State University and Harvard Medical School-Brigham and Women’s Hospital. He is currently an Associate Professor of Pathology at the University of Calgary.
A specific fusion of pieces of two chromosomes is present in 50 percent of prostate cancers and is thought to drive the disease. In addition, a normal protein named PTEN suppresses tumor development unless genetically altered as is the case in many advanced prostate cancer cases. Dr. Bismar proposes to study both of these changes in model systems in an attempt to discover how together they deregulate the control of growth and survival that result in prostate cancer.
Peter Forsyth, MD, an accomplished physician-scientist in molecular biology, will provide mentorship for Dr. Bismar.
The 2012 Sternlicht Family Foundation – PCF Young Investigator Award
Androgens and Androgen Receptor (AR) fuel prostate cancer. Therefore, androgen deprivation therapy (ADT) is usually the preferred treatment modality. However, prostate tumors employ multiple alternate mechanisms to bypass the need for androgens or AR, progressing on the path to castration-resistance. Despite the fact that several prognostic markers for disease progression and/or response to anti-androgen therapy are being evaluated in the clinical setting, not many are accurate for disease prognosis and clinical decision management. Thus there is a serious unmet need for novel prognostic biomarkers for prostate cancer.
Several recent studies in Dr. Mark Rubin’s laboratory and others have shown that prostate tumors express the Estrogen Receptor a (ERa) at early onset of the disease. However, the role of ERa in prostate cancer still remains unclear. ERa has also been shown to trigger an oncogenic cascade that is driven and maintained by a class of nucleic acids called long-non coding RNA (lncRNA). LncRNAs are a subset of RNA that do not code for functional protein products. The main role of these lncRNAs in the cell is gene regulation. Emerging data hint at a role of ERa in inducing the abnormal overexpression and activity of lncRNAs, which in turn switch on the ‘bad’ genes in prostate cancer. LnCRNAs amplify oncogenic signaling in an ‘always-on’ (constitutive) fashion that allows cancer to overcome drug inhibition and proliferate.
Dr. Dimple Chakravarthy proposes to study this ERa-lncRNA axis in prostate cancer. She will validate the prognostic relevance of ERa and ERa-regulated lncRNA as prognostic biomarkers of tumor progression and therapy response. Dr. Chakravarthy will also evaluating the therapeutic potential of knocking down lncRNAs using nanoparticles. She will test the combinatorial therapy with anti-androgens and anti-lncRNA medications to control prostate cancer growth and metastasis.
Mentor: Mark Rubin, MD
The 2012 John A. Moran – PCF Young Investigator Award
Systematic identification of genetic variants within AR binding sites that are associated with altered AR signaling and prostate cancer
Androgen Receptor (AR) mediates the action of the male hormones, androgens by binding to genomic DNA and regulating gene expression. This AR-mediated cellular signaling is dysregulated in prostate cancer. As the cancer progresses towards treatment resistance, AR becomes independent of the presence/absence of androgens and upregulates pro-cancer gene expression. The precise sites on the genome to which AR binds are called AR Response Elements (AREs) or AR binding sites. Recent reports have shown that approximately 1/3 of all known prostate cancer risk-associated genetic variants reside in these AR binding sites. Genetic variations that predispose a man to prostate cancer are usually found to be concentrated in the specific DNA regions to which AR binds.
Other PCF-funded studies have shown that AR signaling is causally related to the formation and/or expression of recurrent oncogenic gene fusions (e.g. TMPRSS2-ERG), suggesting that altered AR signaling caused by inherited genetic changes may have a profound impact on the pathogenesis and progression of prostate cancer. To test this hypothesis, Dr. Junjie Feng proposes to 1) identify genome-wide AR binding sites and prostate cancer-specific fusion genes; 2) prostate cancer risk/aggressiveness-associated genetic variants that are located within AR binding sites, and 3) assess whether these genetic variants cause altered AR signaling and influence the formation and/or expression of fusion genes.
Dr. Feng’s research will deepen our understanding of the pivotal role of the androgen-AR signaling axis in the pathogenesis and progression of prostate cancer. These results will also impact the clinical management of the disease by efficient patient stratification based on their specific underlying genetic predispositions. The genetic variants identified in this study also have the potential to serve as valuable biomarkers for accurate prostate cancer screening and diagnosis.
Mentor: Jiangfeng Xu, MD, PhD
The 2012 Steve Wynn – PCF Young Investigator Award
Identifying non-coding RNA repertoires of aggressive prostate cancer
Genetic information flows from genes on DNA as follows: gene (DNA)?RNA?protein. RNAs, which are the products of DNA, either give rise to proteins (coding RNAs) or donot produce proteins (non-coding RNAs). However, these non-coding RNAs (ncRNAs) are functional molecules that perform specialized roles in the cell, such as regulation of gene expression. Many ncRNAs have recently been shown to play important roles in various types of cancer.
Recent reports have provided evidence for the role of small ncRNAs in the development and progression of prostate cancer. Dr. Stephen Finn proposes to identify the ncRNA repertoire associated with aggressive prostate cancer (defined by failure to respond to Androgen Deprivation Therapy (ADT); disease specific mortality etc.). He will then validate the ncRNA profile in tissue samples and circulating tumor cells (CTCs) from patients to confirm their association with aggressive prostate cancer. Dr. Finn’s research will identify the role of ncRNAs in aggressive prostate cancer and correlate these to prostate cancer-specific outcome, laying the groundwork for the design of novel ncRNA-targeting therapeutics. These studies will also provide reliable biomarkers of aggressiveness which can help in patient stratification for therapy and more efficient disease monitoring.
Mentors: John O’Leary, MD, PhD and Lorelei Mucci, ScD, MPH
The 2012 Lowell Milken – PCF Young Investigator Award
Investigation of genomic mechanisms of androgen biosynthesis inhibitor resistance in castration resistant prostate cancer
Description: In most cases the first line of therapy for patients with prostate cancer is Androgen Deprivation Therapy (ADT). ADT aims to deplete the levels of androgens, the male hormones that bind to their receptor (Androgen Receptor-AR) and drive prostate cancer progression. One of the medications used for ADT is the recently FDA-approved Abiraterone (Zytiga) which targets the biosynthesis of androgens in the adrenal glands and more importantly, in the tumor itself. Though patients respond well to Abiraterone and other ADT medications, almost all develop resistance to this therapy and their cancers progress. This stage of treatment resistance is termed castration resistant prostate cancer (CRPC). CRPC is hypothesized to develop due to either 1) the increased production of androgens by the tumor itself, or 2) mutations in the AR that make it independent of the presence/absence of androgens.
Dr. Terence Friedlander proposes to investigate the specific genetic changes in prostate cancer cells that occur during the development and progression of castration resistance. He will determine whether CRPC is mediated by the upregulation of androgen synthesis by the tumors or whether castration resistance is mediated by androgen-independent AR activity. During the course of these investigations, Dr. Friedlander will conduct two separate clinical trials: one that evaluates the effectiveness of using an increased-dose of abiraterone in men who have developed resistance to standard-dose abiraterone, and a second trial that evaluates the effect of treating men with abiraterone resistance, with a new hormonal medication called ARN-509. Dr. Friedlander will collect metastatic tumor biopsies and circulating tumor cells from these patients to evaluate the precise mechanisms underlying abiraterone resistance. A better understanding of the mechanisms that cause CRPC development will allow clinicians to optimize and sequence the new therapies available for the treatment of CRPC.
Mentor: Charles Ryan, MD and Pamela Paris, PhD
The 2012 Mortimer Sackler – PCF Young Investigator Award
Novel small molecule modulators of FOXO1 localization in prostate cancer: antitumor activity, preclinical pharmacology, and pharmacodynamic marker development
The FOXO (Forkhead transcription factors, Class O) proteins belong to a family of proteins called transcription factors that regulate a variety of critical cellular functions. Dysregulation of transcription factors, in particular the FOXO proteins, has been associated with several different types of cancers.
The protein FOXO1 regulates cellular growth and survival pathways in normal cells. To effect its function, FOXO1 has to move from its location outside the nucleus (the cellular compartment that harbors the genome (DNA)) to inside the nucleus. Prostate cancer (PCa) cells, however, redirect the cellular localization of FOXO1 and sequester it outside of the nucleus, in its inactive form. Scientific approaches to relocalize FOXO1 to the nucleus represent a novel strategy for the treatment of prostate cancer, especially treatment resistant PCa.
A group of chemical compounds called the tricyclic neuroleptics have previously been shown to inhibit the transport of FOXO1 proteins from the nucleus. Tricyclic neuroleptics have been FDA approved to treat psychiatric conditions. Certain properties of this class of compounds make their use in the oncology setting very difficult. However, Dr. Matthew Galsky and his team have ‘reverse engineered’ these parent drugs, generating a novel set of compounds that decouple the potent neurological side effects from the anticancer (FOXO1 relocalizing) property.
Under this PCF-funded study, Dr. Galsky will explore the anticancer effects and mechanism of action of these novel compounds in preclinical prostate cancer models. He will also study circulating tumor cells from castration-resistant prostate cancer (CRPC) patients to identify suitable pharmacodynamic markers that can efficiently report the localization of FOXO1 in patient tumors. Dr. Galsky’s research will set the stage for early phase clinical trials of these experimental medications for the treatment of advanced prostate cancer.
Mentor: William Oh, MD and Michael Ohlmeyer, PhD
The 2012 Leon and Debra Black – PCF Young Investigator
Investigating the biological significance of novel recurrent chimeric RNAs in prostate cancer
Chimeric RNAs are the fused products of two different genes. Recent studies have shown that chimeric RNAs are present in normal cells and their presence allows the limited number of human genes to encode a substantially larger number of RNAs and proteins, forming an additional layer of cellular complexity.
Dr. Kalpana Kannan and her team recently identified 27 novel, highly recurrent chimeric RNAs in prostate cancer. Their results showed that these chimeric RNAs occurred at a higher frequency in cancer compared to normal cells. These preliminary findings show that chimeric RNAs form a potentially unique class of molecular alterations in prostate cancer. During the three year funding cycle of this 2012 PCF Young Investigator Award, Dr. Kannan proposes to study the biological significance and potential clinical applications of these recurrent chimeric RNAs in prostate cancer. She will study the differences in the occurrence/quantities of these molecules in normal prostate tissue, localized prostate cancer and in metastatic prostate cancer. Dr. Kannan will also evaluate the significance of these chimeric RNAs in prostate cancer diagnosis and prognosis. If validated, these chimeric RNAs will serve as useful biomarkers for the identification of prostate cancer subtypes. New therapeutic targets for advanced prostate cancer may also emerge from this work.
Mentor: Laising Yen, PhD and Michael Ittman, MD, PhD
The 2012 Michael Milken – PCF Young Investigator Award
Lifestyle, guidelines, and etools to improve prostate cancer survivorship
Under the mentorship of Dr. Chan and Dr. Stampfer, Dr. Kenfield has evaluated whether diet and lifestyle factors after prostate cancer diagnosis are associated with disease progression in men with localized disease. This proposal is a natural extension of this work and will focus specifically on men with advanced and recurrent prostate cancer and whether diet and lifestyle factors can reduce risk of distant metastasis or prostate cancer-specific mortality. The ultimate goal of this work is to translate these results into cancer survivorship tools for the community. First, Dr. Kenfield will develop a prognostic score for prostate cancer mortality and other outcomes that will incorporate clinical, pathological, and lifestyle variables. The analyses will be performed in two large studies with extensive data available on lifestyle factors: the Health Professionals Follow-Up Study and CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) and the findings could be important in guiding physician counseling of men with prostate cancer. Second, she will examine whether diet and other lifestyle factors may reduce progression in men with advanced or recurrent prostate cancer, which may elucidate strategies for reducing progression of disease. Third, she will build novel web-based cancer survivorship tools and use them in a clinical trial to determine if a web-based intervention program can help men with prostate cancer adopt healthier behaviors associated with reduced prostate cancer mortality. If successful, it could be administered efficiently in a variety of settings and scaled up to reach larger populations of men with prostate cancer.
Mentor: June Chan, ScD
The 2012 Steve Wynn – PCF Young Investigator Award
GPR30 as a potential therapeutic target for castration-resistant prostate cancer
The protein G-protein coupled receptor 30 (GPR30) regulates several signaling pathways governing cell growth, migration etc. In previous studies, Dr. Hung-Ming Lam has shown that the chemical compound G1 tightly binds GPR30 in highly selective manner and this G1-GPR30 complex inhibits the growth of prostate cancer cells.
In this study, Dr. Lam proposes to evaluate the efficacy of GPR30 inhibition by G1 for the treatment of castration-resistant prostate cancer (CRPC).Previous studies have shown that the expression of GPCR in cells shows an inverse correlation with the levels of androgens. Androgens are the male hormones that fuel prostate cancer. Therefore, as the levels of androgens in tumors decline upon Androgen Deprivation Therapy (ADT), the levels of GPR30 increase. Thus in CRPC when androgen levels are very low, GPR30 levels are very high and this setting provides the best opportunity to employ the G1-GPR30 prostate cancer inhibitory action.
The recently FDA-approved medication Abiraterone acetate (Zytiga) inhibits androgen synthesis. Dr. Lam proposes to evaluate combinatorial therapy with G1 and Abiraterone to treat prostate cancer in a two-pronged fashion: 1) delaying cancer relapse and the emergence of metastatic CRPC and, 2) extending the time to chemotherapy in patients with advanced cancer. Dr. Lam also aims to determine the levels of GPR30 before and after ADT in human specimens with bone and lymph node metastases. Her studies will help define a group of patients most suitable for GPR30-targeted therapy.
Mentor: Shuk-Mei Ho, PhD
The 2012 John A. Moran – PCF Young Investigator Award
Determining the role of the androgen receptor acetylation in prostate cancer
Prostate cancer is driven by the male hormones, androgens which mediate their activity through the androgen receptor (AR). Unfortunately most prostate cancerous tumors progressively become resistant to the preferred treatment modality, androgen deprivation therapy. This stage of treatment resistance is termed as Castration Resistant Prostate Cancer (CRPC). CRPC is usually the result of the over-activity of AR which becomes independent of the presence/absence of androgens and continues to drive aggressive growth of tumors. Due to its key role in promoting prostate cancer tumorigenesis in CRPC, it is essential to define efficient mechanisms for AR inhibition.
One of the mechanisms proposed to enhance the activity of AR in CRPC, even in the absence of androgens, is the addition of a small chemical group/moiety to the AR protein. This modification of AR is termed as acetylation and is proposed to convert the protein to a ‘super-AR’. However, there is currently no experimental data to show that AR acetylation directly enhances AR-dependent prostate cancer cell viability.
Dr. Heather Montie proposes to evaluate the role of AR acetylation in the enhanced AR functional activity central to CRPC. She will study the precise mechanisms by which this modification of AR enhances its cancer-promoting activity. Dr. Montie will also validate the potential of AR acetylation as a therapeutic target for castrate-resistant prostate cancer.
Mentors: Diane Merry, PhD and Karen Knudsen, PhD
The 2012 Lori Milken – PCF Young Investigator Award
Evaluating the contribution of AR deficient stem/progenitor cells in Castrate Resistant Prostate Cancer
The use of anti-androgens is standard treatment for prostate cancer patients in the management of PSA recurrence and metastatic disease. However, all men with metastatic prostate cancer become castrate resistant (CRPC) during which time conventional androgen deprivation therapy is no longer effective. This indicates that cancerous cells may become less reliant upon androgen or androgen receptor (AR) mediated signaling and more dependent upon alternative survival pathways either as a consequence of treatment or during the natural disease evolution.
Recent studies on stem cells in in vitro experimental systems have shown that the deletion of important housekeeping genes can give rise to castration-resistant prostate cancerous tumors. In an extension to these observations, Dr. Mulholland proposes to study whether stem/progenitor cells with tumorigenic capabilities may acquire independence from the androgen/AR signaling axis and whether such cells are a potential source of the initiation of prostate cancer or the progression of aggressive metastatic prostate cancer. The short term goal of this proposal is to ascertain whether cancer initiating cells with impaired AR function can reconstitute disease progression in a manner that is entirely autonomous from AR function. The long term goal is the identification of alternative survival pathways, and therefore relevant targets, for cancers that are non-responsive to anti-androgen therapy.
Mentor: Hong Wu, MD, PhD
The 2012 Heritage Medical Research Institute – PCF Young Investigator Award
Identification and integration of clinical features, genetic factors, and biomarkers to optimize prostate cancer risk stratification and treatment selection
One of the most pressing dilemmas in the care of patients with prostate cancer is the ability to distinguish indolent from aggressive disease. Most of the currently available clinical tools such as PSA, cancer stage and Gleason score rely exclusively on a small number of standard clinical parameters, and cannot always reliably distinguish patients who need treatment from those who do not. As a result, a majority of patients diagnosed with prostate cancer choose radical treatments and suffer from associated side effects, even though only a small minority would have died from their disease without treatment.
However, considering the complexity of the disease, it is important to note that no single marker or diagnostic modality will likely account for all of the variability in prostate cancer outcome. In this proposal, Dr. Nguyen proposes to combine multiple markers of disease outcome into a single prognostic model to achieve maximum predictive accuracy. The overall goal of Dr. Nguyen’s efforts is to identify and integrate underlying genetic differences (polymorphisms), serum biomarkers, imaging characteristics and novel clinical factors to enhance the predictive ability of the current tools. He will study prostate cancer patient blood and tissue samples to identify biological and clinical predictors of outcome.
For biological predictors, Dr. Nguyen and his team will examine the biomarkers and genetic changes relevant to the link between obesity and aggressive prostate cancer. For clinical predictors, Dr. Nguyen will evaluate the prognostic value of clinical and MRI-based predictors of prostate cancer outcome. These factors will ultimately be tested in a large clinical cohort to determine their combined prognostic ability. Therefore, Dr. Nguyen’s research will potentially provide a single unified system that integrates multiple types of prognostic information. These results will ultimately allow patients to understand their risk of cancer recurrence with greater certainty, and make better treatment choices.
Mentor: Anthony D’Amico, MD, PhD and Phillip Kantoff, MD
The 2012 Shmuel Meitar – PCF Young Investigator Award
The role of recurrent gene fusion SDK1-AMACR in prostate cancer
Gene fusions are the erroneous juxtaposition of two genes that do not normally lie next to each other on the genome. As a result of this abnormal placement of two genes, their expression is altered and this may lead to the development and progression of cancer. The TMPRSS2-ERG gene fusions are a hallmark of prostate cancer (PCa), found in ~50% of Caucasian patients. Recent studies have shown that these TMPRSS2-ERG gene fusions occur at a much lower frequency of ~15-20% in prostate cancer patients in China. The underlying genetic heterogeneity/differences among different ethnic populations may explain this observation.
Dr. Shancheng Ren has identified a novel gene fusion in prostate cancer patients in China that results in to the juxtaposition of the SDK1 and the AMACR genes. Dr. Ren proposes to study the relative prevalence and clinical significance of this SDK1-AMACR gene fusion in Chinese PCa patients. These studies will therefore help in the molecular subtyping of Chinese PCa patients in terms of their clinico-pathologic features, clinical outcome as well as response to therapy.
Dr. Ren also proposes to investigate the SDK1-AMACR gene fusion as a novel, non-invasive marker for the detection of prostate cancer in Chinese patients. He will further evaluate the role of this gene fusion in prostate cancer initiation and progression. These studies will lay the foundation for the potential development of the SDK1-AMACR gene fusion as a therapeutic target.
Mentor: Yinghao Sun, MD, PhD
The 2012 Foundation 14 – PCF Young Investigator Award
Androgen receptor splice variants: novel drivers of castration-resistant prostate cancer
The androgen receptor (AR), which mediates the action of male sex hormones, androgens, fuels prostate cancer. Therefore, the primary treatment for prostate cancer is androgen deprivation therapy (ADT) which prevents AR signalling. Unfortunately, almost all patients develop resistance to ADT and their cancers resume growth despite hormone therapy. These cancers that gain resistance to ADT and continue to spread are termned castration-resistant prostate cancer (CRPC).
Recent research has revealed that highly active variants of AR rather than the normal AR protein may be the key drivers of CRPC. These androgen receptor variants (ARVs) usually lack the ability to bind androgens and are independent of the presence/absence of androgens. Therefore, ARVs can easily drive prostate cancer even during ADT. Recent studies have shown that these ARVs increase in response to castration and other AR-targeted therapies. These studies point to a role of ARVs in mediating ADT-resistance and the progression of the disease towards CRPC. Dr. Luke Selth proposes to study the molecular mechanisms by which AR variants initiate and drive CRPC. He will identify the precise genes activated by AR variants to promote CRPC. Dr. Selth will also determine the co-factors that regulate ARV-driven CRPC.
Dr. Selth’s research will be a crucial next step in the development of strategies to counter the role of AR variants in CRPC development. His studies have the potential to be used as a platform for the development of new medications against ARVs, which will potentially prevent CRPC development and progression. Dr. Selth’s results will also inform clinical management strategies for men with metastatic prostate cancer.
Mentor: Wayne Tilley, PhD
The 2012 Drew Foundation – PCF Young Investigator Award
Targeting MYC-dependent metabolism in prostate cancer
The gene MYC regulates normal cellular metabolism. Mutations in MYC result in the unregulated expression of several genes involved in cell proliferation, resulting in aggressive cancers. MYC is known to play crucial roles in aggressive and metastatic prostate cancer, and rationally designing potent inhibitors of MYC has traditionally been difficult. Dr. Martin Sos plans to develop rationally designed inhibitors of the protein PRPS2, an enzyme that is up regulated in MYC-driven cancers. PRPS2 also plays a key role in the downstream signaling of MYC, therefore targeting PRPS2 might be effective in abrogating MYC activity.
Dr. Sos will evaluate these inhibitors in mouse models of prostate cancer that are MYC-driven. These studies will help establish the appropriate subtype of prostate cancer that will be best targeted by these inhibitory compounds.
Dr. Sos’ studies will also improve our understanding of all cellular pathways involved in the context of MYC-driven cancer metabolism, laying the groundwork for effective targeting of MYC-driven cancers.
Mentors: Kevan Shokat, PhD; Phillip Febbo, MD; Davide Ruggero, PhD
The 2012 Chris and Felicia Evensen – PCF Young Investigator Award
Determining the link between dietary carcinogens, pathogenic bacteria and IL-6 levels in prostate cancer initiation and progression
As our understanding of the complexities of human cancer deepens, it is increasingly apparent that cancer initiation and progression are multi-factorial processes. The major risk factors for the development of prostate cancer are advanced age, family history, and African-American race; however, there is also a distinct geographic distribution to prostate cancer incidence, and an apparent increase in risk with the adoption of a “Westernized” lifestyle. Therefore, there is a high probability that prostate cancer development involves environmental factors in addition to hereditary factors.
Two major environmental factors shown to have a strong linkage with prostate cancer are 1) dietary carcinogens, such as the chemical PhIP that is generated in meats cooked at very high temperatures (charbroiled) and 2) chronic infections that lead to inflammation in patients, which over time leads to the initiation of prostate cancer. Dietary carcinogens, such as PhIP, have been shown to initiate cancer in animal models, albeit relatively inefficiently. Similarly, inflammation induced by chronic infection can contribute to cancer initiation, but often requires additional co-factors such as underlying genetics or carcinogen exposure.
Dr. Sfanos proposes that the combined effects of both dietary carcinogens and tumor-promoting inflammation may lead to enhanced prostate cancer initiation and/or tumor progression, in a process mediated by the molecule IL-6 (Figure). IL-6 is a cell signaling molecule that stimulates immune response against a variety of conditions, such as infection, trauma (burns) etc. IL-6 levels are significantly elevated in several cancers such as advanced metastatic prostate cancer. Due to its elevated levels in patients with advanced prostate cancer, IL-6 has been proposed as a therapeutic target for several cancers. Dr. Sfanos proposes to study the link of IL-6 to dietary carcinogens and inflammation in promoting prostate cancer initiation and progression.
Mentor: Angelo deMarzo, MD, PhD and William Nelson, MD, PhD
The 2012 Joyce and Larry Stupski – PCF Young Investigator Award
Targeting TMPRSS2-ERG in Prostate Cancer
Approximately half of all prostate cancers carry an abnormal genetic rearrangement that juxtaposes the gene TMPRSS2 against the gene ERG, resulting in the abnormal gene fusion TMPRSS2-ERG, which results in erroneous pro-cancer activity of the ERG protein. TMPRSS2-ERG represents an attractive therapeutic target in prostate cancer and Dr. David Takeda proposes to inhibit its activity using small molecule inhibitors and re-purposed FDA-approved drugs.
Since the precise role of this gene fusion in promoting carcinogenesis remains unclear, Dr. Takeda proposes developing and using a gene expression signature that is turned on only in prostate cancer cells carrying the TMPRSS2-ERG fusion. This gene expression signature will serve as a marker of the aberrant cancer-specific ERG activity and will be useful for evaluating appropriate inhibitors that target this activity.
If successful, this research will lead to the development of the first high-throughput gene expression assay to measure the activity of ERG, and its application to identify chemical inhibitors of ERG. This will potentially represent a significant step towards TMRPSS2-ERG targeted therapy in prostate cancer.
Mentors: Todd Golub, MD, Levi Garraway, MD, PhD, William Hahn, MD, PhD
The 2012 David H. Koch – PCF Young Investigator Award
Development of 89Zr-5A10, a novel radiotracer to address AR signaling in advanced prostate cancer
The androgen receptor (AR) signaling pathway is a key component in the progression of prostate cancer to its lethal form, castration resistant prostate cancer (CRPC). Several, recently developed, potent inhibitors of AR-signaling have shown encouraging, though highly variable responses in patients. One of the reasons for this inconsistent response is the biological heterogeneity of different cancerous lesions in the same patient. Therefore, documenting the response of individual tumor lesions to therapy is important for prostate cancer clinical management (e.g. understanding the overall patient therapeutic response; decision-making for dose escalation or designing therapy combinations that more completely suppress AR-signaling etc.).
Employing molecular imaging tools such as PET (Positron Emission Tomography) is an efficient way to estimate the biological diversity of prostate cancer. Dr. David Ulmert has developed a novel radiotracer called 89Zr-5A10 that specifically detects the Prostate Specific Antigen (PSA) upon PET imaging. PSA is a protein whose production is governed by AR-signaling and is solely produced in the prostatic tissue and prostate cancerous tumors. In this study, Dr. Ulmert aims to evaluate the efficiency of 89Zr-5A10-PET for measuring tumor response to next-generation androgen-deprivation therapeutics such as MDV3100 and Abiraterone. Dr. Ulmert also proposes to conduct first-in-man studies to determine if 89Zr-5A10 can detect CRPC.
If successful, this radiotracer (89Zr-5A10) will potentially be an important molecular imaging tool to definitively measure AR inhibition in individual tumor lesions in response to AR pathway-directed therapies. Since the complexities of metastatic CRPC still remain unclear, understanding the biology of responsive and resistant lesions could provide a clear rationale for the individualization of patient care, impacting decisions for dose escalation and/or combination therapy to completely suppress AR signaling.
Mentor: Jason Lewis, PhD
The 2012 Shmuel Meitar – PCF Young Investigator Award
The role of prostate cancer stem cell regulated by microRNA in the formation of androgen-independent prostate cancer
Male hormones (androgens) fuel prostate cancer progression and the first line of treatment is Androgen Deprivation Therapy (ADT). Unfortunately, most prostate cancer patients ultimately become resistant to ADT. This stage of prostate cancer is termed castration-resistant prostate cancer (CRPC) and heralds metastasis and an increased risk for death.
Researchers recently identified prostate cancer-specific stem cells (PrCSC) that are proposed to play a major role in the development of treatment resistance and progression of prostate cancer. Studies of PrCSCs have shown that these cells are capable of self-renewal, possess enhanced tumor-initiating capabilities, do not rely on androgens for growth and survival and are therefore more resistant to treatment than other cancerous cells. In a previous study, Dr. Zhang has identified a sub-population of PrCSCs that increase in numbers upon treatment with ADT. He observed that this specific sub-population of stem cells decreased when the castration-resistant tumors were treated with androgens and a different PrCSC subset became more prominent in the tumors.
Based on these findings, Dr. Zhang proposes that there are two different sub-populations of stem cells that arise during prostate cancer progression from the androgen-dependent stage to castration-resistance. Based on the enhanced self-renewal and tumor-initiating capabilities of stem cells, Dr. Zhang proposes a transition of one type of PrCSC from one type to another during the progression of the disease. He proposes to study the individual populations of stem cells and the genes that govern their development.
MicroRNAs (miRNAs) are nucleic acids that regulate gene expression. Dr. Zhang proposes to identify the specific miRNAs that regulate the transformation of androgen-dependent prostate stem cells to androgen-independent stem cells. These studies proposed by Dr. Zhang may provide validation for miRNAs as potential targets for therapy against the development of androgen-independent prostate cancer.
Mentor: Chuize Kong, MD, PhD
In 2012, PCF also funded the first four Candian Young Investigators through the Coaltion to Cure Prostate Cancer. Read about them here.