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1.  Everolimus Combined With Gefitinib in Patients with Metastatic Castration-Resistant Prostate Cancer: Phase I/II Results and Signaling Pathway Implications 
Cancer  2015;121(21):3853-3861.
The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in PTEN-null tumors, thus we tested the combination of mTOR inhibition (everolimus) and EGFR inhibition (gefitinib) in castration-resistant prostate cancer (CRPC).
In phase I, 12 patients (10 CRPC, 2 glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase II, 27 CRPC patients received gefitinib with everolimus 70 mg.
Phase I revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase II, 18 of 27 (67%) patients discontinued treatment before the 12-week evaluation due to progression as evidenced by prostate-specific antigen (PSA) levels (n=6) or imaging (n=5), or grade ≥2 toxicity (n=7). Thirteen of the total 37 (35%) CRPC patients exhibited a rapidly rising PSA after starting treatment which declined upon discontinuation. Fluorodeoxyglucose positron emission tomography at 24 to 72 hours after starting treatment showed a decrease in standardized uptake value consistent with mTOR inhibition in 27 of 33 (82%) evaluable patients; there was a corresponding rise in PSA in 20 of these 27 patients (74%).
The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data that PI3K pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.
PMCID: PMC4618268  PMID: 26178426
prostatic neoplasms; sirolimus derivatives (everolimus); TOR serine-threonine kinases (mTOR); pharmacokinetics; quinazolines (gefitinib)
2.  Rates of Teratoma and Viable Cancer at Post-Chemotherapy Retroperitoneal Lymph Node Dissection after Induction Chemotherapy for Good Risk Non-Seminomatous Germ Cell Tumors 
The Journal of urology  2014;193(2):513-518.
Patients with good risk nonseminomatous germ cell tumors receive induction chemotherapy with either 4 cycles of etoposide and platinum (EPx4) or three cycles of bleomycin, etoposide, and platinum (BEPx3). We report the histologic results at post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) after induction chemotherapy in patients treated either with EP or BEP for good risk NSGCT.
Materials and Methods
PC-RPLND was performed in 579 patients following induction chemotherapy. Five-hundred five patients were treated with EPx4 and 74 patients were treated with BEPx3 or BEPx4. Clinical and pathologic features are reported.
No difference in the frequency of viable residual cancer was observed between BEP and EP (5% vs 6%, respectively, P=NS). Teratoma was more prevalent in the BEP group vs. EP (57% vs. 34%, respectively, p<0.001). On multivariate analysis, patients that received induction BEP had a 2-fold greater risk of harboring teratoma at PC-RPLND (OR 2.0, 95% CI 1.0, 4.0, p=0.04). When excluding patients that received BEPx4, patients that received BEPx3 still had a 3.7 fold increased risk of having teratoma in the retroperitoneum (OR 3.7, 95% CI 1.5, 8.9, p=0.004). Relapse-free survival and disease-specific survivals were not different between the two regimens.
Viable cancer was equally uncommon after treatment with both regimens. Overall, relapse-free, and disease-specific survivals did not differ. The discrepancy between regimens in the frequency of teratoma is not explained, but may be due to an unrecognized selection bias than an effect of the regimen.
PMCID: PMC4354932  PMID: 25150639
3.  Feedback suppression of PI3Kα signaling in PTEN mutated tumors is relieved by selective inhibition of PI3Kβ 
Cancer cell  2014;27(1):109-122.
In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.
PMCID: PMC4293347  PMID: 25544636
PI3Kβ; PI3Kα; isoform-selective inhibitors; feedback inhibition; PTEN-mutated tumors; IGF1R/IRS1 signaling pathway; RTKs; prostate cancer; Triple negative breast cancer
4.  Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling 
Molecular cancer therapeutics  2014;14(1):278-288.
Copy number alterations (CNAs) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non-MET amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non-Met amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late state prostate cancer.
PMCID: PMC4297258  PMID: 25381262
MET; Prostate Cancer; GEM models; secondary genomic alterations; targeted therapy
5.  An allelic series of miR-17~92 mutant mice uncovers functional specialization and cooperation among members of a miRNA polycistron 
Nature genetics  2015;47(7):766-775.
Polycistronic microRNA clusters are a common feature of vertebrate genomes. The coordinated expression of miRNAs belonging to different seed families from a single transcription unit suggests functional cooperation, but this hypothesis has not been experimentally tested. Here we report the characterization of an allelic series of genetically engineered mice harboring selective targeted deletions of individual components of miR-17~92. Our results demonstrate the co-existence of functional cooperation and specialization among members of this cluster, identify a novel function for the miR-17 seed family in controlling axial patterning in vertebrates, and show that loss of miR-19 selectively impairs Myc-driven tumorigenesis in two models of human cancer. By integrating phenotypic analysis and gene expression profiling, we provide a genome-wide view of how components of a polycistronic miRNA-cluster affect gene expression in vivo. The reagents and datasets reported here will accelerate exploration of the complex biological functions of this important miRNA cluster.
PMCID: PMC4485521  PMID: 26029871
6.  Slug Regulates E-cadherin Repression via p19Arf in Prostate Tumorigenesis 
Molecular oncology  2014;8(7):1355-1364.
SLUG represses E-Cadherin to promote epithelial-mesenchymal transition (EMT) in various cancers. Mechanisms that regulate SLUG/E-Cadherin pathway remain poorly understood, especially during tumorigenesis in vivo. Here we report that p19Arf (p14ARF in human) stabilizes Slug to inhibit E-Cadherin in prostate cancer mouse models. Inactivation of p19Arf reduces Slug levels, resulting in increased E-Cadherin expression and delaying the onset and progression of prostate cancer in Pten/Trp53 double null mice. Mechanistically, p14ARF stabilizes SLUG through increased sumoylation at lysine residue 192. Importantly, levels of SLUG and p14ARF are positively correlated in human prostate cancer specimens. These data demonstrated that ARF modulates the SLUG/ECadherin signaling axis for augmenting prostate tumorigenesis in vivo, revealing a novel paradigm where the oncogenic functions of SLUG require ARF to target E-Cadherin in prostate cancer. Collectively, our findings further support that ARF has dual tumor suppressive/oncogenic roles in cancers in a context-dependent manner.
PMCID: PMC4198473  PMID: 24910389
SLUG; prostate cancer; SUMO1; mouse model
7.  Organoid cultures derived from patients with advanced prostate cancer 
Cell  2014;159(1):176-187.
The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D “organoid” system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression and CHD1 loss. Whole exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as of DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.
PMCID: PMC4237931  PMID: 25201530
8.  Cabozantinib Resolves Bone Scans in Tumor-Naïve Mice Harboring Skeletal Injuries 
Molecular imaging  2014;13:10.2310/7290.2014.00026.
The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the remodeling bone. To test this hypothesis, we surgically induced bone remodeling via physical insult in non–tumor-bearing mice and performed 18F–sodium fluoride (18F-NaF) positron emission tomographic (PET) and technetium 99m–methylene diphosphonate (99mTc-MDP) single-photon emission computed tomographic (SPECT) scans pre- and posttreatment with cabozantinib and related inhibitors. A consistent reduction in the accumulation of either radiotracer at the site of bone remodeling was observed in animals treated with cabozantinib. Given that cabozantinib is known to inhibit several receptor tyrosine kinases, we drugged animals with various permutations of more selective inhibitors to attempt to refine the molecular basis of bone scan resolution. Neither the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib, the MET inhibitor crizotinib, nor the combination was capable of inhibiting 18F-NaF accumulation at known bioactive doses. In summary, although the mechanism by which cabozantinib suppresses radionuclide incorporation into foci undergoing bone remodeling remains unknown, that this phenomenon occurs in tumor-naïve models indicates that caution should be exercised in interpreting the clinical significance of this event.
PMCID: PMC4545649  PMID: 25248353
9.  Precisely mapping a major gene conferring resistance to Hessian fly in bread wheat using genotyping-by-sequencing 
BMC Genomics  2015;16(1):108.
One of the reasons hard red winter wheat cultivar ‘Duster’ (PI 644016) is widely grown in the southern Great Plains is that it confers a consistently high level of resistance to biotype GP of Hessian fly (Hf). However, little is known about the genetic mechanism underlying Hf resistance in Duster. This study aimed to unravel complex structures of the Hf region on chromosome 1AS in wheat by using genotyping-by-sequencing (GBS) markers and single nucleotide polymorphism (SNP) markers.
Doubled haploid (DH) lines generated from a cross between two winter wheat cultivars, ‘Duster’ and ‘Billings’ , were used to identify genes in Duster responsible for effective and consistent resistance to Hf. Segregation in reaction of the 282 DH lines to Hf biotype GP fit a one-gene model. The DH population was genotyped using 2,358 markers developed using the GBS approach. A major QTL, explaining 88% of the total phenotypic variation, was mapped to a chromosome region that spanned 178 cM and contained 205 GBS markers plus 1 SSR marker and 1 gene marker, with 0.86 cM per marker in genetic distance. The analyses of GBS marker sequences and further mapping of SSR and gene markers enabled location of the QTL-containing linkage group on the short arm of chromosome 1A. Comparative mapping of the common markers for the gene for QHf.osu-1Ad in Duster and the Hf-resistance gene for QHf.osu-1A74 in cultivar ‘2174’ showed that the two Hf resistance genes are located on the same chromosome arm 1AS, only 11.2 cM apart in genetic distance. The gene at QHf.osu-1Ad in Duster has been delimited within a 2.7 cM region.
Two distinct resistance genes exist on the short arm of chromosome 1A as found in the two hard red winter cultivars, 2174 and Duster. Whereas the Hf resistance gene in 2174 is likely allelic to one or more of the previously mapped resistance genes (H9, H10, H11, H16, or H17) in wheat, the gene in Duster is novel and confers a more consistent phenotype than 2174 in response to biotype GP infestation in controlled-environment assays.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1297-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4347651  PMID: 25765046
Hessian fly resistance; Genotyping-by-sequencing (GBS); Insect resistance pathway; Quantitative trait loci (QTL); Wheat
10.  Retroperitoneal Histology of Patients with Elevated Serum Alpha-Fetoprotein and Pure Seminoma at Orchiectomy 
Urology  2011;78(4):844-847.
A histologic diagnosis of seminoma at orchiectomy with an elevation in serum alpha-fetoprotein (AFP) indicates the likelihood of unrecognized NSGCT elements. We report the retroperitoneal histology of a contemporary series of patients with pure seminoma at orchiectomy with an elevation in serum AFP that were managed as NSGCT.
We identified 22 patients between 1989 and 2009 with pure seminoma diagnosed at orchiectomy with an elevated serum AFP (> 15 ng/ml) either pre- or post-orchiectomy. Retroperitoneal histology and relapse data are reported.
Median pre-orchiectomy and pre-chemotherapy serum AFP levels were 248 ng/ml (IQR 48, 4693) and 279 ng/ml (IQR 66, 5311), respectively. Percentage of patients with clinical stage I, II, and III was 5%, 50%, and 45%, respectively. Percentage of patients with IGCCCG good, intermediate, and poor risk status was 32%, 32%, and 36%, respectively. Twenty-one patients had induction chemotherapy followed by PC-RPLND. Overall, 67% of patients had NSGCT elements in the retroperitoneum. Histologic findings were pure teratoma in 38%, malignant transformation in 14%, and viable NSGCT in 14%. Fifty-nine percent had some component of teratoma in the RP. One patient (5%) had any seminoma in the RP, but this patient also had RP teratoma. Seven patients relapsed and received salvage chemotherapy. Actuarial relapse free survival at 5 and 10 years was 76% and 61% reflecting a high percentage of patients with stage II/III disease.
Pure seminoma at orchiectomy with an elevated serum AFP portends a high likelihood of harboring NSGCT elements in the RP.
PMCID: PMC4237276  PMID: 21782217
testicular cancer; seminoma; AFP; RPLND
Cancer  2010;116(22):5243-5250.
Lymph node counts are a measure of quality assurance and are associated with prognosis for numerous malignancies. To date, investigations of lymph node counts in testis cancer are lacking.
Using the Memorial Sloan-Kettering Testis Cancer Database, we identified 255 patients treated with primary retroperitoneal lymph node dissection (RPLND) for nonseminomatous germ cell tumors (NSGCT) between 1999 and 2008. Features associated with node counts, positive nodes, number of positive nodes, and risk of positive contralateral nodes were evaluated with regression models.
Median (IQR) total node count was 38 (27–53) and was 48 (34 – 61) during the most recent 5 years. Features associated with higher node count on multivariate analysis included high volume surgeon (p=0.034), clinical stage (p=0.036), and more recent year of surgery (p<0.001) while pathologist was not significantly associated with node count (p=0.3). Clinical stage (p<0.001) and total node count (p=0.045) were significantly associated with finding positive nodes on multivariate analysis. The probability of finding positive nodes were 23%, 23%, 31%, and 48% if the total node count was <21, 21 – 40, 41 – 60, and >60, respectively. With a median follow-up of 3.0 years all patients were still alive and 16 patients relapsed while no patient relapsed in the paracaval, interaortocaval, paraaortic, or iliac regions.
Our results suggest that >40 lymph nodes removed at RPLND improves the diagnostic efficacy of the operation. These results will be useful for future trials comparing RPLND, especially when assessing the adequacy of lymph node dissection.
PMCID: PMC4174298  PMID: 20665486
Testicular neoplasms; Lymph nodes; Lymph node excision; Neoplasm staging
Urology  2011;79(2):361-364.
Lymph node counts are a proposed measure of quality assurance for numerous malignancies. Investigation of patient factors associated with lymph node counts are lacking. We sought to determine if body mass index (BMI) is associated with lymph node counts in patients treated with a primary retroperitoneal lymph node dissection (RPLND).
Using the Memorial Sloan-Kettering Testis Cancer Database, we identified 255 patients treated with a primary RPLND for nonseminomatous germ cell tumors (NSGCT) from 1999–2008. The associations between BMI and node counts were evaluated using linear regression models in univariate and multivariable models adjusting for features reported to predict higher node counts (year of surgery, stage, and surgeon volume).
Median BMI (IQR) was 26.1 (23.4 – 28.7) and median (IQR) total node count was 38 (27–53). Median total node count for patients with a BMI <25, 25–<30, and >30 was 35, 42, and 44 nodes, respectively. In a univariate analysis, higher BMI was significantly associated with higher total node counts (coefficient 0.7 nodes for each 1 unit increase in BMI; p=0.026). Features associated with higher node count on multivariate analysis included high volume surgeon (p=0.047), pathologic stage (p=0.017), more recent year of surgery (p<0.001), and higher BMI (p=0.009).
Our results suggest for the first time that BMI is independently associated with higher lymph node counts during a lymph node dissection. If confirmed by others, these results may be important when using lymph node counts as a surrogate for adequacy of a lymph node dissection.
PMCID: PMC4170790  PMID: 22173172
Testicular neoplasms; Lymph nodes; Lymph node excision; Neoplasm staging; Body mass index
13.  Association Analysis of Stem Rust Resistance in U.S. Winter Wheat 
PLoS ONE  2014;9(7):e103747.
Stem rust has become a renewed threat to global wheat production after the emergence and spread of race TTKSK (also known as Ug99) and related races from Africa. To elucidate U.S. winter wheat resistance genes to stem rust, association mapping was conducted using a panel of 137 lines from cooperative U.S. winter wheat nurseries from 2008 and simple sequence repeat (SSR) and sequence tagged site (STS) markers across the wheat genome. Seedling infection types were evaluated in a greenhouse experiment using six U.S. stem rust races (QFCSC, QTHJC, RCRSC, RKQQC, TPMKC and TTTTF) and TTKSK, and adult plant responses to bulked U.S. races were evaluated in a field experiment. A linearization algorithm was used to convert the qualitative Stakman scale seedling infection types for quantitative analysis. Association mapping successfully detected six known stem rust seedling resistance genes in U.S. winter wheat lines with frequencies: Sr6 (12%), Sr24 (9%), Sr31 (15%), Sr36 (9%), Sr38 (19%), and Sr1RSAmigo (8%). Adult plant resistance gene Sr2 was present in 4% of lines. SrTmp was postulated to be present in several hard winter wheat lines, but the frequency could not be accurately determined. Sr38 was the most prevalent Sr gene in both hard and soft winter wheat and was the most effective Sr gene in the adult plant field test. Resistance to TTKSK was associated with nine markers on chromosome 2B that were in linkage disequilibrium and all of the resistance was attributed to the Triticum timopheevii chromosome segment carrying Sr36. Potential novel rust resistance alleles were associated with markers Xwmc326-203 on 3BL, Xgwm160-195 and Xwmc313-225 on 4AL near Sr7, Xgwm495-182 on 4BL, Xwmc622-147 and Xgwm624-146 on 4DL, and Xgwm334-123 on 6AS near Sr8. Xwmc326-203 was associated with adult plant resistance to bulked U.S. races and Xgwm495-182 was associated with seedling resistance to TTKSK.
PMCID: PMC4114971  PMID: 25072699
14.  Lrf suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion 
Nature genetics  2013;45(7):739-746.
Lrf has been previously described as a powerful proto-oncogene. Here we surprisingly demonstrate that Lrf plays a critical oncosuppressive role in the prostate. Prostate specific inactivation of Lrf leads to a dramatic acceleration of Pten-loss-driven prostate tumorigenesis through a bypass of Pten-loss-induced senescence (PICS). We show that LRF physically interacts with and functionally antagonizes SOX9 transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long non-coding RNA precursor for an Rb-targeting miRNA. Inactivation of Lrf in vivo leads to Rb down-regulation, PICS bypass and invasive prostate cancer. Importantly, we found that LRF is genetically lost, as well as down-regulated at both the mRNA and protein levels in a subset of human advanced prostate cancers. Thus, we identify LRF as a context-dependent cancer gene that can act as an oncogene in some contexts but also displays oncosuppressive-like activity in Pten−/− tumors.
PMCID: PMC4036521  PMID: 23727861
Urology  2010;77(2):368-372.
Recent observations suggest that surgeon volume is associated with lymph node counts during retroperitoneal lymph node dissection (RPLND). We report our contemporary single-surgeon experience with lymph node counts during primary RPLND for nonseminomatous germ cell tumors (NSGCT).
Using the Memorial Sloan-Kettering Testis Cancer Database, we identified 124 consecutive patients treated with primary RPLND by a single experienced surgeon for NSGCT between 2004 and 2008. Predictors of positive nodes and number of positive nodes were evaluated with logistic and linear regression models adjusting for year of surgery and clinical stage.
Positive lymph nodes were observed in 37 (30%) while 87 (70%) patients were pN0. Mean total node count was 51 (SD= 23) during the 5 year study period. Mean node counts for the paracaval, interaortocaval, and paraaortic regions were 8 (SD= 6), 17 (SD= 9), and 26 (SD= 15), respectively. In a multivariate analysis, higher total node count was significantly associated with finding positive nodes (odds ratio 1.02 for each additional node counted; p=0.037) and finding multiple positive nodes (coefficient 0.04 for each additional node counted; p=0.004). Year of surgery (p<0.001) was associated with higher total node counts, while clinical stage and pathologist were not (p>0.5 for each).
The average total node count for a primary RPLND by an experienced surgeon is approximately 50 nodes with nearly half of the nodes originating in the paraaortic region. These results will be useful when assessing the adequacy of lymph node dissections for testis, renal, and upper tract urothelial malignancies.
PMCID: PMC4012337  PMID: 21109294
Testicular neoplasms; Lymph node excision; Neoplasm staging; Retroperitoneal space; Lymph nodes
16.  Androgen receptor signaling regulates DNA repair in prostate cancers 
Cancer discovery  2013;3(11):1245-1253.
We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy (ADT) synergizes with ionizing radiation (IR). Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output which correlates with expression of a set of DNA repair genes. Employing RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with IR plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical non-homologous end joining.
PMCID: PMC3888815  PMID: 24027196
17.  ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss 
Nature medicine  2013;19(8):1023-1029.
Studies of ETS-mediated prostate oncogenesis have been hampered by the lack of suitable experimental systems. Here we describe a new conditional mouse model which gives robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG significantly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included restoration of AR transcriptional outut and genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETV1 positively regulated AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, ERG and ETV1 expression correlated with higher AR transcriptional output in PTEN-negative prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.
PMCID: PMC3737318  PMID: 23817021
18.  TaMFT-A1 Is Associated with Seed Germination Sensitive to Temperature in Winter Wheat 
PLoS ONE  2013;8(9):e73330.
The ability of seed to germinate under favorable environmental conditions is critical for seedling emergence, plant establishment, subsequent development and growth of adult plants, and it is controlled by internal genetic factors and external environmental factors. Winter wheat in the southern Great Plains is often planted six weeks before the optimal planting date to produce more biomass for cattle grazing during the winter season. A high seed germination rate in this higher soil temperature environment is required for this specific management system. In this study, a major QTL for temperature-sensitive germination was mapped on the short arm of chromosome 3A (QTsg.osu-3A) in a RIL population generated from two winter wheat cultivars. Furthermore, TaMFT-A1, previously reported to regulate seed dormancy and pre-harvest sprouting in spring wheat cultivars, was mapped tightly associated with the peak of QTsg.osu-3A. However, allelic variation in TaMFT-A1 between the two winter wheat cultivars differed from that was observed in spring wheat cultivars. There were 87 SNPs (single nucleotide polymorphisms) and 12 indels (insertions/deletions) in TaMFT-A1 between the Jagger allele for high germination and the 2174 allele for low germination in the after-ripened seeds, in comparison with 2 SNPs between the two alleles for differential pre-harvest sprouting in spring wheat cultivars. The Jagger TaMFT-A1 allele is a novel haplotype and appears extensively in winter wheat cultivars. TaMFT-A1 transcript levels were up-regulated by high temperature but down-regulated by low temperature or seed storage time. These findings suggest that TaMFT-A1 may invoke different mechanisms for controlling seed dormancy/germination among winter wheat cultivars.
PMCID: PMC3772017  PMID: 24069187
19.  Translating insights of AR signaling from mouse models 
Androgen receptor (AR) signaling plays a critical role in the physiology of the prostate and thus the biology of prostate cancer. Agents targeting the AR pathway have been the mainstay of treatment for patients with locally advanced and metastatic prostate cancer. In this review we will cover the role of androgen signaling in prostate cancer mouse models with an emphasis on how tumorigenic molecular alterations impact response to AR pathway inhibition and downstream AR target gene expression. Both of these concepts have meaningful implications for the management of patients with prostate cancer.
PMCID: PMC4708180  PMID: 26816737
Mouse models; prostate cancer; androgen receptor (AR)
20.  Genetic association of OPR genes with resistance to Hessian fly in hexaploid wheat 
BMC Genomics  2013;14:369.
Hessian fly (Mayetiola destructor) is one of the most destructive pests of wheat. The genes encoding 12-oxo-phytodienoic acid reductase (OPR) and lipoxygenase (LOX) play critical roles in insect resistance pathways in higher plants, but little is known about genes controlling resistance to Hessian fly in wheat.
In this study, 154 F6:8 recombinant inbred lines (RILs) generated from a cross between two cultivars, ‘Jagger’ and ‘2174’ of hexaploid wheat (2n = 6 × =42; AABBDD), were used to map genes associated with resistance to Hessian fly. Two QTLs were identified. The first one was a major QTL on chromosome 1A (QHf.osu-1A), which explained 70% of the total phenotypic variation. The resistant allele at this locus in cultivar 2174 could be orthologous to one or more of the previously mapped resistance genes (H9, H10, H11, H16, and H17) in tetraploid wheat. The second QTL was a minor QTL on chromosome 2A (QHf.osu-2A), which accounted for 18% of the total phenotypic variation. The resistant allele at this locus in 2174 is collinear to an Yr17-containing-fragment translocated from chromosome 2N of Triticum ventricosum (2n = 4 × =28; DDNN) in Jagger. Genetic mapping results showed that two OPR genes, TaOPR1-A and TaOPR2-A, were tightly associated with QHf.osu-1A and QHf.osu-2A, respectively. Another OPR gene and three LOX genes were mapped but not associated with Hessian fly resistance in the segregating population.
This study has located two major QTLs/genes in bread wheat that can be directly used in wheat breeding programs and has also provided insights for the genetic association and disassociation of Hessian fly resistance with OPR and LOX genes in wheat.
PMCID: PMC3674912  PMID: 23724909
Hessian fly resistance; Insect resistance pathway; lipoxygenase (LOX); 12-oxophytodienoic acid reductase (OPR); Quantitative trait loci (QTL); Wheat
21.  Preservation of Ejaculation in Patients Undergoing Nerve-Sparing Post-Chemotherapy Retroperitoneal Lymph Node Dissection for Metastatic Testicular Cancer 
Urology  2008;73(2):328-332.
We evaluated clinical parameters associated with recovery of ejaculation following nerve-sparing post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) for non-seminomatous germ cell tumor.
We queried our institutional database for all patients who underwent nerve-sparing PC-RPLND between 1995 and 2005 using a bilateral template. Nerve-sparing was carried out whenever technically feasible and oncologically prudent. Antegrade ejaculation was defined as any seminal fluid expulsion and was determined by patient report. We evaluated recovery of antegrade ejaculation based on clinical and pathologic parameters and fit a logistic regression model to determine which pre-operative variables are associated with antegrade ejaculation.
A total of 341 patients had PC-RPLND during the study period, 136 (40%) with nerve sparing techniques. Post-operative antegrade ejaculation was reported by 107/136 (79%) of patients with information available. On the multivariable analysis, a right-sided primary testicular tumor (OR 0.4, 95% CI: 0.1, 1.0, p=0.044) and residual masses ≥5 cm (OR 0.1, 95% CI: 0.0, 0.7, p=0.020) were associated with retrograde ejaculation. However, 40/54 (74%) with right-sided primary tumors and 4/9 (44%) with mass ≥5 cm reported antegrade ejaculation. The 5-year relapse free survival was 98% with a median follow up of 39 months (IQR 19, 66).
Nerve-sparing PC-RPLND is associated with excellent functional return of antegrade ejaculation, is feasible in select patients with bulky disease, and has excellent oncologic outcomes.
PMCID: PMC3665266  PMID: 19022490
Testicular Cancer; Chemotherapy; Surgery; Ejaculation; Retroperitoneal Lymph Node Dissection
22.  The Total Number of Retroperitoneal Lymph Nodes Resected Impacts Clinical Outcome Following Chemotherapy for Metastatic Testicular Cancer 
Urology  2010;75(6):1431-1435.
Following the multidisciplinary management of metastatic germ cell tumor, approximately 10 to 15% of patients with the histologic finding of fibrosis or teratoma will suffer disease recurrence. We evaluated the prognostic significance of the total number of lymph nodes obtained at post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Materials and Methods
From 1989 to 2006, a total of 628 patients underwent PC-RPLND and were found to have either fibrosis or teratoma. Following Institutional Review Board approval, complete clinical and pathologic data were obtained from our prospective testis cancer surgical database. A Cox proportional hazards regression model was constructed to evaluate the association of the total number of lymph nodes obtained at PC-RPLND on disease recurrence.
On pathologic evaluation, 248 (57%) patients had fibrosis and 184 (43%) patients had teratoma. The median number of lymph nodes resected was 25 (IQ range 15, 37). On multivariable analysis, increasing post-chemotherapy nodal size and decreasing lymph node counts were significant predictors of disease recurrence (p=0.01, 0.04, respectively). For patients with 10 nodes removed, the predicted 2 year relapse free probability was 90%, compared to 97% when 50 nodes were removed.
Our data suggests that the total number of lymph nodes removed and analyzed is an independent predictor of disease recurrence following PC-RPLND. This has implications both for the urologist to assure completeness of resection and for the pathologist to meticulously assess the pathologic specimens.
PMCID: PMC3654386  PMID: 20299079
testis cancer; surgery; chemotherapy; lymph node count
23.  β4 Integrin signaling induces expansion of prostate tumor progenitors 
The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that β4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.
PMCID: PMC3561800  PMID: 23348745
24.  Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression 
Cancer cell  2011;20(2):173-186.
Hyper-activation of the PI 3-Kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, upon partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the co-deletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN-mutant prostate cancer to life-threatening disease.
PMCID: PMC3176728  PMID: 21840483
25.  Modulators of Prostate Cancer Cell Proliferation and Viability Identified by Short-Hairpin RNA Library Screening 
PLoS ONE  2012;7(4):e34414.
There is significant need to identify novel prostate cancer drug targets because current hormone therapies eventually fail, leading to a drug-resistant and fatal disease termed castration-resistant prostate cancer. To functionally identify genes that, when silenced, decrease prostate cancer cell proliferation or induce cell death in combination with antiandrogens, we employed an RNA interference-based short hairpin RNA barcode screen in LNCaP human prostate cancer cells. We identified and validated four candidate genes (AKT1, PSMC1, STRADA, and TTK) that impaired growth when silenced in androgen receptor positive prostate cancer cells and enhanced the antiproliferative effects of antiandrogens. Inhibition of AKT with a pharmacologic inhibitor also induced apoptosis when combined with antiandrogens, consistent with recent evidence for PI3K and AR pathway crosstalk in prostate cancer cells. Recovery of hairpins targeting a known prostate cancer pathway validates the utility of shRNA library screening in prostate cancer as a broad strategy to identify new candidate drug targets.
PMCID: PMC3324507  PMID: 22509301

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