Owen N. Witte

University of California, Los Angeles | UCLA · Department of Microbiology, Immunology & Molecular Genetics

Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers comprised of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer c...

The ability to selectively bind to antigenic peptides and secrete effector molecules can define rare and low-affinity populations of cells with therapeutic potential in emerging T cell receptor (TCR) immunotherapies. We leverage cavity-containing hydrogel microparticles, called nanovials, each coated with peptide-major histocompatibility complex (p...

CAR (chimeric antigen receptor) T cell therapy has shown clinical success in treating hematological malignancies, but its treatment of solid tumors has been limited. One major challenge is on-target, off-tumor toxicity, where CAR T cells also damage normal tissues that express the targeted antigen. To reduce this detrimental side-effect, Boolean-lo...

Mutated Ras and Raf kinases are well-known to promote cancer metastasis via flux through the Ras/Raf/MEK/ERK (mitogen-activated protein kinase [MAPK]) pathway. A role for non-mutated Raf in metastasis is also emerging, but the key mechanisms remain unclear. Elevated expression of any of the three wild-type Raf family members (C, A, or B) can drive...

The MYC proto-oncogene contributes to the pathogenesis of more than half of human cancers. Malignant transformation by MYC transcriptionally up-regulates the core pre-mRNA splicing machinery and causes misregulation of alternative splicing. However, our understanding of how splicing changes are directed by MYC is limited. We performed a signaling p...

Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)–targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (N...

Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen receptor (AR) signaling. Androgen deprivation therapy and second-generation AR-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by whether the tumor expresses ei...

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric a...

Metastatic castration resistant prostate cancer (mCRPC) remains a significant challenge with limited durable therapeutic responses, and innovative and effective treatment strategies are needed. Advanced mCRPC often comprises a heterogeneous population of prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC), and current targeted...

The ability to selectively bind to antigenic peptides and secrete cytokines can define populations of cells with therapeutic potential in emerging T cell receptor (TCR) immunotherapies. We leverage cavity-containing hydrogel microparticles, called nanovials, each coated with millions of peptide-major histocompatibility complex (pMHC) monomers to is...

The Myc proto-oncogene contributes to the pathogenesis of more than half of human cancers. Malignant transformation by Myc transcriptionally upregulates the core pre-mRNA splicing machinery and causes mis-regulation of alternative splicing. However, our understanding of how splicing changes are directed by Myc is limited. We performed a signaling p...

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transc...

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understandi...

Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide–major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicti...

Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate‐limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellul...

Many aggressive epithelial cancers do not carry targetable driver mutations (Mendiratta et al. 2021, NCI-MATCH Clinical trial NCT02465060). Commonly altered signaling pathways highlight the propensity for tumors to depend on such pathways for growth and survival where genomic alterations may not be required for pathway activation. The Raf family ki...

T cell receptor (TCR)-engineered T cells are a promising approach to cell therapy for cancer. TCRs targeting public tumor associated antigens (TAAs) offer the widest potential coverage of patients within and across tumor types. TAA-specific TCRs, however, are rare in the blood and when detected are frequently of low affinity due to negative selecti...

Small cell carcinomas of the lung, bladder, and prostate share similar transcription patterns and drug sensitivities. Due to their high cellular plasticity, these cancers often escape treatment through a trans-differentiation from adenocarcinoma to the neuroendocrine state. We previously developed a pan small cell cancer in vitro/in vivo model name...

5058 Background: Castration-resistant prostate cancer (CRPC) is the lethal form of the disease. One of the principal therapies in CRPC is the potent androgen receptor (AR) signaling inhibitor enzalutamide (enza). Most patients benefit from enza, but disease progression is nearly universal. A variety of resistance mechanisms have been described by c...

Cross-reactivity and direct killing of target cells remain underexplored for SARS-CoV-2 specific CD8+ T cells. Isolation of T cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T cell reactivity profiling. We identify SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp/NSP12) as highly conserved likely due to its critical r...

Cell-based immunotherapy has become the new-generation cancer medicine, and “off-the-shelf” cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targe...

Cancer transcriptomes frequently exhibit RNA dysregulation. As the resulting aberrant transcripts may be translated into cancer-specific proteins, there is growing interest in exploiting RNA dysregulation as a source of tumor antigens (TAs) and thus novel immunotherapy targets. Recent advances in high-throughput technologies and rapid accumulation...

Significance T cell receptors (TCRs) surveil cellular environment by recognizing peptides presented by the major histocompatibility complex. TCR sequencing allows for understanding the scope of T cell reactivity in health and disease. Specific TCR clones can be used as therapeutics in cancer and autoimmune disease. We present a technique that allow...

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes th...

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentia...

5507 Background: While recent studies have delineated the genomic landscape of mCRPC, its epigenomic landscape has not been as well characterized. The goal of this study was to define the comprehensive methylation landscape of mCRPC. Methods: mCRPC patients (pts) underwent a metastasis biopsy as part of a multi-institutional study (NCT02432001). De...

Significance The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with metastatic castration-resistant prostate cancer. However, not all patients respond, and de novo resistance mechanisms are largely unknown. To clarify mechanisms that contribute to enzalutamide resistance, we conducted a single-arm enzalut...

We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known cancer driver alterations. To do so, we compiled a metadataset composed of 876 RNA-sequencing (RNA-Seq) samples from five publicly available sources representing a range of prostate phenotypes from normal tissue to dru...

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenoty...

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR ⁺ luminal tumor cells and AR ⁻ neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purificati...

Background: Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for exi...

Aberrant alternative splicing (AS) is widespread in cancer, leading to an extensive but largely unexploited repertoire of potential immunotherapy targets. Here we describe IRIS, a computational platform leveraging large-scale cancer and normal transcriptomics data to discover AS-derived tumor antigens for T-cell receptor (TCR) and chimeric antigen...

Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for non-invasively visualizing these cells in a living organi...

Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells...

Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells...

Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanopart...

Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SC...

Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendoc...

T cell receptor (TCR) ligand discovery is essential for understanding and manipulating immune responses to tumors. We developed a cell-based selection platform for TCR ligand discovery that exploits a membrane transfer phenomenon called trogocytosis. We discovered that T cell membrane proteins are transferred specifically to target cells that prese...

Purpose: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinica...

Significance T immune cells can be engineered to express tumor-specific T cell receptor (TCR) genes and thereby kill cancer cells. This approach—termed TCR gene therapy—is effective but can cause serious adverse events if the target is also expressed in healthy, noncancerous tissue. NY-ESO-1 is a tumor-specific antigen that has been targeted succes...

Some (re)programming notes on cancer Epithelial cancers develop resistance to targeted therapies in a number of different ways. Several cancer types do so by undergoing phenotypic conversion to a highly aggressive cancer called small cell neuroendocrine carcinoma (SCNC). Whether distinct cancer types accomplish this “reprogramming” through the same...

Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched f...

Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)–targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, m...

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants a...

Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (18F-FDG and 18F-FAC...

Significance Advanced prostate cancer is a deadly disease made up of multiple cancer subtypes that evolve during its natural history. Unfortunately, antibody- and cell-based therapies in development that target single tumor antigens found in conventional prostate cancer do not account for this heterogeneity. Here, we show that two major subtypes of...

Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed.Methods:We evaluate in a p...

Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanopart...

The median survival of patients with small cell neuroendocrine carcinoma is significantly shorter than that of patients with classic acinar-type adenocarcinoma. Small cell neuroendocrine carcinoma is traditionally diagnosed based on histologic features because expression of current immunohistochemical markers is inconsistent. This is a challenging...

The immune system is dynamic and continually adapts to maintain the health of the whole body. Innate immune cells survey tissues for abnormalities and are able to detect and infiltrate infected and/or abnormal tissues. Signals from the initial infiltrating antigen-presenting immune cells lead to activation of the adaptive immune system including: (...

Inactivation of the tumor suppressor gene encoding the transcriptional regulator Ikaros ( IKZF1 ) is a hallmark of BCR-ABL1 ⁺ precursor B cell acute lymphoblastic leukemia (pre–B ALL). However, the mechanisms by which Ikaros functions as a tumor suppressor in pre–B ALL remain poorly understood. Here, we analyzed a mouse model of BCR-ABL1 ⁺ pre–B AL...

Inflammation is a risk factor for prostate cancer, but the mechanisms by which inflammation increases that risk are poorly understood. Here, we demonstrate that low expression of CD38 identifies a progenitor-like subset of luminal cells in the human prostate. CD38lo luminal cells are enriched in glands adjacent to inflammatory cells and exhibit epi...

The Stand Up 2 Cancer/Prostate Cancer Foundation–funded West Coast Dream Team project is a prospective multi-institutional study focused on acquiring metastatic castration-resistant prostate cancer (mCRPC) biopsy tissue at the time of resistance to abiraterone or enzalutamide. It is the first large-scale study designed to analyze mCRPC tissue speci...

Significance A high nuclear Notch homolog 1, translocation-associated (Notch1) intracellular domain level distinguishes high-risk prostate cancer and castration-resistant prostate cancer from benign and low/intermediate-risk prostate cancer. Chronic activation of Notch1 cooperates with multiple oncogenic pathways altered in early prostate cancer, i...

We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway anticle-abstract" id="abs0010"> We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obta...

Metastatic castration resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. The need to identify new actionable targets in this disease is crucial as we begin to examine the resistance mechanisms related to androgen withdrawal. Pathway activation of signaling proteins, such as kinases, are hypothesized to drive...

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA New generation of anti-androgen treatments such as enzalutamide and abiraterone are improving survival of men with advanced and metastatic prostate cancers, but resistance to these inevitably arises. The molecular mechanisms governing the emergence of treatment resista...

Inactivation of the transcriptional factor Ikaros (IKZF1) correlates with poor prognosis in progenitor B-cell acute lymphoblastic leukemia (pre-B ALL), and is a hallmark of the BCR-ABL1+ subgroup of pre-B ALL. Ikaros is a critical regulator of hematopoietic development and required for B-cell development, however the mechanisms by which Ikaros func...

Positron emission tomography (PET) is a powerful noninvasive imaging technique able to measure distinct biological processes in vivo by administration of a radiolabeled probe. Whole-body measurements track the probe accumulation providing a means to measure biological changes such as metabolism, cell location, or tumor burden. PET can also be appli...

Significance This study demonstrates that both primary human basal and luminal epithelial cells are cells of origin for prostate cancer through the use of a prostate organoid culture system. This technology enables the monitoring of early stages of prostate tumorigenesis in vitro and the interrogation of human prostate epithelial populations with s...

Significance Deoxycytidine kinase (dCK) is required for the activation of multiple nucleoside analog prodrugs used in cancer therapy and is a potential new therapeutic target in hematological malignancies. Here, we identify [ ¹⁸ F]Clofarabine; 2-chloro-2′-deoxy-2′-[ ¹⁸ F]fluoro-9-β- d -arabinofuranosyl-adenine ([ ¹⁸ F]CFA) as a new candidate PET pr...

MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostat...

The rapidly advancing field of cancer immunotherapy is currently limited by the scarcity of noninvasive and quantitative technologies capable of monitoring the presence and abundance of CD8(+) T cells and other immune cell subsets. In this study, we describe the generation of (89)Zr-desferrioxamine-labeled anti-CD8 cys-diabody ((89)Zr-malDFO-169 cD...

Animal models of cancer provide fundamental insight into the cellular and molecular mechanisms of human cancer development. As an alternative to genetically engineered mouse models, increasing evidence shows that tissue recombination and transplantation models represent an efficient approach to faithfully recapitulate solid epithelial cancer in mic...

Significance Therapies are urgently needed to treat metastatic prostate cancer. Mutationally activated and wild-type kinases such as BCR-ABL and BTK are effective therapeutic targets in multiple cancers. Genetically altered kinases are rare in prostate cancer. Wild-type kinases may be implicated in prostate cancer progression, but their therapeutic...

MANY OVERSIGHT MECHANISMS exist for research involving human subjects and cells, as well as the transfer of materials into other vertebrates, partly to reassure the public that biomedical research is ethically conducted. In the recently posted notice NOT-OD-15-158, the NIH stated that it “will not

An appropriate microenvironment provided by the mesenchyme is important for establishing tissue recombination models for epithelial cancer. Urogenital sinus mesenchymal (UGSM) cells derived from embryonic rodent show potent inductive effects for prostate regeneration. Genetic manipulation of these mesenchymal cells allows us to define the contribut...

Tissue recombination models are useful for studying cancer initiation, progression, and metastasis. They also provide an in vivo environment in which to investigate the functional role of stem cells in tissue repair. In this protocol, we describe in detail the dissociated prostate regeneration assay. Dissociated adult murine prostate cells are comb...

Tumor heterogeneity and the dynamic tumor immune microenvironment have become important topics in the field of cancer immunotherapy. The ability to noninvasively monitor immune cells in vivo via surface markers on immune cell subsets using immuno-positron emission tomography (immuno-PET) is an attractive means of visualizing both systemic and intra...

Significance Aggressive cancers often possess functional and molecular traits characteristic of normal stem cells. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. Here, we transcriptionally profiled epithelial populations from the human prostate and show that aggre...

Human small cell prostate carcinoma (SCPC) represents up to 25% of lethal castration-resistant prostate cancer. Molecular characterization of a panel of SCPCs recently identified frequent genomic amplification of both MYCN and AURKA. The oncogenic function of N-Myc has been characterized in many cancer types but its role in the initiation of human...

Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations or DNA amplifications of kinases are rare. We previously demonstrated that 1) expression of wild type (wt) Src in combination with the androgen receptor synergizes to produce aggressive prostate adenocarcinoma, 2) tyrosine phosphorylation increases with prost...

Emerging evidence demonstrates that the DNA repair kinase DNA-PK exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PK functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression...

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The first line of treatment for men with advanced prostate cancers is androgen deprivation therapy. However, the disease commonly relapses in its lethal metastatic form referred to as castration-resistant prostate cancer (CRPC). CRPC is the primary cause of prostate c...

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppress...

Life-threatening, acute liver failure can be triggered by a variety of factors, including common drugs such as acetaminophen. Positron emission tomography (PET) is rarely used to monitor liver function, in part due to a lack of specific imaging agents for liver function. Here we report a new PET probe, 2-deoxy-2-[18F]fluororibose ([18F]-2-DFR), for...

The proliferation and trafficking of T lymphocytes in immune responses are crucial events in determining inflammatory responses. To study whole body T lymphocyte dynamics non-invasively in vivo, we have generated anti-CD4 and -CD8 cys-diabodies (cDbs) derived from the parental antibody hybridomas GK1.5 and 2.43, respectively, for (89)Zr-immunoPET d...

Adoptive transfer of tumor-reactive T cells can successfully reduce tumor burden; however, in rare cases, lethal on-target/off-tumor effects have been reported. A noninvasive method to track engineered cells with high sensitivity and resolution would allow observation of correct cell homing and/or identification of dangerous off-target locations in...

Background: The efficacy of androgen signaling inhibitors such as Abiraterone (Abi) or Enzalutamide (Enz) has changed the standard of care in mCRPC. However, adaptive resistance to these agents is a consistent outcome with this therapy that undermines their benefit. The mechanisms underlying acquired resistance to Abi or Enz are poorly understood....

Significance This article describes a new method for generating large numbers of invariant natural killer T (iNKT) cells in mice through genetic engineering of blood stem cells. iNKT cells are potent immune cells that regulate many human diseases, including cancer, infections, allergies, and autoimmunity. However, both the study of iNKT cell biolog...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Androgen ablation remains the mainstay of treatment for men with advanced and metastatic prostate cancer. However, despite the introduction of new generation anti-androgens, a majority of men succumb to castration resistant prostate cancer (CRPC). The molecular mechanisms govern...

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA New therapeutic strategies are needed to treat prostate cancer as it progresses to the castration resistant stage following treatment with drugs to reduce androgen production or interfere with androgen receptor function. Genetic analyses of DNA alterations and RNA expression sho...

Aim: The mechanisms of resistance to androgen signaling inhibitors such as Abi or Enz are poorly understood. A growing proportion of these pts are developing treatment resistant NEPC. Progressive mCRPC has historically been challenging to biopsy and characterize on a molecular basis because of its bone tropism. As part of the WCDT project, which ai...

Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response...

Engineering immunity against cancer by the adoptive transfer of hematopoietic stem cells (HSC) modified to express antigen-specific T-cell-receptors (TCR) or chimeric antigen receptors (CAR) generates a continual supply of effector T-cells, potentially providing superior anti-cancer efficacy compared with the infusion of terminally differentiated T...

Significance The saccharide ribose is naturally present in food and circulates in the blood. Previous studies suggest that cells internalize ribose directly from the extracellular space, but how, why, and where this occurs in the body are not well understood. Here, we developed a new PET probe to monitor this process in vivo. Using this probe and [...