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  • 1
    Online Resource
    Online Resource
    Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 8 ( 2015-08-01), p. 1777-1793
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 8 ( 2015-08-01), p. 1777-1793
    Abstract: Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl–driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain–mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl–mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies. Mol Cancer Ther; 14(8); 1777–93. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-14-0883
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    A genomic classifier to identify men with adverse pathology post radical prostatectomy who benefit from adjuvant radiation therapy.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 7_suppl ( 2015-03-01), p. 168-168
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 7_suppl ( 2015-03-01), p. 168-168
    Abstract: 168 Background: The optimal timing of postoperative radiotherapy following radical prostatectomy (post-RP RT) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into the development of clinical metastases in men receiving post-RP RT and inform decision-making. Methods: GC scores were calculated from 188 patients with pT3 or margin positive PCa, who received post-RP RT at Thomas Jefferson University and Mayo Clinic, between 1990 and 2009. The primary endpoint was clinical metastasis. Prognostic accuracy of the models were tested using c-index and decision curve analysis. Cox regression tested the relationship between GC and metastasis. Results: The cumulative incidence of metastasis at 5 years post-RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (p=0.002). In multivariable analysis, GC and pre-RP PSA were independent predictors of metastasis (both p 〈 0.01). Within the low GC score ( 〈 0.4), there were no differences in the cumulative incidence of metastasis comparing those who received adjuvant or salvage RT (p=0.79). However, for patients with higher GC scores (≥0.4) cumulative incidence of metastasis at 5-year was 6% vs. 23% for patients treated with adjuvant vs. salvage RT (p 〈 0.01). Conclusions: In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical/pathologic features. Though preliminary, patients with low GC are best treated with salvage radiation, while those with high GC benefit from adjuvant therapy. These findings provide the first rationale selection of timing of post-RP RT.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.7_suppl.168
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Online Resource
    Can post-operative prostate fossa radiation be omitted in patients with high-risk features using a genomic classifier?
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 101-101
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 101-101
    Abstract: 101 Background: At our institution, based upon the AUA/ASTRO guidelines, discussion of adjuvant radiation therapy (ART) for patients with adverse pathologic features (APF) (pT3/positive margins) occurs in a multidisciplinary setting. We had previously offered ART to approximately 50% of these patients. We describe our evaluation of Decipher genomic testing to select patients to offer observation following prostatectomy (RP). Methods: Since March 2014, patients at Thomas Jefferson University with APF and undetectable post-operative PSA underwent Decipher genomic testing. Collectively, we decided to offer observation with salvage radiation therapy (SRT) for patients with low or intermediate risk Decipher scores. The primary outcome of this analysis was biochemical progression free survival (bPFS) with failure defined as a PSA ≥0.1 ng/mL. Results: From March of 2014 through September of 2016, 47 patients met the above criteria. The median patient age was 64 and median follow up was 16 months. Median pre-treatment PSA was 6.0 ng/mL (2.94 to 22.7 ng/mL). With regard to pathologic stage: 19% had T2c, 68% had T3a, and 13% had T3b disease. Pathologic Gleason grouping was 6%, 49%, 34%, 6%, and 4% for groups 1-5, respectively. 51% of patients had positive margins, 36% had lymph-vascular space invasion, and 53% had perineural invasion. Four patients received ART and 1 patient was lost to follow up after his initial visit. Of the remaining 42 patients, 3 patients experienced biochemical failure at 8, 27, and 44 months. Conclusions: This is the first prospective report utilizing Decipher genomic testing to stratify men with undetectable PSA and adverse pathologic features into an observation cohort following RP. Despite the stringency of our definition of biochemical failure, our observed bPFS was 87% at 3 years. Historically, in an unselected population the 3 year bPFS was 90% in those receiving ART and 65% in those receiving SRT. While these initial findings are promising, longer follow up is warranted. Our findings demonstrate the utility of genomic classifiers in patient selection and provide a safe approach to reducing over treatment in the post RP setting.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.101
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 18 ( 2019-09-15), p. 5623-5637
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 18 ( 2019-09-15), p. 5623-5637
    Abstract: DNA-dependent protein kinase catalytic subunit (DNA-PK) is a pleiotropic kinase involved in DNA repair and transcriptional regulation. DNA-PK is deregulated in selected cancer types and is strongly associated with poor outcome. The underlying mechanisms by which DNA-PK promotes aggressive tumor phenotypes are not well understood. Here, unbiased molecular investigation in clinically relevant tumor models reveals novel functions of DNA-PK in cancer. Experimental Design: DNA-PK function was modulated using both genetic and pharmacologic methods in a series of in vitro models, in vivo xenografts, and patient-derived explants (PDE), and the impact on the downstream signaling and cellular cancer phenotypes was discerned. Data obtained were used to develop novel strategies for combinatorial targeting of DNA-PK and hormone signaling pathways. Results: Key findings reveal that (i) DNA-PK regulates tumor cell proliferation; (ii) pharmacologic targeting of DNA-PK suppresses tumor growth both in vitro, in vivo, and ex vivo; (iii) DNA-PK transcriptionally regulates the known DNA-PK–mediated functions as well as novel cancer-related pathways that promote tumor growth; (iv) dual targeting of DNA-PK/TOR kinase (TORK) transcriptionally upregulates androgen signaling, which can be mitigated using the androgen receptor (AR) antagonist enzalutamide; (v) cotargeting AR and DNA-PK/TORK leads to the expansion of antitumor effects, uncovering the modulation of novel, highly relevant protumorigenic cancer pathways; and (viii) cotargeting DNA-PK/TORK and AR has cooperative growth inhibitory effects in vitro and in vivo. Conclusions: These findings uncovered novel DNA-PK transcriptional regulatory functions and led to the development of a combinatorial therapeutic strategy for patients with advanced prostate cancer, currently being tested in the clinical setting.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-2207
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
    Online Resource
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    Decipher test’s impact on the postoperative management of prostate cancer.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 146-146
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 146-146
    Abstract: 146 Background: The Decipher Prostate Cancer Test provides risk stratification for prostate cancer aggressiveness and predicts the probability of metastasis after surgery. We aim to determine the impact on clinical decision-making Decipher risk designation has had at our institution since its implementation. Methods: A prospectively maintained single institution database was analyzed for patients who underwent prostate biopsy and prostatectomy between 2006-2017. Patients with pathologic T3 cancer, Gleason ≥3+4, or positive surgical margins were considered for the study. In cohort 1, patients’ Decipher scores were available prior to postoperative decision-making, in cohort 2 patients’ scores were not available. Postoperative management was then compared between cohorts to determine if presence of Decipher score influenced the rate of adjuvant and salvage radiation administered. The EMR was queried for the words “adjuvant”, “RT”, “salvage”, “SRT”, to record rates of radiation given to each patient. Chi Square and Mann Whitney test was used to compare rates between cohorts and Decipher risk categories. Results: 454 patients were included in the study with median (IQR) age of 62.0 (7.0) years. Mean time of follow-up was 2.0 years and 8.2 years in cohorts 1 and 2, respectively. In the cohort that received Decipher scores, rate of adjuvant radiation administered was significantly higher than in patients who did not receive a Decipher score (27.0% vs. 6.8%, p 〈 0.001), and higher Decipher risk was associated with higher rate of adjuvant administration (9% vs 27.8% vs 35.4% for low, average and high risk, respectively; p 〈 0.001). Rate of salvage radiation given was not significantly different between the cohorts (5.2% vs 4.0%; p=0.228). Conclusions: The Decipher Prostate Cancer Test provides valuable data regarding risk stratification of disease. As demonstrated here, the availability of Decipher scores has lead to a demonstrable effect in the postoperative management of prostate cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.146
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    Evaluating the effect of therapy duration on survival in patients with metastatic castration-resistant prostate cancer receiving radium-223.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 6_suppl ( 2017-02-20), p. e593-e593
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 6_suppl ( 2017-02-20), p. e593-e593
    Abstract: e593 Background: The use of radium-223 in patients with metastatic castration-resistant prostate cancer (mCRPC) improves overall survival (OS) and quality of life. Combination of radium-223 with second-generation anti-androgens has further improved OS; however, the optimal length of radium-223 treatment for maximal effect remains unknown. Methods: We reviewed 35 consecutive patients with mCRPC who received radium-223 from December 2012 to August 2015 at Thomas Jefferson University. Patients were divided into two groups: those who received full treatment of 6 injections (n = 18) versus those who received less than 6 injections (n = 17). Kaplan-Meier analysis of OS were tested for difference by treatment group using Log Rank test. Univariable association with survival outcomes was calculated with univariable Cox regression and Log Rank tests. Results: Mean age was 73 ± 10 years and Karnofsky performance status (KPS) ranged from 50-90 (median, 80). Median follow-up was 13.9 months. Eighteen patients were receiving concurrent second generation anti-androgens at the start of treatment. Median OS was 12 months for patients who received 6 injections and 6.48 months for patients who received less than 6 injections (p = 0.0045). The results of univariate Cox regression analysis revealed full treatment was associated with increased OS (p = 0.0013). On multivariate analysis accounting for KPS, full treatment was significantly associated with improved OS (p = 0.0028). Conclusions: In this retrospective, single-institution analysis, we demonstrated that full course completion of radium-223 was associated with improved OS in patients with mCRPC. These patients should be optimally supported during treatment to allow for therapy completion.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.6_suppl.e593
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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