Christopher P Evans

University of California, Davis, Davis, California, United States

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Publications (131)730.04 Total impact

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    ABSTRACT: miR-124 targets the androgen receptor transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer (CaP). In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of CaP cells in vitro and sensitizes them to inhibitors of androgen receptor signaling (ARSIs). Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant CaP. We employed xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine (PEI)-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to CaP progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment.
    Cancer Research 11/2015; DOI:10.1158/0008-5472.CAN-14-0795 · 9.33 Impact Factor
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    Thenappan Chandrasekar · Joy C Yang · Allen C Gao · Christopher P Evans ·
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    ABSTRACT: Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.
    BMC Medicine 09/2015; 13(1):206. DOI:10.1186/s12916-015-0457-6 · 7.25 Impact Factor
  • Joy C. Yang · Allen C. Gao · Christopher P. Evans ·

    Cancer Research 08/2015; 75(15 Supplement):4969-4969. DOI:10.1158/1538-7445.AM2015-4969 · 9.33 Impact Factor
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    ABSTRACT: INTRODUCTION AND OBJECTIVES: We sought to assess the significance of disease presentation in patients with renal cell carcinoma with venous tumor thrombus (RCCVT) in predicting the pathological features of the disease and subsequent survival outcomes.
    AUA 2015 meeting. The Journal Of Urology, New Orleans; 05/2015
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    ABSTRACT: INTRODUCTION AND OBJECTIVES: We sought to assess the significance of disease presentation in patients with renal cell carcinoma with venous tumor thrombus (RCCVT) in predicting the pathological features of the disease and subsequent survival outcomes. METHODS: We queried the IRCC-VTC database of 2552 patients across 24 international centers. Disease presentation was separated into incidental detection of cancer (INC), local symptomatology (LSx), and systemic symptomatology (SSx). Our primary outcomes were overall (OS) and disease-specific (DSS) survival. Secondary outcomes included clinical stage with pathological features of cancer and perioperative outcomes. We utilized chi-square analysis +/-Fisher's exact test, Kruskall Wallis H test, and Kaplan-Meier (KM) estimator. RESULTS: We analyzed a total of 1479 patients who had symptomatology data. Of these patients, 453 (30.6%) had INC, 630 (42.6%) presented with LSx, and 396 (26.8%) presented with SSx. There was a significant association between symptomatology and clinical stage of the primary tumor, involvement of regional lymph nodes, and distant metastases, as well as with the level of thrombus (mean ranks of INC<LSx<SSx for each parameter, all p<0.0005). Symptomatology was also significantly associated with multiple pathological features, including: Fuhrman grade, presence of sarcomatoid component, microscopic IVC wall invasion, multifocal neoplasia, and tumor necrosis (all p<0.0005), in addition to presence of collecting system invasion (p=0.001). Patients with SSx had greater intraoperative blood loss, higher rate and grade of Clavien complications postoperatively, as well as longer length of stay compared to those with INC or LSx. The survival distributions from surgery were significantly different among disease presentations, with median OS of 3.636, 3.253, and 1.440 years (χ2=47.412, p<0.0005) and median DSS of 1.528, 1.760, and 0.977 years (χ2=23.101, p<0.0005) for patients with INC, LSx, and SSx, respectively (see figure). CONCLUSIONS: In patients with RCCVT, SSx was significantly associated with higher clinical staging, pathological features that conferred a poorer prognosis, worse perioperative outcomes, and worse survival outcomes compared to INC and LSx. Interestingly, patients with LSx had similar outcomes to those with INC.
    AUA 2015 meeting. The Journal of Urology, New Orleans; 05/2015
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    Chengfei Liu · Wei Lou · Cameron Armstrong · Yezi Zhu · Christopher P Evans · Allen C Gao ·
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    ABSTRACT: PURPOSE It is known that over expression of IL6 in prostate cancer cells confer enzalutamide resistance and that this may occur through constitutive Stat3 activation. Additionally, recent pre-clinical studies suggested enzalutamide might have the potential adverse effect of inducing metastasis of prostate cancer cells via Stat3 activation. This study is aimed to target Stat3 activation and improve enzalutamide therapy. EXPERIMENTAL DESIGN Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Wound healing and invasion assays were performed to determine cell migration and invasion in vitro. Quantitative reverse transcription-PCR, ELISA and Western blotting were performed to detect expression levels of PSA, c-Myc, survivin, Stat3, and AR. ChIP assay was performed to examine recruitment of AR to the PSA promoter. RESULTS In the present study, we found niclosamide, a previously identified novel inhibitor of androgen receptor variant (AR-V7), inhibited Stat3 phosphorylation, and expression of downstream target genes. Niclosamide synergistically reversed enzalutamide resistance in prostate cancer cells and combination treatment of niclosamide with enzalutamide significantly induced cell apoptosis and inhibited cell growth, colony formation, cell migration and invasion. Knock down of Stat3 abrogated enzalutamide resistance resulting in reduced recruitment of AR to the PSA promoter in prostate cancer cells expressing IL6. Moreover, niclosamide reversed enzalutamide resistance by down-regulating Stat3 target gene expression Stat3and abrogating recruitment of AR to PSA promoter resulting in PSA inhibition. CONCLUSIONS This study demonstrated the IL6-Stat3-AR axis in prostate cancer is one of the crucial mechanisms of enzalutamide resistance. Niclosamide has the potential to target the IL6-Stat3-AR pathway to overcome enzalutamide resistance and inhibit migration and invasion in advanced prostate cancer.
    The Prostate 05/2015; 75(13). DOI:10.1002/pros.23015 · 3.57 Impact Factor
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    Allison Glass · Neil Pugashetti · Marc A. Dall'Era · Christopher P. Evans · Stanley A. Yap ·

    The Journal of Urology 04/2015; 193(4):e508-e509. DOI:10.1016/j.juro.2015.02.1588 · 4.47 Impact Factor

  • The Journal of Urology 04/2015; 193(4):e546. DOI:10.1016/j.juro.2015.02.1570 · 4.47 Impact Factor
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    ABSTRACT: Castration resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one of the principal mechanisms that promote the development of resistance to next-generation anti-androgens such as enzalutamide. Here, we demonstrate that the splicing factor heterogeneous nuclear RNA-binding protein A1 (hnRNPA1) plays a pivotal role in the generation of AR splice variants such as AR-V7. HnRNPA1 is overexpressed in prostate tumors compared to benign prostates and its expression is regulated by NF-kappaB2/p52 and c-Myc. CRPC cells resistant to enzalutamide exhibit higher levels of NF-kappaB2/p52, c-Myc, hnRNPA1, and AR-V7. Levels of hnRNPA1 and of AR-V7 are positively correlated with each other in PCa. The regulatory circuit involving NF-kappaB2/p52, c-Myc and hnRNPA1 plays a central role in the generation of AR splice variants. Downregulation of hnRNPA1 and consequently of AR-V7 resensitizes enzalutamide-resistant cells to enzalutamide, indicating that enhanced expression of hnRNPA1 may confer resistance to AR-targeted therapies by promoting the generation of splice variants. These findings may provide a rationale for co-targeting these pathways to achieve better efficacy through AR blockade. Copyright © 2015, American Association for Cancer Research.
    The Journal of Urology 04/2015; 193(4):e544. DOI:10.1016/j.juro.2015.02.1566 · 4.47 Impact Factor
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    ABSTRACT: The impact of cardiopulmonary bypass (CPB) usage in level III-IV tumor thrombectomy on surgical and oncologic outcomes is unknown. We sought to determine the impact of cardiopulmonary bypass (CPB) on overall and cancer specific survival, as well as surgical complication rates, and immediate outcomes in patients undergoing nephrectomy and level III-IV tumor thrombectomy with or without CPB. We retrospectively analyzed 362 patients with RCC and with level III or IV tumor thrombus from 1992 to 2012 in 22 US and European centers. Cox proportional hazards models were used to compare overall and cancer-specific survival between patients with and without CPB. Perioperative mortality and complications rates were assessed using logistic regression analyses. The median overall survival was 24.6 months in non-CPB patients and 26.6 months in CPB patients. Overall survival and cancer-specific survival (CSS) did not differ significantly in both groups, neither in univariate analysis nor when adjusting for known risk factors. In multivariate analysis, no significant differences were seen in hospital LOS, Clavien 1-4 complication rate, intraoperative or 30 day mortality, and CSS between both groups. Limitations include the retrospective nature of the study. In our multi-institutional analysis, the use of cardiopulmonary bypass did not significantly impact cancer specific survival or overall survival in patients undergoing nephrectomy and level III or IV tumor thrombectomy. Neither approach was independently associated with increased mortality in the multivariate analysis. Higher surgical complications were not independently associated with the use of CPB. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of urology 03/2015; 194(2). DOI:10.1016/j.juro.2015.02.2948 · 4.47 Impact Factor

  • Clinical Cancer Research 02/2015; 21(4 Supplement):A12-A12. DOI:10.1158/1557-3265.PMS14-A12 · 8.72 Impact Factor
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    ABSTRACT: The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene expression analysis showed that steroid biosynthesis pathway is activated in enzalutamide resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in enzalutamide resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide resistant prostate cancer cells to enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance, targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 02/2015; 75(7). DOI:10.1158/0008-5472.CAN-14-3080 · 9.33 Impact Factor
  • Derya Tilki · Sun Il Kim · Brian Hu · Marc A Dall'Era · Christopher P Evans ·
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    ABSTRACT: Prostate-specific antigen (PSA) is an important tool for monitoring of patients with prostate cancer (PCa) after radical prostatectomy (RP). Ultrasensitive PSA (uPSA) assays with a lower limit of detection (LLD) of as low as 0.001 ng/ml are being increasingly used. This systematic review examines current available uPSA technologies and the role of uPSA in monitoring patients after RP. A search of relevant literature was performed using the Medline database. Studies that presented serial uPSA (lower detection limit <0.1 ng/ml) data of men following RP and had comparative data from standard PSA (lower detection limit ≥0.1 ng/ml) for a variety of study objectives, were eligible for review. The utilization of uPSA can detect PCa recurrence potentially years earlier when compared with standard PSA assays. The specificity of detectable uPSA is low. uPSA kinetics may improve the positive predictive value in detecting cancer recurrence. However, utility of PSA doubling time at the ultrasensitive level remains controversial. An undetectable nadir uPSA value after RP confers a low risk of disease recurrence. A detectable nadir uPSA above 0.01 ng/ml needs additional measurements and consideration of other risk factors for management decision to avoid overtreatment. uPSA monitoring may spare high risk disease patients adjuvant radiation therapy for more selective early salvage radiation. There is currently no data that demonstrates improvement in survival following early salvage therapy prompted by uPSA surveillance. uPSA is useful in the early diagnosis of cancer recurrence after RP. Its specificity, however, is poor. To date, there is lack of evidence that earlier detection of recurrence translates into prolonged time to metastasis. Integration of uPSA with other clinicopathologic factors can help determine optimal utilization of adjuvant and salvage therapy. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of Urology 10/2014; 193(5). DOI:10.1016/j.juro.2014.10.087 · 4.47 Impact Factor
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    ABSTRACT: Context Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC). Objective To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC. Evidence acquisition PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included. Evidence synthesis This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression. Conclusions The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC. Patient summary We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non–AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.
    European Urology 10/2014; 67(3). DOI:10.1016/j.eururo.2014.09.049 · 13.94 Impact Factor
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    Emma Shtivelman · Tomasz M Beer · Christopher P Evans ·
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    ABSTRACT: Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge.
    Oncotarget 09/2014; 5(17):7217-59. DOI:10.18632/oncotarget.2406 · 6.36 Impact Factor
  • Jason M Farrow · Joy C Yang · Christopher P Evans ·
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    ABSTRACT: Autophagy, or 'self-eating', is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of autophagy is generally considered beneficial, autophagy can also enhance nutrient utilization and improve growth characteristics of cancer cells. Moreover, autophagy can promote greater cellular robustness in the context of therapeutic intervention. In advanced prostate cancer, preclinical data provide evidence that autophagy facilitates both disease progression and therapeutic resistance. Notably, androgen deprivation therapy, taxane-based chemotherapy, targeted kinase inhibition, and nutrient restriction all induce significant cellular distress and, subsequently, autophagy. Understanding the context-dependent role of autophagy in cancer development and treatment resistance has the potential to improve current treatment of advanced prostate cancer. Indeed, preclinical studies have shown that the pharmacological inhibition of autophagy (with agents including chloroquine, hydroxychloroquine, metformin, and desmethylclomipramine) can enhance the cell-killing effect of cancer therapeutics, and a number of these agents are currently under investigation in clinical trials. However, many of these autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is still a concern. Moving forward, refinement of autophagy modulation is needed.
    Nature Reviews Urology 08/2014; 11(9). DOI:10.1038/nrurol.2014.196 · 4.84 Impact Factor
  • Christopher P Evans · Primo N Lara ·

    Nature Reviews Urology 07/2014; 11(8). DOI:10.1038/nrurol.2014.179 · 4.84 Impact Factor
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    ABSTRACT: Purpose: Metastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival. Materials and methods: The records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates. Results: Lymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival. Conclusions: In our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.
    European Urology Supplements 07/2014; 193(2). DOI:10.1016/j.juro.2014.07.087 · 3.37 Impact Factor
  • William Thieu · Derya Tilki · Ralph W. deVere White · Christopher P Evans ·
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    ABSTRACT: Introduction: Castration-resistant prostate cancer (CRPC) has a historically low median survival rate, but recent advances and discoveries in microRNAs (miRNAs) have opened the potential for new prognostication modalities to enhance therapeutic success. As new chemotherapies and immunotherapies are developed, there is an increasing need for precision and stratification of CRPC to allow for optimization and personalization of therapy. Methods: A systematic literature review was conducted via electronic database resulting in the selection of 42 articles based on title, abstract, study format, and content by a consensus of all participating authors. Most selected articles were published between 2002 and 2013. In this review, we discuss the robustness of miRNAs as a biomarker platform, miRNAs associated with prostate cancer, and recent discoveries of miRNA associations with CRPC. Results: The associations discovered have been of interest owing to the ability to differentiate between CRPC and localized prostate cancer. With the evaluation of multiple miRNAs, it is possible to provide a profile regarding tumor characteristics. Furthermore, actions of miRNAs on CRPC tumor cells have the ability to suppress metastatic phenotypes. Conclusion: miRNAs may have a growing role in CRPC prognostication and may potentially transform into a therapeutic potential.
    Urologic Oncology 07/2014; 32(5):517-523. DOI:10.1016/j.urolonc.2013.11.004 · 2.77 Impact Factor
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    ABSTRACT: Understanding the mechanisms by which compounds discovered using cell-based phenotypic screening strategies might exert their effects would be highly augmented by new approaches exploring their potential interactions with the genome. For example, altered androgen receptor (AR) transcriptional programs, including castration resistance and subsequent chromosomal translocations, play key roles in prostate cancer pathological progression, making the quest for identification of new therapeutic agents and an understanding of their actions a continued priority. Here we report an approach that has permitted us to uncover the sites and mechanisms of action of a drug, referred to as "SD70," initially identified by phenotypic screening for inhibitors of ligand and genotoxic stress-induced translocations in prostate cancer cells. Based on synthesis of a derivatized form of SD70 that permits its application for a ChIP-sequencing-like approach, referred to as "Chem-seq," we were next able to efficiently map the genome-wide binding locations of this small molecule, revealing that it largely colocalized with AR on regulatory enhancers. Based on these observations, we performed the appropriate global analyses to ascertain that SD70 inhibits the androgen-dependent AR program, and prostate cancer cell growth, acting, at least in part, by functionally inhibiting the Jumonji domain-containing demethylase, KDM4C. Global location of candidate drugs represents a powerful strategy for new drug development by mapping genome-wide location of small molecules, a powerful adjunct to contemporary drug development strategies.
    Proceedings of the National Academy of Sciences 06/2014; 111(25). DOI:10.1073/pnas.1404303111 · 9.67 Impact Factor

Publication Stats

3k Citations
730.04 Total Impact Points


  • 2001-2015
    • University of California, Davis
      • Department of Urology
      Davis, California, United States
  • 2002-2012
    • California State University, Sacramento
      Sacramento, California, United States
  • 2010
    • Tianjin Medical University
      • Department of Radiology
      T’ien-ching-shih, Tianjin Shi, China
  • 2003-2008
    • Davis School District
      Davis, California, United States